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

Study Overview
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Brief Summary
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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 PLATCOV study is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

Detailed Description
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The platform trial will assess drugs with potential SARS-CoV-2 antiviral Activity of two general types: A. Small molecule drugs: currently nitazoxanide, molnupiravir, nirmatrelvir/ritonavir, ensitrelvir, a combination of molnupiravir and nirmatrelvir/ritonavir, and hydroxychloroquine 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. Monoclonal antibodies: Sotrovimab and any other monoclonal antibodies that become available. 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 will be included if there is local availability and regulatory approval. 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. Recruitment into the molnupiravir arm was stopped on February 22nd 2023 due to meeting the pre-defined stopping criteria. Recruitment into the fluoxetine arm was stopped on May 8th 2023 due to meeting the pre-defined stopping criteria. Recruitment into the evusheld arm was stopped on July 4th 2023 due to meeting the pre-defined stopping criteria.

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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Nirmatrelvir/ritonavir (e.g. PAXLOVID™)
* Drug: Monoclonal antibodies
* Drug: Fluoxetine
* Drug: Molnupiravir
* Drug: Nitazoxanide
* Other: No treatment
* Drug: Ensitrelvir
* Drug: Molnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™)
* Drug: Sotrovimab
* Drug: Monoclonal antibodies
* Drug: Favipiravir
* Drug: Ivermectin
* Drug: Remdesivir
* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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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 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). 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Positive control: Nirmatrelvir/ritonavir (e.g. PAXLOVID™)<br> | Drug: Nirmatrelvir/ritonavir (e.g. PAXLOVID™)<br>* Nirmatrelvir 300mg BD for 5/7 Ritonavir 100mg BD for 5/7<br>|
| Experimental: AZD7442 (EVUSHELD™) [This arm is now closed to recruitment]<br> | Drug: Monoclonal antibodies<br>* Monoclonal antibodies: 300mg tixagevimab/ 300 mg cilgavimab given once on D0<br>|
| Experimental: Fluoxetine [This arm is now closed to recruitment]<br> | Drug: Fluoxetine<br>* Fluoxetine 40mg OD for 7/7<br>|
| Experimental: Molnupiravir [This arm is now closed to recruitment]<br> | Drug: Molnupiravir<br>* Molnupiravir 800mg BD for 5/7<br>|
| Experimental: Nitazoxanide<br> | Drug: Nitazoxanide<br>* Nitazoxanide 1.5g BD 7/7<br>|
| Other: Negative control group<br> | Other: No treatment<br>* No treatment (except antipyretics- paracetamol)<br>|
| Experimental: Ensitrelvir<br> | Drug: Ensitrelvir<br>* Ensitrelvir 375mg OD D0 and 125mg OD for a further 4/7<br>|
| Experimental: Molnupiravir and Nirmatrelvir/ritonavir (e.g. PAXLOVID™)<br> | Drug: Molnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™)<br>* Molnupiravir 800mg BD for 5/7, Nirmatrelvir 300mg BD for 5/7, Ritonavir 100mg BD for 5/7<br>|
| Experimental: Sotrovimab [Pending addition]<br> | Drug: Sotrovimab<br>* Sotrovimab 500mg given once on D0<br>|
| Active Comparator: Positive control (REGN-COV2) [This arm is now closed to recruitment]<br> | Drug: Monoclonal antibodies<br>* Monoclonal antibodies: 600mg casirivimab/ 600mg imdevimab given once on D0<br>|
| Experimental: Favipiravir [This arm is now closed to recruitment]<br> | Drug: Favipiravir<br>* Favipiravir 1800mg BD D0 and 800mg BD for a further 6/7.<br>|
| Experimental: Ivermectin [This arm is now closed to recruitment]<br> | Drug: Ivermectin<br>* Ivermectin 600micrograms/kg/day for 7/7.<br>|
| Experimental: Remdesivir [This arm is now closed to recruitment]<br> | Drug: Remdesivir<br>* Remdesivir 200mg D0 and 100mg for a further 4/7.<br>|
| Experimental: Hydroxychloroquine [Pending addition]<br> | Drug: Hydroxychloroquine<br>* Hydroxychloroquine 400mg D0 BD and 400MG OD for a further 6/7<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Days 0-5 | 
| 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) | Days 0-5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Days 0-5 | 
| 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 | Days 0-5 | 
| 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 | Days 6-14 | 
| 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 | Days 0-14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Phase 2, Antiviral Pharmacodynamics