Clinical trial NCT04746183: AGILE (Early Phase Platform Trial for COVID-19)
Official title: AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 Treatment
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Covid19
Keywords: SARS coronavirus 2
SARS-CoV-2
Phase I
Phase II
Platform trial
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: Liverpool School of Tropical Medicine
name: Royal Liverpool University Hospital
name: University of Cambridge
First posted: 2021-02-09
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: CST2:Open-label 2:1 randomised controlled phaseI of EIDD-2801 VS standard of care followed by a 1:1 blinded controlled parallel group PhaseII trial of EIDD-2801 VS placebo CST3A:single arm, open-label phase Ia to confirm the optimum dose, safety and tolerability of Nitazoxanide in healthy volunteers CST3B:Openlabel 1:1 randomised controlled phase Ib of Nitazoxanide VS 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 VS SOC CST5:3:1 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 VS placebo CST6:2:1 randomised open-label standard of care controlled phase I IV favipiravir CST8:Open-label 2:1 randomised controlled Phase I de-escalation study of molnupiravir + Paxlovid versus SOC alone CST9:1:1:1 randomised openlabel Phase II of ALG-097558 versus ALG-097558+ remdesivir VS SOC
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

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-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

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

Primary outcomes:
measure: Master Protocol: Dose-finding/Phase I
timeFrame: 29 days from randomisation
measure: Master Protocol: Efficacy evaluation/Phase II - Severe patients (Group A)
timeFrame: 29 days from randomisation
measure: Master Protocol: Efficacy evaluation/Phase II - Mild to moderate patients (Group B)
timeFrame: 15 days from randomisation
measure: CST-2 Phase I: To determine the safety and tolerability of multiple ascending doses of EIDD-2801 to recommend dose for phase II.
timeFrame: 7 days from randomisation
measure: 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.
timeFrame: 29 days from randomisation
measure: CST6 Phase I: To determine the safety and tolerability of multiple doses of IV Favipiravir in patients with COVID-19
timeFrame: 29 days from randomisation
measure: CST6 Phase I: To determine the maximum safe dose of IV Favipiravir for efficacy evaluation in phase II
timeFrame: 8 days from randomisation
measure: CST-8 Phase I: Dose Limiting Toxicities up to and including Day 11
timeFrame: 11 days from randomisation
measure: CST-9a: Dose limiting toxicities up to and including Day 11
timeFrame: 11 days from randomisation
measure: CST-9a: to determine the safety and tolerability of ALG-097558 and ALG-097558 plus remdesivir combination
timeFrame: 11 days from randomisation
measure: CST-9a: Change in viral titre overtime following administration of ALG-097558 alone and in combination with RDV versus Standard of Care (SoC)
timeFrame: 11 days from randomisation
measure: CST-9a: Sustained symptom resolution
timeFrame: 29 days from randomisation
Secondary outcomes:
measure: Master Protocol: Safety assessed by rate of adverse events
timeFrame: Up to 29 days from randomisation
measure: Master Protocol: To evaluate clinical improvement
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate clinical improvement using WHO clinical progression scale
timeFrame: From randomisation to day 15
measure: Master Protocol: To evaluate clinical improvement using WHO clinical progression scale
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate clinical improvement using SpO2/FiO2
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate discharge
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate admission to ICU
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate safety further (WCC)
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate safety further (Hg)
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate safety further (platelets)
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate safety further (creatinine)
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate safety further (ALT)
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate overall mortality
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate the number of oxygen-free days
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate ventilator-free days
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate incidence of new mechanical ventilation use
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate National Early Warning Score (NEWS)2/qSOFA
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate translational outcomes (Viral Load)
timeFrame: From randomisation to day 29
measure: Master Protocol: To evaluate translational outcomes (Baseline SARS-COV-2)
timeFrame: From randomisation to day 29
measure: 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.
timeFrame: Samples collected on Day 1 and Day 5 post-randomisation
measure: CST-2 Additional: Virologic Objective: To assess the difference in viral clearance (time to negative PCR) between EIDD-2801 and control.
timeFrame: Swabs taken on Day 1 (day of randomisation), 3, 5, 8, 11, 15, 22 and 29
measure: 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)
timeFrame: From randomisation to Day 29
measure: 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).
timeFrame: From randomisation to Day 29
measure: 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)
timeFrame: From randomisation to Day 29
measure: 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)
timeFrame: From randomisation to Day 29
measure: 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)
timeFrame: From randomisation to Day 29
measure: CST-6 Additional: To characterise the pharmacokinetics (PK) of multiple doses of IV Favipiravir
timeFrame: From randomisation to Day 8
measure: CST-6 Additional: To investigate the ability of IV Favipiravir to reduce the duration of signs and symptoms of COVID-19 in-patients
timeFrame: Randomisation to Day 15 and Day 29
measure: CST-6 Additional: To investigate the effect of IV Favipiravir on SARS-CoV-2 viral load
timeFrame: From randomisation to Day 29
measure: CST-8: Assess feasibility for late phase study by reviewing any recorded AEs and SAEs
timeFrame: From randomisation to Day 29
measure: CST-8: Assess feasibility for late phase study by reviewing hospitalisation or death up to Day 29
timeFrame: From randomisation to Day 29
measure: CST-8: Measure concentrations of IMP re evidence of virological efficacy
timeFrame: From randomisation to Day 11
measure: CST-8: Measure PK of each drug within the combination
timeFrame: From randomisation to Day 11
measure: CST8: Review evidence of virological efficacy via viral elimination slopes
timeFrame: From baseline to Day 11
measure: CST8: Vital signs (Heart Rate) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11
timeFrame: From randomisation to Day 11
measure: CST-8: Vital signs (Blood Pressure) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11
timeFrame: From randomisation to Day 11
measure: CST-8: Vital signs (Respiratory Rate) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11
timeFrame: From randomisation to Day 11
measure: CST-8: Vital signs (Temperature) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11
timeFrame: From randomisation to Day 11
measure: CST-8: Vital signs (Oxygen Saturation) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11
timeFrame: From randomisation to Day 11
measure: CST-9a: Measure PK of ALG-097558 plus remdesivir in plasma
timeFrame: Day 1 to day 3
measure: CST-9a: establish disease progression endpoints including visits to emergency department, hospitalisations, all- cause mortality
timeFrame: From randomisation to Day 29
measure: CST-9a: incidence of rebound SARS-CoV-2 infection
timeFrame: From randomisation to Day 29
measure: CST-9a: Symptom improvement in subgroup of severely immunosuppressed participants or with high baseline viral titre
timeFrame: From randomisation to Day 29
measure: CST-9: Viral dynamics in subgroup of severely immunosuppressed participants or with high baseline viral titre
timeFrame: From randomisation to Day 29
Other outcomes:
measure: CST-8: Measure PK of nirmatrelvir and ritonavir in tears, saliva and nasal secretions
timeFrame: From randomisation to Day 5
measure: CST-8:To characterise genetic variability in SARS-CoV-2 before and during treatment via PCR analysis
timeFrame: From randomisation to Day 11
measure: CST-9a: To characterise pharmacokinetics of ALG-097558 in tears, saliva, and nasal secretions
timeFrame: day 1 to day 3
measure: CST-9a: To characterise genetic variability in SARS-CoV-2 before and during treatment
timeFrame: From randomisation to Day 11
measure: CST-9a: To evaluate changes in culturable virus during treatment
timeFrame: From randomisation to Day 11
measure: CST-9a: To characterise time dependent changes in host response to infection or drug exposure
timeFrame: From randomisation to Day 11
Locations:
city: Cape Town
country: South Africa
facility: Desmond Tutu Health Foundation
city: Johannesburg
country: South Africa
facility: Ezintsha
city: Liverpool
country: United Kingdom
facility: Liverpool University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: University of Liverpool
name: Saye Khoo
role: PRINCIPAL_INVESTIGATOR
References:
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