The trial will develop and validate a platform for quantitative assessment of antiviral effects in low-risk patients with high viral burdens and uncomplicated COVID-19 to determine in-vivo antiviral activity. In this randomized open label, controlled, group sequential adaptive platform trial, we will assess the performance of three distinct types of intervention relative to control (no treatment):
A: Small molecule drugs; B: Monoclonal antibodies; C: Dose finding for the constituent parts of nirmatrelvir/ritonavir
PLATCOV study is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.
Patient understands the procedures and requirements and is willing and able to give informed consent for full participation in the study.
Previously healthy adults, male or female, aged 18 to 60 years at time of consent with early symptomatic COVID-19
SARS-CoV-2 positive by lateral flow antigen test OR a positive PCR test for SARS-CoV-2 within the last 24hrs with a Ct value of less than 25 (all viral targets)
Symptoms of COVID-19 (including fever, or history of fever) for less than 4 days (96 hours).
Taking any concomitant medications or drugs (see appendix 4)†
Presence of any chronic illness/ condition requiring long term treatment, or other significant comorbidity (e.g. diabetes, obesity but see appendix 4 for the full list)
Laboratory abnormalities discovered at screening (see appendix 4)
For females: pregnancy, actively trying to become pregnant, or lactation
Parallel
Nirmatrelvir/ritonavir (e.g. PAXLOVID™)
DrugNirmatrelvir 300mg BD for 5/7 Ritonavir 100mg BD for 5/7
Nitazoxanide
DrugNitazoxanide 1.5g BD 7/7
Molnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™)
DrugMolnupiravir 800mg BD for 5/7, Nirmatrelvir 300mg BD for 5/7, Ritonavir 100mg BD for 5/7
Hydroxychloroquine
DrugHydroxychloroquine 400mg D0 BD and 400MG OD for a further 6/7
No treatment
Other interventionNo treatment (except antipyretics- paracetamol)
Monoclonal antibodies
DrugMonoclonal antibodies: 300mg tixagevimab/ 300 mg cilgavimab given once on D0
Fluoxetine
DrugFluoxetine 40mg OD for 7/7
Molnupiravir
DrugMolnupiravir 800mg BD for 5/7
Sotrovimab
DrugSotrovimab 500mg given once on D0
Ensitrelvir
DrugEnsitrelvir 375mg OD D0 and 125mg OD for a further 4/7
Monoclonal antibodies
DrugMonoclonal antibodies: 600mg casirivimab/ 600mg imdevimab given once on D0
Favipiravir
DrugFavipiravir 1800mg BD D0 and 800mg BD for a further 6/7
Ivermectin
DrugIvermectin 600micrograms/kg/day for 7/7.
Remdesivir
DrugRemdesivir 200mg D0 and 100mg for a further 4/7.
Atilotrelvir/ritonavir
DrugAtilotrelvir 150mg BD for 5/7 Ritonavir 100mg BD for 5/7
Metformin
DrugMetformin 500mg TDS 5/7
Nirmatrelvir/ritonavir
DrugNirmatrelvir 300mg BD for 5/7 Ritonavir 50mg BD for 5/7
Nirmatrelvir/ritonavir
DrugNirmatrelvir 150mg BD for 5/7 Ritonavir 50mg BD for 5/7
Nirmatrelvir
DrugNirmatrelvir 300mg BD for 5/7
19
Treatment groupsSee each treatment group below.
Rate of viral clearance for interventions relative to the no study arm (This is a superiority comparison)
Rate of viral clearance- estimated from the log10 viral density derived from qPCR of standardised duplicate oropharyngeal swabs/ saliva taken daily from baseline (day 0) to day 5 for each intervention compared with the no antiviral treatment control i.e., those not receiving study drug
Rate of viral clearance for interventions relative to the positive control arm (This is a non-inferiority or superiority comparison).
Rate of viral clearance- estimated from the log10 viral density derived from qPCR of standardised duplicate oropharyngeal swabs/ saliva taken daily from baseline (day 0) to day 5 for interventions compared with the current best antiviral treatment option (accelerated viral clearance relative to the positive control arm)
Viral kinetic levels in early COVID-19 disease
Rate of viral clearance estimated from the log10 viral density derived from qPCR of standardised duplicate oropharyngeal swabs/ saliva taken daily from baseline (day 0) to day 5 for each therapeutic arm compared with the no antiviral treatment control i.e., those not receiving study drug
Optimal dosing regimens through pharmacometric assessment for antiviral drugs with evidence of efficacy in the literature or from the trial data (e.g., Nirmatrelvir/ritonavir, Ensitrelvir etc).
Rate of viral clearance- estimated from the log10 viral density derived from qPCR of standardised duplicate oropharyngeal swabs/ saliva taken daily from baseline (day 0) to day 5 for each therapeutic arm compared with the no antiviral treatment control i.e., those not receiving study drug
Viral rebound of studied treatment arms in comparison to contemporaneous controls (e.g. no study drug arm, positive control)
After stopping treatment for at least 24 hours (or 5 days if no drug is given or a single dose monoclonal antibody is given), rebound is defined as an oropharyngeal eluate viral density estimate \>1000 genomes per ml for at least 1 timepoint (average 2 swabs), after \>2 consecutive days of average daily viral density estimate less than 100 genomes per ml
Rates of fever clearance and symptom resolution with respect to no treatment
The following endpoints will be used: * Time to resolution of fever * Area Under the Curve of recorded temperature * Time to resolution of symptoms
Rates of hospitalisation by treatment arm (hospitalisation for clinical reasons)
Number of hospitalisations up to Day 28 in a treatment arm with an increased rate of viral clearance compared with the negative control i.e. patients not receiving study drug
Relationship between viral clearance, randomisation arm and other measures (covariates) and development of post- acute COVID-19 (i.e. long COVID)
Score on post-acute COVID-19 (i.e. long COVID) questionnaire at day 120 - modified COVID-19 Yorkshire Rehabilitation Scale (C19 YRSm)
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