AGILE (Early Phase Platform Trial for COVID-19)

Sponsor

University of Liverpool (Other)

Overall Status

Recruiting

CT.gov ID

NCT04746183

Collaborator

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

600

Enrollment

Locations

Arms

45.9

Anticipated Duration (Months)

100

Patients Per Site

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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. 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.

Condition or Disease	Intervention/Treatment	Phase
Covid19	Drug: CST-2: EIDD-2801 Drug: CST-2: Placebo Drug: Nitazoxanide Drug: VIR-7832 Drug: VIR-7831 Drug: CST-5: Placebo Drug: Favipiravir	Phase 1/Phase 2

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

600 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

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 favipiravirCST-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

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 3, 2020

Anticipated Primary Completion Date :

Nov 18, 2023

Anticipated Study Completion Date :

Apr 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CST-2 EIDD-2801 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 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
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).
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.
Experimental: CST-5 VIR-7832 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: 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.
Placebo Comparator: CST-5 Placebo Phase I and II placebo blinded controlled	Drug: CST-5: Placebo CST-5 Phase 1, Phase II: Placebo given by intravenous infusion over 1 hour
Experimental: CST3B Nitazoxanide	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

Outcome Measures

Primary Outcome Measures

Master Protocol: Dose-finding/Phase I [29 days from randomisation]
Determination of a dose(s) for efficacy evaluation. Dose limiting toxicities (Safety and Tolerability of drug under study - CTCAE v5 Grade ≥3 adverse events)
Master Protocol: Efficacy evaluation/Phase II - Severe patients (Group A) [29 days from randomisation]
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.
Master Protocol: Efficacy evaluation/Phase II - Mild to moderate patients (Group B) [15 days from 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. [7 days from randomisation]
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. [29 days from randomisation]
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 [29 days from randomisation]
Adverse events and serious adverse events
CST6 Phase I: To determine the maximum safe dose of IV Favipiravir for efficacy evaluation in phase II [8 days from randomisation]
Dose limiting toxicities (Safety and Tolerability of IV Favipiravir- CTCAE v5 Grade ≥3 adverse events)

Secondary Outcome Measures

Master Protocol: Safety assessed by rate of adverse events [Up to 29 days from randomisation]
Adverse event rate according to CTCAE v5
Master Protocol: To evaluate clinical improvement [From randomisation to day 29]
Proportion of patients with clinical improvement (as defined above) at day 8, 15 and day 29.
Master Protocol: To evaluate clinical improvement using WHO clinical progression scale [From randomisation to day 15]
Change at day 8 and 15 from randomisation in the WHO Clinical Progression Scale
Master Protocol: To evaluate clinical improvement using WHO clinical progression scale [From randomisation to day 29]
Time to a one point change on the WHO Clinical Progression Scale
Master Protocol: To evaluate clinical improvement using SpO2/FiO2 [From randomisation to day 29]
The ratio of the oxygen saturation to fractional inspired oxygen concentration (SpO2/FiO2)
Master Protocol: To evaluate discharge [From randomisation to day 29]
Proportion of patient discharged at days 8, 15 and 29
Master Protocol: To evaluate admission to ICU [From randomisation to day 29]
Admission rate to ICU
Master Protocol: To evaluate safety further (WCC) [From randomisation to day 29]
White cell count on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29
Master Protocol: To evaluate safety further (Hg) [From randomisation to day 29]
Haemoglobin on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29
Master Protocol: To evaluate safety further (platelets) [From randomisation to day 29]
Platelets on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29
Master Protocol: To evaluate safety further (creatinine) [From randomisation to day 29]
Creatinine on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29
Master Protocol: To evaluate safety further (ALT) [From randomisation to day 29]
ALT on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29
Master Protocol: To evaluate overall mortality [From randomisation to day 29]
Mortality at Days 8, 15 and 29. Time to death from randomisation
Master Protocol: To evaluate the number of oxygen-free days [From randomisation to day 29]
Duration (days) of oxygen use and oxygen-free days
Master Protocol: To evaluate ventilator-free days [From randomisation to day 29]
Duration (days) of mechanical ventilation and mechanical ventilation-free days
Master Protocol: To evaluate incidence of new mechanical ventilation use [From randomisation to day 29]
Incidence of new mechanical ventilation use
Master Protocol: To evaluate National Early Warning Score (NEWS)2/qSOFA [From randomisation to day 29]
NEWS2/qSOFA assessed daily while hospitalised
Master Protocol: To evaluate translational outcomes (Viral Load) [From randomisation to day 29]
Change in viral load over time
Master Protocol: To evaluate translational outcomes (Baseline SARS-COV-2) [From randomisation to day 29]
Change in viral load over time
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. [Samples collected on Day 1 and Day 5 post-randomisation]
Concentrations of EIDD-2801 and -1931 in plasma
CST-2 Additional: Virologic Objective: To assess the difference in viral clearance (time to negative PCR) between EIDD-2801 and control. [Swabs taken on Day 1 (day of randomisation), 3, 5, 8, 11, 15, 22 and 29]
Qualitative (and quantitative when possible) PCR for SARS-CoV-2 by nasal swab.
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) [From randomisation to Day 29]
Patient Reported Outcome Measures (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). [From randomisation to Day 29]
WHO Progression Scale at day 15 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 (NEWS2) [From randomisation to Day 29]
NEWS2 (National Early Warning Score2) assessed during study clinic visit on days 15 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 (mortality) [From randomisation to Day 29]
Mortality at Days 15 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 (death) [From randomisation to Day 29]
Time from randomisation to death
CST-6 Additional: To characterise the pharmacokinetics (PK) of multiple doses of IV Favipiravir [From randomisation to Day 8]
Plasma PK parameters of IV Favipiravir
CST-6 Additional: To investigate the ability of IV Favipiravir to reduce the duration of signs and symptoms of COVID-19 in-patients [Randomisation to Day 15 and Day 29]
WHO Progression Scale (WHO, 2020)
CST-6 Additional: To investigate the effect of IV Favipiravir on SARS-CoV-2 viral load [From randomisation to Day 29]
Viral load change from baseline over time

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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) .
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).
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:

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

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Desmond Tutu Health Foundation	Cape Town	South Africa
2	Ezintsha	Johannesburg	South Africa
3	Liverpool University Hospitals NHS Foundation Trust	Liverpool	United Kingdom	L7 8XP
4	Kings College Hospital NHS Foundation Trust	London	United Kingdom
5	Manchester University NHS Foundation Trust	Manchester	United Kingdom
6	University Hospital Southampton NHS Foundation Trust	Southampton	United Kingdom	SO16 6YD