COVID-19
Conditions
Keywords
COVID-19, Phase 2, Antiviral Pharmacodynamics
Brief summary
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.
Detailed description
The platform trial will assess drugs with potential SARS-CoV-2 antiviral activity of three general types: A. Small molecule drugs: currently nitazoxanide, nirmatrelvir/ritonavir, hydroxychloroquine, atilotrelvir/ritonavir and metformin. 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. C. : Dose finding for the constituent parts of nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir has shown clinical efficacy in phase III studies, however, there are disadvantages to using it (drug-drug interactions, side effects, cost). In the urgent context of the pandemic, a higher dose of ritonavir was chosen to guarantee maximum boosting effect. We do not know if the maximal boosting effect could have been achieved with less, or even without ritonavir. It will be investigated whether reducing the doses of the constituent parts can still retain the effectiveness. 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. Recruitment into the ensitrelvir arm was stopped on April 21st 2024 due to meeting the pre-defined stopping criteria. Recruitment into the combination molnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™) arm was stopped on May 31st 2024 due to meeting the pre-defined stopping criteria.
Interventions
DRUGNirmatrelvir/ritonavir (e.g. PAXLOVID™)
Nirmatrelvir 300mg BD for 5/7 Ritonavir 100mg BD for 5/7
DRUGNitazoxanide
Nitazoxanide 1.5g BD 7/7
DRUGMolnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™)
Molnupiravir 800mg BD for 5/7, Nirmatrelvir 300mg BD for 5/7, Ritonavir 100mg BD for 5/7
DRUGHydroxychloroquine
Hydroxychloroquine 400mg D0 BD and 400MG OD for a further 6/7
OTHERNo treatment
No treatment (except antipyretics- paracetamol)
Monoclonal antibodies: 300mg tixagevimab/ 300 mg cilgavimab given once on D0
DRUGFluoxetine
Fluoxetine 40mg OD for 7/7
DRUGMolnupiravir
Molnupiravir 800mg BD for 5/7
DRUGSotrovimab
Sotrovimab 500mg given once on D0
DRUGEnsitrelvir
Ensitrelvir 375mg OD D0 and 125mg OD for a further 4/7
DRUGFavipiravir
Favipiravir 1800mg BD D0 and 800mg BD for a further 6/7
DRUGIvermectin
Ivermectin 600micrograms/kg/day for 7/7.
DRUGRemdesivir
Remdesivir 200mg D0 and 100mg for a further 4/7.
DRUGAtilotrelvir/ritonavir
Atilotrelvir 150mg BD for 5/7 Ritonavir 100mg BD for 5/7
DRUGMetformin
Metformin 500mg TDS 5/7
Nirmatrelvir 300mg BD for 5/7 Ritonavir 50mg BD for 5/7
DRUGNirmatrelvir
Nirmatrelvir 300mg BD for 5/7
Sponsors
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of viral clearance for interventions relative to the no study arm (This is a superiority comparison) | Days 0-5 | 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). | Days 0-5 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Viral kinetic levels in early COVID-19 disease | Days 0-5 | 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). | Days 0-5 | 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) | Days 6-14 | 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 | Days 0-14 | The following endpoints will be used: * Time to resolution of fever * Area Under the Curve of recorded temperature * Time to resolution of symptoms |
Countries
Brazil, Laos, Nepal, Pakistan, Thailand
Contacts
CONTACTWilliam Schilling, MD
CONTACTNicholas J White, Prof.
Outcome results
None listed