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)

Overview

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

• 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

Primary outcome measures

• Rate of viral clearance for interventions relative to the no study arm (This is a superiority comparison) [Time frame: Days 0-5]
• Rate of viral clearance for interventions relative to the positive control arm (This is a non-inferiority or superiority comparison). [Time frame: Days 0-5]

Secondary outcome measures (4)

• Viral kinetic levels in early COVID-19 disease [Time frame: Days 0-5]
• 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). [Time frame: Days 0-5]
• Viral rebound of studied treatment arms in comparison to contemporaneous controls (e.g. no study drug arm, positive control) [Time frame: Days 6-14]
• Rates of fever clearance and symptom resolution with respect to no treatment [Time frame: Days 0-14]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Thailand · 3 centers

• Vajira hospital — Bangkok
• Faculty of Tropical Medicine, Mahidol University — Bangkok
• Bangplee Hospital — Mueang Samut Prakan

Brazil · 1 center

• Universidade Federal de Minas Gerais — Minas Gerais

Laos · 1 center

• Laos-Oxford-Mahosot Wellcome Trust Research Unit — Vientiane

Nepal · 1 center

• Sukraraj Tropical & Infectious Disease Hospital — Kathmandu

Pakistan · 1 center

• The Aga Khan University Hospital — Karachi

Publications

• Kaewkhao N, Tarning J, Blessborn D. LC-MS/MS Method Validation for Quantification of Nirmatrelvir in Human Plasma. Int J Anal Chem. 2025 Nov 17;2025:6625833. doi: 10.1155/ianc/6625833. eCollection 2025. PMID 41321979
• Schilling WHK, Jittamala P, Wongnak P, Watson JA, Boyd S, Luvira V, Siripoon T, Ngamprasertchai T, Batty EM, Beer E, Singh S, Asawasriworanan T, Seers T, Phommasone K, Evans TJ, Kruabkontho V, Ngernseng T, Tubprasert J, Abdad MY, Madmanee W, Kouhathong J, Suwannasin K, Pagornrat W, Piteekan T, Hanboonkunupakarn B, Poovorawan K, Potaporn M, Srisubat A, Loharjun B, Chotivanich K, Imwong M, Pukrittay PMID 41082886
• Jittamala P, Boyd S, Schilling WHK, Watson JA, Ngamprasertchai T, Siripoon T, Luvira V, Batty EM, Wongnak P, Esper LM, Almeida PJ, Cruz C, Ascencao FR, Aguiar RS, Ghanchi NK, Callery JJ, Singh S, Kruabkontho V, Ngernseng T, Tubprasert J, Madmanee W, Suwannasin K, Promsongsil A, Hanboonkunupakarn B, Poovorawan K, Potaporn M, Srisubat A, Loharjun B, Taylor WRJ, Qamar F, Kazi AM, Beg MA, Chommanam D, PMID 39896880
• Wongnak P, Schilling WHK, Jittamala P, Boyd S, Luvira V, Siripoon T, Ngamprasertchai T, Batty EM, Singh S, Kouhathong J, Pagornrat W, Khanthagan P, Hanboonkunupakarn B, Poovorawan K, Mayxay M, Chotivanich K, Imwong M, Pukrittayakamee S, Ashley EA, Dondorp AM, Day NPJ, Teixeira MM, Piyaphanee W, Phumratanaprapin W, White NJ, Watson JA; PLATCOV Collaborative Group. Temporal changes in SARS-CoV-2 cle PMID 38677300
• Luvira V, Schilling WHK, Jittamala P, Watson JA, Boyd S, Siripoon T, Ngamprasertchai T, Almeida PJ, Ekkapongpisit M, Cruz C, Callery JJ, Singh S, Tuntipaiboontana R, Kruabkontho V, Ngernseng T, Tubprasert J, Abdad MY, Keayarsa S, Madmanee W, Aguiar RS, Santos FM, Hanboonkunupakarn P, Hanboonkunupakarn B, Poovorawan K, Imwong M, Taylor WRJ, Chotivanich V, Chotivanich K, Pukrittayakamee S, Dondorp A PMID 38225598
• Schilling WHK, Jittamala P, Watson JA, Boyd S, Luvira V, Siripoon T, Ngamprasertchai T, Batty EM, Cruz C, Callery JJ, Singh S, Saroj M, Kruabkontho V, Ngernseng T, Tanglakmankhong N, Tubprasert J, Abdad MY, Madmanee W, Kouhathong J, Suwannasin K, Pagornrat W, Piaraksa N, Hanboonkunupakarn P, Hanboonkunupakarn B, Poovorawan K, Potaporn M, Srisubat A, Loharjun B, Taylor WRJ, Chotivanich V, Chotivani PMID 37778363
• Jittamala P, Schilling WHK, Watson JA, Luvira V, Siripoon T, Ngamprasertchai T, Almeida PJ, Ekkapongpisit M, Cruz C, Callery JJ, Boyd S, Anunsittichai O, Hongsuwan M, Singhaboot Y, Pagornrat W, Tuntipaiboontana R, Kruabkontho V, Ngernseng T, Tubprasert J, Abdad MY, Keayarsa S, Madmanee W, Aguiar RS, Santos FM, Batty EM, Hanboonkunupakarn P, Hanboonkunupakarn B, Sookprome S, Poovorawan K, Imwong M, PMID 37470445
• Schilling WHK, Jittamala P, Watson JA, Ekkapongpisit M, Siripoon T, Ngamprasertchai T, Luvira V, Pongwilai S, Cruz C, Callery JJ, Boyd S, Kruabkontho V, Ngernseng T, Tubprasert J, Abdad MY, Piaraksa N, Suwannasin K, Hanboonkunupakarn P, Hanboonkunupakarn B, Sookprome S, Poovorawan K, Thaipadungpanit J, Blacksell S, Imwong M, Tarning J, Taylor WRJ, Chotivanich V, Sangketchon C, Ruksakul W, Chotivan PMID 36803992

Identifiers

NCT: NCT05041907 · VIR21001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗