Clinical trial NCT05041907: Finding Treatments for COVID-19: A Trial of Antiviral Pharmacodynamics in Early Symptomatic COVID-19 (PLATCOV)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
Phase 2
Antiviral Pharmacodynamics
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2021-09-13
Enrollment: 3800
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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

Primary outcomes:
measure: Rate of viral clearance for interventions relative to the no study arm (This is a superiority comparison)
timeFrame: Days 0-5
measure: Rate of viral clearance for interventions relative to the positive control arm (This is a non-inferiority or superiority comparison).
timeFrame: Days 0-5
Secondary outcomes:
measure: Viral kinetic levels in early COVID-19 disease
timeFrame: Days 0-5
measure: 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).
timeFrame: Days 0-5
measure: Viral rebound of studied treatment arms in comparison to contemporaneous controls (e.g. no study drug arm, positive control)
timeFrame: Days 6-14
measure: Rates of fever clearance and symptom resolution with respect to no treatment
timeFrame: Days 0-14
Other outcomes:
measure: Rates of hospitalisation by treatment arm (hospitalisation for clinical reasons)
timeFrame: Days 0-28
measure: Relationship between viral clearance, randomisation arm and other measures (covariates) and development of post- acute COVID-19 (i.e. long COVID)
timeFrame: Days 0-120
Locations:
city: Minas Gerais
country: Brazil
facility: Universidade Federal de Minas Gerais
city: Vientiane
country: Lao People's Democratic Republic
facility: Laos-Oxford-Mahosot Wellcome Trust Research Unit
city: Kathmandu
country: Nepal
facility: Sukraraj Tropical & Infectious Disease Hospital
city: Karachi
country: Pakistan
facility: The Aga Khan University Hospital
city: Bangkok
country: Thailand
facility: Vajira hospital
city: Bangkok
country: Thailand
facility: Faculty of Tropical Medicine, Mahidol University
city: Samut Prakan
country: Thailand
facility: Bangplee Hospital
Study officials:
References: