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Covid19Phase 1/2AGILENCT04746183

AGILE (Early Phase Platform Trial for COVID-19)

A Phase 1/2 study testing CST-2: EIDD-2801, Nitazoxanide and VIR-7832 in people with Covid19, run by University of Liverpool at 7 sites in 2 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Covid19
What is being tested?
CST-2: EIDD-2801, Nitazoxanide and VIR-7832
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
600 participants
Where
7 sitesin 2 countries
Study dates
3 Jul 2020to 31 Mar 2027
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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) .
  2. 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).
  3. 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:

  1. Has signs or symptoms of COVID-19 that began within 5 days of the planned first dose of study drug.
  2. Is in generally good health (except for current respiratory infection) and is free of uncontrolled chronic conditions.
  3. Is willing and able to comply with all study procedures and attending clinic visits through the 4th week.
  4. 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-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

CST-9b Exclusion criteria:

  1. Prior SARS-CoV-2 infection diagnosed <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 severe renal impairment defined as CKD stage 5 (an eGFR <15 mL/min/1.73 m2 at screening, or current acute kidney injury in most recent eGFR in 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 standard of care antiviral therapy for COVID-19 at the time of screening
  10. Received sotrovimab at any point during the current SARS-CoV-2 infection prior to enrolment
  11. Oxygen saturations <94% on room air. NOTE: Participants on stable oxygen therapy, including use of NIPPV (non-invasive positive pressure ventilation), for a pre-existing medical condition (e.g., COPD) may be included with oxygen saturation of <94% on room air, provided there is no new increased oxygen requirement.
  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 within 5 half-lives of the last administered dose of an investigational medicinal product.
  15. Participants eligible for other antiviral treatment according to DHSC criteria, or those otherwise eligible for CST9a.

Trial locations and contacts

7 sites in 2 countries. Contact the study team or a site near you to ask about taking part.

Helen E Reynolds contact

+44 (0)1517945553

livagile@liv.ac.uk

7 sites in 2 countries

United Kingdom5 sites, 4 recruiting

  • Liverpool University Hospitals NHS Foundation Trust

    Liverpool, L7 8XP

    +44 (0)151 706 4863, crf.contact@liverpoolft.nhs.uk

    +44(0)7342065915

    Recruiting

  • Kings College Hospital NHS Foundation Trust

    London

    Active, not recruiting

  • Royal Free Hospital

    London

    Sanjay Bhagani

    Recruiting

  • Manchester University NHS Foundation Trust

    Manchester

    Shazaad Ahmad

    Recruiting

  • University Hospital Southampton NHS Foundation Trust

    Southampton, SO16 6YD

    +44 (0)7469565895, UHS.SouthamptonCRF@nhs.net

    Chris Edwards

    Recruiting

Other trials in United Kingdom

South Africa2 sites

  • Desmond Tutu Health Foundation

    Cape Town

    Completed

  • Ezintsha

    Johannesburg

    Completed

Other trials in South Africa

About this study

Official title: 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 based on pre-clinical data, evidence in the clinical setting and GMP capabilities.

Read the 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 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

Candidate-Specific Trial 9 (CST-9a): A multicentre, adaptive Phase II Platform trial to evaluate the safety, efficacy and virological response of ALG-097558 as monotherapy and in combination with Remdesivir in high-risk population for the treatment of COVID-19 disease.

Candidate-Specific Trial 9 (CST-9b): A Multicentre, Adaptive Phase II Randomised Double-Blind Placebo Controlled Trial to Evaluate the Safety, Efficacy and Virological response of ALG-097558 for the Treatment of COVID-19 disease.

Conditions
Covid19
Being tested
CST-2: EIDD-2801, CST-2: Placebo, Nitazoxanide, VIR-7832, VIR-7831
Keywords
SARS coronavirus 2, SARS-CoV-2, Phase I, Phase II, Platform trial
Medical subject headings
COVID-19

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CST-2: EIDD-2801Drug

    Also called MK-4482, Molnupiravir

    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.

  • CST-2: PlaceboDrug

    Also called Placebo

    CST-2 Phase II: Placebo will be administered orally, twice daily (BID) for 10 doses (5 or 6 days).

  • NitazoxanideDrug

    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.

  • VIR-7832Drug

    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.

  • VIR-7831Drug

    Also called Sotrovimab

    CST-5 Phase II: A 500 mg dose of VIR-7831 will also be given by IV infusion over 1 hour.

  • CST-5: PlaceboDrug

    Also called Placebo

    CST-5 Phase 1, Phase II: Placebo given by intravenous infusion over 1 hour

  • FavipiravirDrug

    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).

  • MolnupiravirDrug

    Also called Lagevrio

    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.

  • PaxlovidDrug

    Also called nirmatrelvir and ritonavir

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

  • ALG-097558Drug

    ALG-097558 600 mg Twice a day (BD) for 5 days

  • ALG-097558 and RemdesivirDrug

    Also called ALG-097558 and veklury

    ALG-097558 600 mg Twice a day (BD) for 5 days Remdesivir will be administered once daily by intravenous infusion over 30 to 120 minutes. 200 mg will be given on day 1 and 100 mg on day 2 and day 3.

  • NHS standard of care as per COVID-19 treatment guidelinesDrug

    Also called any of the following: nirmatrelvir plus ritonavir (Paxlovid) sotrovimab (Xevudy) molnupiravir (Lagevrio)

    NHS standard of care as per COVID-19 treatment guidelines

  • ALG-097558Drug

    twice daily (Q12H) oral dose of ALG-097558

  • PlaceboDrug

    twice daily (Q12H) oral dose

Study groups in NCT04746183
Study groupRoleWhat they receive
CST-2 EIDD-2801 Phase IbExperimentalEIDD-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.
Receives: Drug: CST-2: EIDD-2801
CST-2 ControlNo interventionPhase 1b only (standard of care)
CST-2 PlaceboPlacebo comparatorPhase II placebo blinded controlled
Receives: Drug: CST-2: Placebo
CST-3A NitazoxanideExperimentalPhase 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
Receives: Drug: Nitazoxanide
CST-5 VIR-7832 Phase IExperimentalPhase 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.
Receives: Drug: VIR-7832
CST-5 VIR-7831 Phase IIActive comparatorPhase II: 500 mg dose of VIR-7831 will be given by IV infusion.
Receives: Drug: VIR-7831
CST-5 Placebo Phase IPlacebo comparatorPhase I: placebo blinded controlled
Receives: Drug: CST-5: Placebo
CST3B NitazoxanideExperimentalPhase II experimental arm.
Receives: Drug: Nitazoxanide
CST3B ControlNo interventionStandard of care
CST6 IV FavipiravirExperimentalIV 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.
Receives: Drug: Favipiravir
CST6 ControlNo interventionStandard of care
CST-2 EIDD-2801 Phase IIExperimentalEIDD-2801 (also known as MK-4482, molnupiravir). Phase II: As per Phase Ib, with the dose determined by the recommended phase II dose.
Receives: Drug: CST-2: EIDD-2801
CST-8 Phase I Molnupiravir + Paxlovid®ExperimentalMolnupiravir 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.
Receives: Drug: Molnupiravir; Drug: Paxlovid
CST-8 Phase I Molnupiravir + Paxlovid® ControlNo interventionStandard of care
CST-5 VIR-7832Active comparatorPhase II: 500 mg dose of VIR-7832 will be given by IV infusion.
Receives: Drug: VIR-7832
CST-5 Placebo Phase IIPlacebo comparatorPhase II: placebo blinded controlled
Receives: Drug: CST-5: Placebo
CST-9a MonotherapyExperimentalPhase II: ALG-097558 600 mg twice a day orally for 5 days
Receives: Drug: ALG-097558
CST-9a CombinationExperimentalPhase II: ALG-097558 600 mg twice a day orally for 5 days in combination with IV remdesivir for 3 days (200 mg day 1, 100 mg day 2 and 3)
Receives: Drug: ALG-097558; Drug: ALG-097558 and Remdesivir
CST-9a ControlActive comparatorPhase II : standard of care
Receives: Drug: NHS standard of care as per COVID-19 treatment guidelines
CST-9b: ALG-097558Experimentaltwice daily dose for 5 days
Receives: Drug: ALG-097558
CST-9b: placebo for ALG097558Placebo comparatorNot described
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: 29 days from randomisation

  2. 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.

    Measured: 29 days from randomisation

  3. 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.

    Measured: 15 days from randomisation

  4. 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

    Measured: 7 days from randomisation

  5. 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

    Measured: 29 days from randomisation

  6. 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

    Measured: 29 days from randomisation

  7. 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)

    Measured: 8 days from randomisation

  8. 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

    Measured: 11 days from randomisation

  9. CST-9a: Dose limiting toxicities up to and including Day 11

    Dose limiting toxicities (Safety and Tolerability of ALG-097558 and ALG-097558 plus remdesivir combination - CTCAE v5 Grade ≥3 adverse events) up to and including Day 11

    Measured: 11 days from randomisation

  10. CST-9a: to determine the safety and tolerability of ALG-097558 and ALG-097558 plus remdesivir combination

    Adverse events, serious adverse events, physical findings, vital signs, ECG and laboratory parameters

    Measured: 11 days from randomisation

  11. CST-9a: Change in viral titre overtime following administration of ALG-097558 alone and in combination with RDV versus Standard of Care (SoC)

    Qualitative (and quantitative when possible) PCR for SARS-CoV-2 by nose and throat swab

    Measured: 11 days from randomisation

  12. CST-9a: Sustained symptom resolution

    Symptom resolution evaluated through questionnaires

    Measured: 29 days from randomisation

  13. CST-9b

    AEs, SAEs

    Measured: 11 Days from randomisation

  14. CST-9b

    Dose Limiting Toxicity (DLT) using CTCAE version 5 (grades 3 and above) up to and including Day 11

    Measured: 11 days from randomisation

  15. CST-9b

    Qualitative (and quantitative when possible) PCR for SARS-CoV-2 by nose and throat swab

    Measured: 11 days from randomisation

Secondary outcomes (50)

  1. Master Protocol: Safety assessed by rate of adverse events

    Adverse event rate according to CTCAE v5

    Measured: Up to 29 days from randomisation

  2. Master Protocol: To evaluate clinical improvement

    Proportion of patients with clinical improvement (as defined above) at day 8, 15 and day 29.

    Measured: From randomisation to day 29

  3. 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

    Measured: From randomisation to day 15

  4. Master Protocol: To evaluate clinical improvement using WHO clinical progression scale

    Time to a one point change on the WHO Clinical Progression Scale

    Measured: From randomisation to day 29

  5. Master Protocol: To evaluate clinical improvement using SpO2/FiO2

    The ratio of the oxygen saturation to fractional inspired oxygen concentration (SpO2/FiO2)

    Measured: From randomisation to day 29

  6. Master Protocol: To evaluate discharge

    Proportion of patient discharged at days 8, 15 and 29

    Measured: From randomisation to day 29

  7. Master Protocol: To evaluate admission to ICU

    Admission rate to ICU

    Measured: From randomisation to day 29

  8. Master Protocol: To evaluate safety further (WCC)

    White cell count on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29

    Measured: From randomisation to day 29

  9. Master Protocol: To evaluate safety further (Hg)

    Haemoglobin on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29

    Measured: From randomisation to day 29

  10. Master Protocol: To evaluate safety further (platelets)

    Platelets on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29

    Measured: From randomisation to day 29

  11. Master Protocol: To evaluate safety further (creatinine)

    Creatinine on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29

    Measured: From randomisation to day 29

  12. Master Protocol: To evaluate safety further (ALT)

    ALT on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29

    Measured: From randomisation to day 29

  13. Master Protocol: To evaluate overall mortality

    Mortality at Days 8, 15 and 29. Time to death from randomisation

    Measured: From randomisation to day 29

  14. Master Protocol: To evaluate the number of oxygen-free days

    Duration (days) of oxygen use and oxygen-free days

    Measured: From randomisation to day 29

  15. Master Protocol: To evaluate ventilator-free days

    Duration (days) of mechanical ventilation and mechanical ventilation-free days

    Measured: From randomisation to day 29

  16. Master Protocol: To evaluate incidence of new mechanical ventilation use

    Incidence of new mechanical ventilation use

    Measured: From randomisation to day 29

  17. Master Protocol: To evaluate National Early Warning Score (NEWS)2/qSOFA

    NEWS2/qSOFA assessed daily while hospitalised

    Measured: From randomisation to day 29

  18. Master Protocol: To evaluate translational outcomes (Viral Load)

    Change in viral load over time

    Measured: From randomisation to day 29

  19. Master Protocol: To evaluate translational outcomes (Baseline SARS-COV-2)

    Change in viral load over time

    Measured: From randomisation to day 29

  20. 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

    Measured: Samples collected on Day 1 and Day 5 post-randomisation

  21. 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.

    Measured: Swabs taken on Day 1 (day of randomisation), 3, 5, 8, 11, 15, 22 and 29

  22. 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).

    Measured: From randomisation to Day 29

  23. 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

    Measured: From randomisation to Day 29

  24. 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.

    Measured: From randomisation to Day 29

  25. 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

    Measured: From randomisation to Day 29

  26. 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

    Measured: From randomisation to Day 29

  27. CST-6 Additional: To characterise the pharmacokinetics (PK) of multiple doses of IV Favipiravir

    Plasma PK parameters of IV Favipiravir

    Measured: From randomisation to Day 8

  28. 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)

    Measured: Randomisation to Day 15 and Day 29

  29. CST-6 Additional: To investigate the effect of IV Favipiravir on SARS-CoV-2 viral load

    Viral load change from baseline over time

    Measured: From randomisation to Day 29

  30. CST-8: Assess feasibility for late phase study by reviewing any recorded AEs and SAEs

    Review of any adverse events

    Measured: From randomisation to Day 29

  31. CST-8: Assess feasibility for late phase study by reviewing hospitalisation or death up to Day 29

    Death and hospitalisation up to Day 29

    Measured: From randomisation to Day 29

  32. CST-8: Measure concentrations of IMP re evidence of virological efficacy

    PK concentrations of both IMPs and their circulating metabolites in plasma.

    Measured: From randomisation to Day 11

  33. CST-8: Measure PK of each drug within the combination

    PK concentrations of both IMPs and their circulating metabolites in plasma.

    Measured: From randomisation to Day 11

  34. 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

    Measured: From baseline to Day 11

  35. 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.

    Measured: From randomisation to Day 11

  36. 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.

    Measured: From randomisation to Day 11

  37. 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.

    Measured: From randomisation to Day 11

  38. 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.

    Measured: From randomisation to Day 11

  39. 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.

    Measured: From randomisation to Day 11

  40. CST-9a: Measure PK of ALG-097558 plus remdesivir in plasma

    PK concentrations of ALG-097558 and remdesivir and metabolites in plasma

    Measured: Day 1 to day 3

  41. CST-9a: establish disease progression endpoints including visits to emergency department, hospitalisations, all- cause mortality

    Death, hospitalisation, and hospital/GP visits

    Measured: From randomisation to Day 29

  42. CST-9a: incidence of rebound SARS-CoV-2 infection

    Proportion of participants with clinical and/or virologic rebound

    Measured: From randomisation to Day 29

  43. CST-9a: Symptom improvement in subgroup of severely immunosuppressed participants or with high baseline viral titre

    Symptom improvement evaluated through questionnaires

    Measured: From randomisation to Day 29

  44. CST-9: Viral dynamics in subgroup of severely immunosuppressed participants or with high baseline viral titre

    Viral dynamics in subgroup of severely immunosuppressed participants or with high baseline viral titre

    Measured: From randomisation to Day 29

  45. CST-9b

    Plasma PK, concentrations ALG-097558 and its metabolites

    Measured: 11 days from randomisation

  46. CST-9b

    Death, hospitalisation, and hospital/GP visits up to Day 29

    Measured: 29 Days from randomisation

  47. CST-9b

    Proportion of participants with clinical and/or virologic rebound

    Measured: 11 Days from randomisation

  48. CST-9b

    Viral dynamics in subgroup of participants with high baseline viral titre (defined as Ct value of <22)

    Measured: 11 Days from randomisation

  49. CST-9b

    Viral dynamics in subgroup of participants randomized within 3 days of symptom onset

    Measured: 11 Days from randomisation

  50. CST-9b

    Time to sustained symptom resolution (evaluated through questionnaires as a participant-reported outcome)

    Measured: 11 Days from randomisation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Feb 2021
  2. Study start3 Jul 2020
  3. Primary completion31 Mar 2027 (estimated)
  4. Study completion31 Mar 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Sequential
Model description
CST2: Closed CST3A: Closed CST3B: Closed CST5: Closed CST6: Closed CST8: Closed CST9a:1:1:1 randomised open label Phase II of ALG-097558 versus ALG-097558+ remdesivir VS SOC CST9b: Double Blind 1:1 stratified randomised controlled adaptive trial with twice daily (Q12H) oral dose of ALG-097558 versus matching placebo for ALG097558.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
600 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04746183
Sponsor's protocol ID
UoL001542i, UoL001542j
Acronym
AGILE
Status last verified
Sep 2025
First submitted
13 Oct 2020
Last updated
1 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Master protocol publication. Data sets will be registered on the University of Liverpool Research Data Catalogue.

Publications

  • 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.

    PubMed 32560744

  • 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.

    PubMed 34311777

  • 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.

    PubMed 34450619

  • 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.

    PubMed 34699618

  • 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.

    PubMed 36272432

  • 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.

    PubMed 35271729

  • Donovan-Banfield I, Penrice-Randal R, Goldswain H, Rzeszutek AM, Pilgrim J, Bullock K, Saunders G, Northey J, Dong X, Ryan Y, Reynolds H, Tetlow M, Walker LE, FitzGerald R, Hale C, Lyon R, Woods C, Ahmad S, Hadjiyiannakis D, Periselneris J, Knox E, Middleton C, Lavelle-Langham L, Shaw V, Greenhalf W, Edwards T, Lalloo DG, Edwards CJ, Darby AC, Carroll MW, Griffiths G, Khoo SH, Hiscox JA, Fletcher T. Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial. Nat Commun. 2022 Nov 26;13(1):7284. doi: 10.1038/s41467-022-34839-9.

    PubMed 36435798

  • Rowland T, FitzGerald R, Challenger E, Dickinson L, Else LJ, Walker L, Hale C, Shaw V, Kelly C, Lyon R, Gibney J, Dhamani K, Irwin M, Enever Y, Tetlow M, Wood W, Reynolds H, Chiong J, Osanlou O, Pertinez H, Bullock K, Greenhalf W, Owen A, Lalloo DG, Jacobs M, Hiscox JA, Jaki T, Mozgunov P, Saunders G, Griffiths G, Khoo SH, Fletcher TE; AGILE CST-6 Study Group. Optimal Dose and Safety of Intravenous Favipiravir in Hospitalized Patients With COVID-19: A Dose-Escalating, Randomized Controlled Phase Ib Study. Clin Pharmacol Ther. 2026 Jun;119(6):1650-1661. doi: 10.1002/cpt.70261. Epub 2026 Mar 18.

    PubMed 41848748

  • 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.

    PubMed 34473343

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing CST-2: EIDD-2801, Nitazoxanide and VIR-7832 in people with Covid19, run by University of Liverpool at 7 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 1 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United Kingdom, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Helen E Reynolds (+44 (0)1517945553, livagile@liv.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Master Protocol: Dose-finding/Phase I (time frame: 29 days from randomisation). The study lists 15 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04746183, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jun 2026.

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