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

• ClinicalTrials.gov Identifier: NCT05041907
• Recruitment Status: Recruiting
• First Posted: September 13, 2021
• Last Update Posted: September 6, 2023
• Sponsor: University of Oxford
• Information provided by (Responsible Party): University of Oxford

Study Description

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: 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.

Condition or disease	Intervention/treatment	Phase
COVID-19	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: Favipiravir; Drug: Ivermectin; Drug: Remdesivir	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Finding Treatments for COVID-19: A Phase 2 Multi-centre Adaptive Platform Trial to Assess Antiviral Pharmacodynamics in Early Symptomatic COVID-19 (PLATCOV)
• Actual Study Start Date: September 30, 2021
• Estimated Primary Completion Date: August 2024
• Estimated Study Completion Date: August 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Rate of viral clearance for newly available and repurposed drugs [ Time Frame: Days 0-7 ]
   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
2. Rate of viral clearance for positive controls (e.g. monoclonal antibodies) [ Time Frame: Days 0-7 ]
   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
3. Rate of viral clearance for small novel molecule drugs [ Time Frame: Days 0-7 ]
   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

Secondary Outcome Measures :

1. Viral kinetic levels in early COVID-19 disease [ Time Frame: Days 0-7 ]
   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
2. 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) [ Time Frame: Days 0-7 ]
   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
3. 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) [ Time Frame: Days 0-7 ]
   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.

Other Outcome Measures:

1. Rates of hospitalisation by treatment arm (hospitalisation for clinical reasons) [ Time Frame: Days 0-28 ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: William Schilling, MD; +662 203 6333; william@tropmedres.ac

Contact: Nicholas J White, Prof.; +662 203 6333; nickw@tropmedres.ac

Locations

Brazil

Universidade Federal de Minas Gerais; Recruiting

Minas Gerais, Brazil

Contact: Mauro Martins Teixeira mmtex.ufmg@gmail.com

Lao People's Democratic Republic

Laos-Oxford-Mahosot Wellcome Trust Research Unit; Recruiting

Vientiane, Lao People's Democratic Republic, 01000

Contact: Koukeo Phommasone, PhD +(85) 620 558 42842 Koukeo@tropmedres.ac

Contact: Elizabeth Ashley, Professor (+85)621 250 752 liz@tropmedres.ac

Thailand

Vajira hospital; Terminated

Bangkok, Thailand, 10300

Faculty of Tropical Medicine, Mahidol University; Recruiting

Bangkok, Thailand, 10400

Contact: Weerapong Phumratanaprapin, MD weerapong.phu@mahidol.ac.th

Bangplee Hospital; Terminated

Samut Prakan, Thailand, 10540

Sponsors and Collaborators

University of Oxford

More Information

• Responsible Party: University of Oxford
• ClinicalTrials.gov Identifier: NCT05041907
• Other Study ID Numbers: VIR21001
• First Posted: September 13, 2021
• Last Update Posted: September 6, 2023
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

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).

• Supporting Materials: Clinical Study Report (CSR); Analytic Code
• Time Frame: after the main paper has been published

Access Criteria

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).

• URL: http://wellcome.ac.uk/press-release/statement-data-sharing-public-health-emergencies

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Oxford:

COVID-19; Phase 2; Antiviral Pharmacodynamics

Additional relevant MeSH terms:

Remdesivir; COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Ritonavir; Ivermectin; Nitazoxanide; Favipiravir; Nirmatrelvir; Sotrovimab; Nirmatrelvir and ritonavir drug combination; Molnupiravir; Antineoplastic Agents, Immunological; Fluoxetine; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; HIV Protease Inhibitors