Finding Treatments for COVID-19: A Trial of Antiviral Pharmacodynamics in Early Symptomatic COVID-19 (PLATCOV) (PLATCOV)

Finding Treatments for COVID-19: A Trial of Antiviral Pharmacodynamics in Early Symptomatic COVID-19 (PLATCOV)

Finding Treatments for COVID-19: A Phase 2 Multi-centre Adaptive Platform Trial to Assess Antiviral Pharmacodynamics in Early Symptomatic COVID-19 (PLATCOV)

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: Newly available and repurposed potential antiviral drugs; B: Positive control: monoclonal antibodies initially but subsequently any therapeutic that is shown to accelerate the rate of viral clearance C: Novel small molecule drugs that have gone through phase 1 testing PLATCOV study is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

The platform trial will assess drugs with potential SARS-CoV-2 antiviral Activity of three general types: A. Newly available and repurposed potential antiviral drugs. (initially from: hydroxychloroquine, ivermectin, lopinavir-ritonavir, miglustat, remdesivir, nitazoxanide, nebulized unfractionated heparin (UFH), favipiravir, molnupiravir, nirmatrelvir/ritonavir (e.g. PAXLOVID™), fluoxetine, fluvoxamine, AZD7442 (EVUSHELD™),ensitrelvir, and a combination of molnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™) Newly available and repurposed drugs are already used and recommended in some countries. Showing that they do not have significant antiviral activity is as important as showing that they do. For the newly approved antivirals, comparing antiviral activities in- vivo will inform health authorities' recommendations. B. Positive control: monoclonal antibodies initially (e.g. casirivimab/imdevimab) but subsequently any therapeutic that is shown to accelerate the rate of viral clearance Monoclonal antibodies are vulnerable to viral escape mutations. Tracking their performance over time is important to characterise the impact and inform the therapeutics of mutant SARS-CoV-2 strains. This will also be important for other antivirals. Monoclonal antibodies are expensive and cannot be produced at large scale currently, but this may change in the near future. These drugs may not be available early in the study, and will be included if there is local availability and regulatory approval. C. Novel small molecule drugs that have gone through phase 1 testing Each site will include a negative control arm consisting of patients not receiving any study drug except for antipyretics- paracetamol. At any given time in the study, it is possible that not all intervention arms are available. Randomization to the no antiviral treatment control arm (no intervention) will be fixed at a minimum of 20% throughout the study. The randomization ratios will be uniform for all available interventions. Recruitment into the ivermectin arm was stopped on April 18th 2022 due to meeting the pre- defined stopping criteria. Recruitment into the remdesivir arm was stopped on June 10th 2022 due to meeting the pre- defined stopping criteria. Recruitment into the REGN-COV2 arm was stopped on October 20th 2022 due to meeting the pre-defined stopping criteria. Recruitment into the favipiravir arm was stopped on October 31st 2022 due to meeting the pre-defined stopping criteria.

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 7 for each newly available and repurposed drug compared with the no antiviral treatment control i.e. those not receiving study drug

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 7 for positive controls (e.g. monoclonal antibodies) compared with the no antiviral treatment control i.e. those not receiving study drug

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 7 for small novel molecule drugs compared with the no antiviral treatment control i.e. those not receiving study drug

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 7 for each therapeutic arm compared with the no antiviral treatment control i.e. those not receiving study drug

Number of antiviral treatment arms that are shown to be effective i.e. a positive signal (>90% probability of >12.5% acceleration in viral clearance)

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 7 for each therapeutic arm compared with the no antiviral treatment control i.e. those not receiving study drug

Rates of viral clearance by treatment arm, as compared against REGN-COV2 (monoclonal antibody cocktail) monoclonal antibody cocktail) or other licensed and available therapeutics with evidence of accelerated viral clearance(monoclonal antibody cocktail)

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 7 for each therapeutic arm compared with positive control (e.g. REGN-COV-2 a monoclonal antibody cocktail) or other licensed and available therapeutics with evidence of accelerated viral clearance.

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

Inclusion Criteria: 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 50 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). Oxygen saturation ≥96% measured by pulse-oximetry at time of screening. Able to walk unaided and unimpeded in ADLs Agrees and is able to adhere to all study procedures, including availability and contact information for follow-up visits Exclusion Criteria: The patient may not enter the study if ANY of the following apply: 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 Contraindication to taking, or known hypersensitivity reaction to any of the proposed therapeutics (see appendix 4) Currently participating in another COVID-19 therapeutic or vaccine trial Evidence of pneumonia (although imaging is NOT required) healthy women on the oral contraceptive pill are eligible to join the study

With patient's consent, clinical data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy with other researchers to use in the future. Data generated from this study will adhere to the 2016 "Statement on data sharing in public health emergencies"(https://wellcome.ac.uk/press-release/statement-data-sharing-public-health-emergencies).

MORU Data Sharing Policy https://www.tropmedres.ac/units/moru-bangkok/bioethics-engagement/data-sharing. The criteria for authorship will be consistent with the international guidelines (http://www.icmje.org/#author).