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

University of Oxford

Status and phase: Enrolling; Phase 2

Conditions: COVID-19

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

Study type: Interventional

Funder types: Other

Identifiers

NCT05041907

VIR21001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 3,800 estimated patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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3,800 participants in 19 patient groups

Positive control: Nirmatrelvir/ritonavir (e.g. PAXLOVID™)

Active Comparator group

Treatment:

Drug: Nirmatrelvir/ritonavir (e.g. PAXLOVID™)

Nitazoxanide

Experimental group

Treatment:

Drug: Nitazoxanide

Molnupiravir and Nirmatrelvir/ritonavir (e.g. PAXLOVID™) [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Molnupiravir and nirmatrelvir/ritonavir (e.g. PAXLOVID™)

Hydroxychloroquine

Experimental group

Treatment:

Drug: Hydroxychloroquine

Negative control group

Other group

Treatment:

Other: No treatment

AZD7442 (EVUSHELD™) [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Monoclonal antibodies

Drug: Monoclonal antibodies

Fluoxetine [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Fluoxetine

Molnupiravir [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Molnupiravir

Sotrovimab [Pending addition]

Experimental group

Treatment:

Drug: Sotrovimab

Ensitrelvir [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Ensitrelvir

Positive control (REGN-COV2) [This arm is now closed to recruitment]

Active Comparator group

Treatment:

Drug: Monoclonal antibodies

Drug: Monoclonal antibodies

Favipiravir [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Favipiravir

Ivermectin [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Ivermectin

Remdesivir [This arm is now closed to recruitment]

Experimental group

Treatment:

Drug: Remdesivir

Atilotrelvir/ritonavir [Pending addition]

Experimental group

Treatment:

Drug: Atilotrelvir/ritonavir

Metformin (modified release) [Pending addition]

Experimental group

Treatment:

Drug: Metformin

Nirmatrelvir/ritonavir - 300/50 - dose finding [Pending addition]

Experimental group

Treatment:

Drug: Nirmatrelvir/ritonavir

Drug: Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir - 150/50 - dose finding [Pending addition]

Experimental group

Treatment:

Drug: Nirmatrelvir/ritonavir

Drug: Nirmatrelvir/ritonavir

Nirmatrelvir - dose finding [Pending addition]

Experimental group

Treatment:

Drug: Nirmatrelvir