The trial will develop and validate a platform for quantitative assessment of antiviraleffects in low-risk patients with high viral burdens and uncomplicated COVID-19 todetermine in-vivo antiviral activity. In this randomized open label, controlled, groupsequential adaptive platform trial, we will assess the performance of three distincttypes of intervention relative to control (no treatment):A: Small molecule drugs; B: Monoclonal antibodies; C: Dose finding for the constituentparts of nirmatrelvir/ritonavirPLATCOV study is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through theCOVID-19 Therapeutics Accelerator.
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.
Drug: Nirmatrelvir/ritonavir (e.g. PAXLOVID™)
Nirmatrelvir 300mg BD for 5/7 Ritonavir 100mg BD for 5/7
Drug: Nitazoxanide
Nitazoxanide 1.5g BD 7/7
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
Drug: Hydroxychloroquine
Hydroxychloroquine 400mg D0 BD and 400MG OD for a further 6/7
Other: No treatment
No treatment (except antipyretics- paracetamol)
Drug: Monoclonal antibodies
Monoclonal antibodies: 300mg tixagevimab/ 300 mg cilgavimab given once on D0
Drug: Fluoxetine
Fluoxetine 40mg OD for 7/7
Drug: Molnupiravir
Molnupiravir 800mg BD for 5/7
Drug: Sotrovimab
Sotrovimab 500mg given once on D0
Drug: Ensitrelvir
Ensitrelvir 375mg OD D0 and 125mg OD for a further 4/7
Drug: Monoclonal antibodies
Monoclonal antibodies: 600mg casirivimab/ 600mg imdevimab given once on D0
Drug: Favipiravir
Favipiravir 1800mg BD D0 and 800mg BD for a further 6/7
Drug: Ivermectin
Ivermectin 600micrograms/kg/day for 7/7.
Drug: Remdesivir
Remdesivir 200mg D0 and 100mg for a further 4/7.
Drug: Atilotrelvir/ritonavir
Atilotrelvir 150mg BD for 5/7 Ritonavir 100mg BD for 5/7
Drug: Metformin
Metformin 500mg TDS 5/7
Drug: Nirmatrelvir/ritonavir
Nirmatrelvir 300mg BD for 5/7 Ritonavir 50mg BD for 5/7
Drug: Nirmatrelvir/ritonavir
Nirmatrelvir 150mg BD for 5/7 Ritonavir 50mg BD for 5/7
Drug: Nirmatrelvir
Nirmatrelvir 300mg BD for 5/7
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
Universidade Federal de Minas Gerais
Minas Gerais, Brazil
Laos-Oxford-Mahosot Wellcome Trust Research Unit
Vientiane, Lao People's Democratic Republic
Sukraraj Tropical & Infectious Disease Hospital
Kathmandu, Nepal
The Aga Khan University Hospital
Karachi, Pakistan
Vajira hospital
Bangkok, Thailand
Faculty of Tropical Medicine, Mahidol University
Bangkok, Thailand
Bangplee Hospital
Samut Prakan, Thailand
William Schilling, MD
+662 203 6333
william@tropmedres.ac
Nicholas J White, Prof.
+662 203 6333
nickwdt@tropmedres.ac
Not Provided