Finding Treatments for COVID-19: A Phase 2 Multi-centre Adaptive Platform Trial to Assess Antiviral Pharmacodynamics in Early Symptomatic COVID-19 (PLATCOV)
Phase: PHASE2
Conditions: COVID-19
Sponsor: University of Oxford

 
 
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Master protocol:  
Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess 
antiviral pharmacodynamics in early symptomatic COVID-19 (PLATCOV) 
Short title: Finding treatments for COVID-19: A phase 2 platform trial of antiviral pharmacodynamics in early 
symptomatic COVID-19 (PLATCOV) 
Acronym: PLATCOV 
OxTREC Ref: 24-21 
Trial Registration Number: NCT05041907 
Protocol number: VIR21001 
Date and Version No: Version 7.0 / 07 August 2024 
Co-Principal Investigators: 
 
 
 
 
 
 
Dr William Schilling (william@tropmedres.ac) 
Research Physician & Infectious Diseases/ Microbiology Registrar 
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok, Thailand  
 
Professor Sir Nicholas J White (nickw@tropmedres.ac)  
Chairman Wellcome Trust Southeast Asian Tropical Medicine Programmes & 
Consultant Physician  
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok, Thailand 
 
Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr. Simon Boyd 
Research Physician 
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok, Thailand 
 
Dr. Ellen Beer 
Research Physician 
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok, Thailand 
 
Dr. Tim Seers 
Research Physician & Infectious Diseases / Microbiology Registrar  
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok, Thailand 
 
Asst. Prof. Podjanee Jittamala  
Department of Tropical Hygiene, 
Faculty of Tropical Medicine, Mahidol University  
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand  
 
Dr Cintia Cruz 
Paediatrician and Clinical Pharmacologist 

 
 
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Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok, Thailand 
 
Dr James A Watson 
Statistician 
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok,Thailand 
 
Professor Nicholas PJ Day  
 
Director & Consultant Physician 
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok,Thailand 
 
Professor Arjen M Dondorp 
Deputy Director and Head of Malaria & Critical Illness 
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, 
Mahidol University, Bangkok,Thailand 
 
Professor Elizabeth Ashley 
Lao-Oxford-Mahosot Hospital- Wellcome Trust Research Unit,  
Vientiane, Laos  
 
Professor M.Asim Beg 
The Aga Khan University Hospital,  
National Stadium Road, Karachi, Karachi City,  
Sindh, Pakistan 
 
Professor Mauro Teixeira 
Professor of Immunology  
Unidade de Pesquisa Clínica, 
Centro de Terapias Avançadas e Inovadoras 
Universidade Federal de Minas Gerais,  
Belo Horizonte, MG, Brasil 
 
Professor Sasithon Pukrittayakamee  
Mahidol Oxford Tropical Medicine Research Unit 
Faculty of Tropical Medicine, Mahidol University 
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand  
 
Assoc. Prof. Weerapong Phumratanaprapin 
Dean of Faculty of Tropical Medicine, Mahidol University 
Department of Clinical Tropical Medicine  
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 
 
Sponsor:  
The University of Oxford 
Research Governance, Ethics and Assurance, Boundary Brook House, Churchill 
Drive, Oxford OX3 7GB United Kingdom 
 
Funder:  
Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics 
Accelerator 
 

 
 
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Investigators’ contributions: 
NJW conceived of the study and initiated the study design with other investigators. WS, JW, CC, JC, NPJD, 
WRJT, and AMD supported development of protocol and implementation. JW provided statistical expertise in 
clinical study design.  
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, 
the Investigator Team, host organisation, and members of the Research Ethics Committee and Regulatory 
Authorities unless authorised to do so. 
 
Investigator Agreement and Declaration of Interests 
“The undersigned has read and understood the trial protocol detailed above and: 
- 
 agrees to conduct the trial in compliance with the protocol. 
- 
 agrees to comply with the principles of the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice. 
and declare no conflict of interest, according to the current version of the Declaration of Helsinki” 
 
Dr William Schilling  
…………………………………… 
Co-Principal Investigator  
Signature 
Date 
 
 
Professor Sir Nicholas J White 
…………………………………… 
Co-Principal Investigator 
Signature 
Date 
 
 
 
 
 
 
 

 
 
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Table of Contents 
1. 
SYNOPSIS ...................................................................................................................... 7 
2. 
ABBREVIATION ............................................................................................................ 11 
3. 
BACKGROUND AND RATIONALE ................................................................................... 13 
3.1. 
Proposal ................................................................................................................... 15 
3.2. 
Pharmacodynamic assessment .................................................................................. 16 
4. 
OBJECTIVES AND ENDPOINTS ....................................................................................... 17 
5. 
STUDY DESIGN ............................................................................................................. 18 
5.1. 
Interventions ............................................................................................................ 18 
5.2. 
Randomisation ......................................................................................................... 20 
6. 
PATIENT IDENTIFICATION AND RECRUITMENT ............................................................. 21 
6.1. 
Study Patients .......................................................................................................... 21 
6.2. 
Inclusion Criteria ...................................................................................................... 21 
6.3. 
Exclusion Criteria ...................................................................................................... 21 
7. 
STUDY SET-UP AND PROCEDURES ................................................................................ 21 
7.1. 
Virological sampling.................................................................................................. 22 
7.2. 
Recruitment ............................................................................................................. 23 
7.3. 
Screening and Eligibility Assessment ......................................................................... 23 
7.4. 
Informed Consent ..................................................................................................... 23 
7.5. 
Baseline Assessments ............................................................................................... 23 
7.7 
Intensive pharmacokinetic sampling ......................................................................... 25 
7.8 
Management of patients who become ill .................................................................. 26 
7.9 
Sample Handling and Retention ................................................................................ 26 
8 
DISCONTINUATION/WITHDRAWAL OF PATIENTS FROM STUDY .................................... 27 
8.1 
Definition of End of Study ......................................................................................... 27 
9 
SAFETY REPORTING ..................................................................................................... 27 
9.1 
Definitions................................................................................................................ 27 
9.2 
Causality .................................................................................................................. 28 
9.3 
Procedures for Recording Adverse Events .................................................................. 29 
9.4 
Grading of laboratory abnormalities ......................................................................... 29 
9.5 
Reporting Procedures for Serious Adverse Events ...................................................... 30 
9.6 
Data Safety Monitoring Board (DSMB) ...................................................................... 30 
10 
STATISTICS AND ANALYSIS ........................................................................................... 31 

 
 
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10.1 
Overview of adaptive study design and overall approach ........................................... 31 
10.2 
Results of the first interim analysis ............................................................................ 31 
10.3 
Bayesian hierarchical model of viral clearance ........................................................... 32 
10.4 
Time varying effects.................................................................................................. 33 
10.5 
Sample size estimation, randomisation and statistical considerations for the Bayesian 
group sequential design ........................................................................................... 33 
10.6 
Sample size for the intensive PK-PD sub-study ........................................................... 34 
10.7 
Change to sampling schedule .................................................................................... 34 
10.8 
Final analysis of primary outcome ............................................................................. 35 
11 
DATA MANAGEMENT .................................................................................................. 35 
11.1 
Access to Data .......................................................................................................... 35 
11.2 
Data Handling and Record Keeping ........................................................................... 35 
12 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ....................................... 36 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 36 
13.1 
Declaration of Helsinki .............................................................................................. 36 
13.2 
Guidelines for Good Clinical Practice ......................................................................... 36 
13.3 
Approvals ................................................................................................................. 37 
13.4 
Patient Confidentiality .............................................................................................. 37 
13.5 
Expenses .................................................................................................................. 37 
13.6 
Risk .......................................................................................................................... 37 
13.7 
Benefits .................................................................................................................... 37 
13.8 
Reporting ................................................................................................................. 37 
13.9 
Finance and insurance .............................................................................................. 38 
13.10 
Data ownership ........................................................................................................ 38 
13.11 
Publication policy ..................................................................................................... 38 
14 
REFERENCES ................................................................................................................ 39 
15 
Appendix 1: Schedule of activities ................................................................................ 41 
16 
Appendix 2: Study drugs .............................................................................................. 43 
16.1 
Nitazoxanide ............................................................................................................ 44 
16.2 
Nirmatrelvir/ritonavir (e.g. PAXLOVID™) ................................................................... 47 
16.3 
Nirmatrelvir/ritonavir (e.g. PAXLOVID™) dose finding ............................................... 49 
16.4 
Hydroxychloroquine ................................................................................................. 52 
16.5 
Atilotrelvir/ritonavir ................................................................................................. 56 
16.6 
Sotrovimab ............................................................................................................... 58 

 
 
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16.7 
Metformin ................................................................................................................ 60 
 
Appendix 3: Sample size simulations ............................................................................ 62 
18 
Appendix 4: Exclusion criteria ...................................................................................... 64 
Nitazoxanide .............................................................................................................................................................. 65 
Sotrovimab ................................................................................................................................................................. 65 
Atilotrelvir/Ritonavir .................................................................................................................................................. 65 
Metformin .................................................................................................................................................................. 65 
Nirmatrelvir/Ritonavir ................................................................................................................................................ 65 
Nirmatrelvir/Ritonavir dose finding ........................................................................................................................... 66 
Hydroxychloroquine ................................................................................................................................................... 66 
19 
Appendix 5: Amendment History ................................................................................. 67 
 
 
 

 
 
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1. SYNOPSIS 
Study Title  
Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform 
trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 
(PLATCOV) 
Protocol no.  
VIR21001 
Rationale 
Quantitative evidence of antiviral activity in patients with COVID-19 is 
required to justify phase 3 clinical trials of putative antivirals  
Study Design  
Randomised, open label, group sequential adaptive platform trial 
Inclusion and Exclusion 
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) 
 
Reported 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: 
 
Taking any concomitant medications or drugs (see appendix 4)† 
 
Presence of any chronic illness/ condition requiring long term 
treatment, or other significant comorbidity (see appendix 4 for 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. 
Planned Sample Size  
Continuously running group sequential adaptive platform trial. There is no 
fixed sample size (see section 10.1 for further discussion). Maximum sample 
size is 200 patients per intervention arm (excluding negative control (no study 
drug/no antiviral treatment)) and positive control e.g. nirmatrelvir/ritonavir, 
ensitrelvir etc), although further recruitment can occur on consultation with 
the DSMB or TSC, if it is felt that more precision of the result is beneficial.  
 

 
 
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This study is expected to enroll approximately 3,800 total participants from 
up to six countries (Thailand, Brazil, Pakistan, Laos, Nepal and yet unconfirmed 
site/sites).  
Planned Study Period  
6 years for total duration of the trial and 120 days for individual patients’ 
involvement 
Interventions  
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. 
C. Dose finding study for the constituent parts of nirmatrelvir/ritonavir 
Control  
1. Negative control: No antiviral treatment (although local hospital 
supportive treatment will remain the same e.g. antipyretics, anti-
tussives, antihistamines, vitamins etc as per the treating Physician’s 
judgement).  
2. Positive control: currently nirmatrelvir/ritonavir at standard dose 
Rationale 
Each intervention type has a different objective: 
A. Small molecule drugs: 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. Monoclonal antibodies: There is good evidence from phase 2 studies 
that monoclonal antibodies reduce viral load in COVID-19 with 
evidence that they reduce hospitalisation in high-risk individuals. 
However, 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. Not all 
these therapeutics may be available, and will be included if there is 
local availability and regulatory approval. 
C. Dose finding study: dose finding of the separate components of 
ritonavir 
and 
nirmatrelvir 
will 
be 
highly 
beneficial. 
Nirmatrelvir/Ritonavir has shown clinical efficacy in phase III studies. 
It is widely considered the most effective COVID-19 medication. 
However, there are disadvantages to using the drug. There are many 
drug-drug interactions from ritonavir which prevents many of the 
highest risk individuals from accessing the medication. Dysgeusia and 
diarrhoea associated with ritonavir may affects patient uptake and 
reduces adherence or compliance. Furthermore, it is very expensive 
($500/course), and may be associated with viral rebound 
phenomenon. 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. This study will aim to investigate 

 
 
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whether changing the doses of ritonavir and nirmatrelvir would 
provide efficacy whilst balancing the negative aspects. 
 
 
 Objectives 
Endpoint 
Primary  
  
For all interventions trialled, there are 
two primary objectives: 
1. To evaluate SARS-CoV-2 
antiviral efficacy in-vivo 
(accelerated viral clearance 
relative to the no study drug 
arm). This is a superiority 
comparison. 
2. To compare SARS-CoV-2 
antiviral efficacy with current 
best antiviral treatment option 
(accelerated viral clearance 
relative to the positive control 
arm). This is a non-inferiority or 
superiority comparison. 
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 5 for each 
therapeutic arm compared with the 
contemporaneous no antiviral 
treatment control/ positive control 
Secondary  
  
To characterise the determinants of 
viral kinetics in early COVID-19 disease 
Rate of viral clearance (as for 
primary endpoint) 
To determine optimal dosing regimens 
through pharmacometric assessment 
for antiviral drugs with evidence of 
efficacy (e.g. Nirmatrelvir/ritonavir, 
Ensitrelvir etc) 
Characterise viral rebound of studied 
treatment arms in comparison to 
contemporaneous controls (e.g. no 
study drug arm, positive control) 
After stopping treatment for at 
least 24 hours (or 5 days if no drug 
is given or a single dose monoclonal 
antibody is given) rebound is 
defined as a oropharyngeal eluate 
viral density estimate >1000 
genomes per ml for at least 1 
timepoint (average 2 swabs), after 
>2 consecutive days of average 
daily viral density estimate less 
than 100 genomes per ml 
 
To compare rates of fever clearance 
and rates of symptom resolution with 
respect to no treatment 
 
The following comparisons will be 
made: 
 
Time to resolution of fever  
 
Area Under the Curve of 
recorded temperature 
 
Time to resolution of 
symptoms 

 
 
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Tertiary 
Characterise the relationship between 
viral clearance and hospitalisation 
(hospitalisation for clinical reasons) 
Hospitalisation for clinical reasons 
up to day 28 
Characterise the relationship between 
viral clearance, randomisation arm and 
other measures (covariates) and 
development of post-acute COVID-19 
(i.e. long COVID) 
Score on post-acute COVID-19 (i.e. 
long COVID) questionnaire at day 
120 – modified COVID-19 Yorkshire 
Rehabilitation Scale (C19 YRSm) 
 
 
 

 
 
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2. ABBREVIATION 
ACT 
Access to COVID-19 Tools 
ADLs 
Activities of daily living 
AE 
Adverse event 
AR  
Adverse reaction 
ARI 
Acute Respiratory Infection 
BD 
Twice a day / twice daily / 2 times daily 
C19 YRSm 
The modified COVID-19 Yorkshire Rehabilitation Scale 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSG 
Clinical Trials Support Group 
CYP450 
Cytochromes P450 
DSMB 
Data Safety Monitoring Board 
EC 
Ethic Committee 
EDTA 
Ethylenediaminetetraacetic acid 
FBC 
Full blood count 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MORU 
Mahidol Oxford Tropical Medicine Research Unit 
NGS 
Next Generation Sequencing 
OxTREC 
Oxford Tropical Research Ethics Committee 
PD 
Pharmacodynamic 
PI 
Prinicipal investigator 
PK 
Pharmacokinetics 

 
 
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POC 
Point-of-care 
PPE 
Personal protective equipment 
RDT 
Rapid diagnostic test 
REGN 
Regeneron 
RT-qPCR 
Real-time quantitative polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SARS-CoV2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TNF 
Tumor necrosis factor 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
U&E 
Urea and Electrolytes 
VTM 
Viral transport medium 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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3. BACKGROUND AND RATIONALE 
There are many potential therapeutics for COVID-19 and a much larger number of vaccines are in 
development. Vaccines were given to individuals with the primary aim of reducing morbidity and mortality 
and the secondary objective of generating herd immunity in the hope of bringing the pandemic to an end. 
However, there is widespread vaccine inequality. As of 31 December 2023, the WHO states that only 44% of 
the total global population have been vaccinated against COVID-19 (1). Vaccinations have protected many 
from severe disease but importantly it is now clear that they provide incomplete protection, and vaccinated 
or previously infected individuals can still get infected and vulnerable individuals can still become ill. The rapid 
evolution of more transmissible and potentially vaccine resistant mutant strains (highlighted by the Omicron 
variant (B.1.1.529), and future variants (which may not be as comparatively mild) is worrying. We know that 
vaccine and disease-induced immunity is imperfect and short-lived so identifying active antiviral drugs is 
extremely important. Many people over the next 2-3 years will get COVID-19 with substantial morbidity and 
hundreds of thousands of deaths. There will always be people, due to their age, comorbidities or being 
immunocompromised that will need early antiviral therapy. For all these reasons effective therapeutics are 
needed urgently. 
 
 
 
 
Symptomatic COVID-19 infection has two overlapping phases (Figure 1). In the first phase, there is rapid viral 
replication with peak viral loads in the pharynx occurring approximately at the time of symptom onset. 
Thereafter viral burdens decline. In this second phase, the viral load decreases (the decline is first order, and 
the rate of decline is slower in sicker patients) (2-6). During the second phase, a small minority of individuals 
(particularly the elderly and those with co-morbidities) progress to severe illness (severe pneumonia) and 
some die. Hospital admission is usually about one week after the onset of illness (7). In those patients requiring 
respiratory support, low dose dexamethasone reduces mortality substantially (8). At this late stage of the 
illness inflammatory processes predominate, and antivirals are less likely to be of benefit (9). Antiviral 
treatments are most likely to be of benefit when given early in the illness. Accelerating viral clearance should 
reduce the subsequent inflammatory pathology, a hypothesis which is supported by studies of monoclonal 
antibody therapies and data from hospitalised patients (10, 11). At the time of writing the initial protocol, 
there were promising monoclonal antibody therapies with evidence of viral clearance acceleration. 
Figure 1 Simplified paradigm of COVID-19 infection and disease. There are two main stages of disease and antiviral therapies should 
be most effective early on. 

 
 
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Hospitalisation rates in RCTs were lower in the patients receiving these antibodies. However, monoclonal 
antibodies are currently expensive and difficult to deploy at scale (although this could change rapidly in the 
near future) and the continued efficacy of monoclonal antibodies is threatened by the evolution and spread 
of spike protein mutants (12, 13). This has been seen recently with the spread of the Omicron variant, and 
successive waves of its descendants, which has led, on the basis of in-vitro studies demonstrating decreased 
neutralization, to curtailment of their use. Two small molecule antivirals (molnupiravir, nirmatrelvir boosted 
by ritonavir) have completed phase 3 testing, and shown in-vivo benefits in COVID-19. They are already 
licensed for clinical use in some countries. However, further studies are needed, for better characterisation of 
the phenomenon of ‘viral rebound’, where there is a recrudescence of active infection which has implications 
for transmission. In-vivo synergy testing of combinations of antivirals will be important to assess the effects 
on viral rebound. This could prevent development of mutations during treatment (i.e. combination therapies 
given in HIV), for the severely immunocompromised and if more severe variants appear. More antivirals are 
following, and comparisons of their antiviral effects, as well as the risk of viral rebound and other 
characteristics, will help healthcare systems decide on their purchase and use. 
Another important area of research is regarding 
Nirmatrelvir/Ritonavir, 
which 
is 
widely 
considered 
the 
most 
effective 
COVID-19 
medication. It comprises of Nirmatrelvir (an oral 
3CL protease inhibitor of SARS-CoV-2) and 
Ritonavir (a CYP450 inhibitor which inhibits the 
metabolism of Nirmatrelvir). The dose of 
Ritonavir chosen to boost Nirmatrelvir was at the 
upper end of the range used to boost other 
protease inhibitors, such as in HIV (100mg BD). 
This 
guaranteed 
maximal 
boosting 
and 
Nirmatrelvir 
levels. 
However, 
dose-finding 
studies with lower dose or no Ritonavir were 
not conducted. It is unknown whether the 
maximum boosting effect could be achieved with less Ritonavir, or even without it. Many protease inhibitors 
are boosted equally well at lower doses of Ritonavir than 100mg BD e.g., saquinavir, fosamprenivir and 
darunavir are boosted equally well with a dose as little as 50mg/day (14). A phase I study in healthy volunteers 
did demonstrate rapid elimination, and low peak levels of Nirmatrelvir given without Ritonavir, although 
without a pharmacodynamic measure of efficacy. At a dose of 150mg (half the current dose of Nirmatrelvir 
used in PAXLOVID), the drug levels surpass the EC90 for several hours, which suggests that the drug will have 
some efficacy (see Figure 2) (15).  If a lower dose of Ritonavir and/or Nirmatrelvir is found to still give the levels 
required for comparable viral clearance, then this could lead to more people being able to take the drug. 
 
There is no optimised or validated approach to rapidly assess potential antiviral therapeutics in COVID-19. 
Drugs are currently being selected for clinical study on the basis of activity in cell culture systems (in-vitro) and 
animal models in-vivo. Unfortunately the animal models are not sufficiently good to be included in the drug 
development critical pathway. Some manufacturers (e.g. Pfizer) have decided not to try and assess antiviral 
activity of candidate drugs in these animal models. Thus drugs currently under consideration are justified only 
on the basis of antiviral activity in cell cultures. In order to identify effective antivirals and optimise their 
dosing, and therefore ensure that phase 3 studies are designed appropriately, and progress is as rapid as 
possible, in-vivo antiviral effects must be characterized adequately. This can be achieved in natural COVID-19 
infections at an early stage of the disease using the following design. Additionally, phase 3 studies looking at 
the endpoints of hospitalisation and death now need to be prohibitively large, due to the scarcity of these 

 
 
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events compared to earlier in the pandemic (16). Phase 3 studies need to be very large to be adequately 
powered and this means they are costly and slow to give answers. The trial will develop and validate a platform 
for quantitative assessment of antiviral effects (5) in low-risk patients with high viral burdens and 
uncomplicated COVID-19. As the assessment is of the antiviral effect on the virus, as distinct from the outcome 
on the clinical course of the infection, the results are applicable to all stages of disease where viral replication 
occurs (including prophylaxis), and can give answers as to the comparative antiviral effect of drugs quickly and 
with smaller numbers of patients recruited, than studies with clinical endpoints of hospitalisation and death. 
The role of viral burden and viral load reduction in the development of post-acute COVID-19 sequelae is 
incompletely understood, but there is evidence that there may be benefit which can be assessed prospectively 
in this study. The estimated burden of post-acute COVID-19 in terms of quality of life and economic impacts 
from days lost to work are huge (17). 
 
3.1. Proposal 
In this randomised 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 Nirmatrelvir/Ritonavir 
 
The trial initially focused on repurposed drugs as 
they were available at the time, and some are used 
widely 
without 
good evidence of 
benefit. 
Subsequently newly developed small molecule 
antiviral drugs have become available (e.g. 
molnupiravir and nirmatrelvir/ritonavir). For these 
newly available and repurposed drugs under 
consideration (type A interventions i.e. small 
molecule drugs), the platform trial is designed 
based on the premise that showing clear evidence 
of an antiviral effect is as important for medicine 
and public health as proving there is no significant 
effect.  
Antivirals showing evidence of an antiviral effect in 
the study, will enter a comparison with the positive 
control and may subsequently be chosen to be the 
positive control (such as with standard dose 
nirmatrelvir/ritonavir) (see Figure 5). Proving that 
a drug does not accelerate viral clearance in-vivo should provide evidence to stop clinical recommendations 
based on claims of putative antiviral activity in ex-vivo cellbased assays. Monoclonal antibodies (to be defined 
as type B interventions) were initially included as a “positive control” until evidence showed loss of activity 
and the effectiveness of nirmatrelvir/ritonavir. This is beneficial to demonstrate that the method does identify 
active compounds. It will be important to calibrate and compare the effects of these validated effective 
therapies relative to the newly identified small molecule antiviral drugs. In addition, for monoclonal antibodies 
it is also important to characterise waning efficacy over time resulting from novel spike protein mutants 
(12,13). 
For the final group, C, it is important to discover whether there are optimal doses of Ritonavir and 
Nirmatrelvir which would allow it to be effective whilst reducing some of the drawbacks to the medication 
Figure 32. Acceleration of viral clearance rates by different amounts 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 16 of 74 
(expense, drug-drug interactions, side effects), thus giving more people access to it. The ritonavir levels have 
been chosen based on the levels used for HIV and the nirmatrelvir based on the phase 1 study (15). They are 
as  follows –  
 
Nirmatrelvir 300mg + Ritonavir 100mg twice daily for 5 days (standard dose and positive (+ve) 
control)  
 
 Nirmatrelvir 300mg + Ritonavir 50mg twice daily for 5 days  
 
Nirmatrelvir 150mg + Ritonavir 50mg twice daily for 5 days  
 
Nirmatrelvir 300mg alone twice daily for 5 days.   
 
We aim to rapidly identify the best candidates of the novel small molecule drugs. The distinct objectives for 
each of these intervention types requires different stopping rules and design features. The rapid turn-round 
in quantitative PCR measurements is key to the success of this project. Analysis of these results will allow for 
frequent interim analyses with the aim of halting study arms early for futility, or triggering an intensive nested 
PK-PD study if there is evidence of clinically significant antiviral activity, although early interim analyses are 
not likely to yield efficacy assessments, and are aimed primarily at validation of the methodology. This will 
speed up the identification of antivirals to be assessed in phase III studies. The key metric is the rate of viral 
clearance (5) (Figure 3).  
3.2. Pharmacodynamic assessment 
We used prospectively collected serial viral load data from 46 individuals infected with SARS-CoV-2 and an 
accompanying pharmacodynamic model to simulate different trial designs for putative antiviral drugs using 
either time-to-clearance or rate-of-clearance as 
the primary trial endpoint (18). This model was 
then tested on data from a small pilot study of 
24 patients with early symptomatic COVID-19 
who were randomised to either ivermectin or 
placebo (19). Rate-of-clearance was shown to 
be a uniformly better endpoint in terms of type 
2 error (i.e. results in increased power) than the 
widely used and reported time-to-clearance 
(4). Rate of decline in oropharyngeal qPCR 
estimates of viral density measured daily also 
allows shorter and more efficient evaluation of 
viral clearance (Figure 4). Our simulations 
(Appendix 3) show that the proposed trial design 
can identify an effective therapy rapidly in the 
setting of a platform trial and quickly discard 
ineffective therapies (both of which are the 
primary objectives of the trial).  
 
Figure 4. The relationship between the number of qPCR viral 
load measurements taken over 10 days and the power (1-
type 2 error) to detect an effect size of 10% increase in viral 
clearance rate relative to control. This assumes that patients are recruited at peak viral load (4). 
 

 
 
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4. OBJECTIVES AND ENDPOINTS 
 
 Objectives 
Endpoint 
Timepoint(s) of 
evaluation of this 
endpoint (if 
applicable) 
Primary  
  
For all interventions trialled, there are two 
primary objectives: 
1) To evaluate SARS-CoV-2 antiviral 
efficacy in-vivo (accelerated viral 
clearance relative to the no study 
drug arm). This is a superiority 
comparison. 
2) To compare SARS-CoV-2 antiviral 
efficacy with current best antiviral 
treatment option (accelerated viral 
clearance relative to the positive 
control arm). This is a non-
inferiority or superiority 
comparison. 
 
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 5 for each therapeutic 
arm compared with the 
contemporaneous no 
antiviral treatment 
control/ positive control) 
Days 0-5 
Secondary To characterise the determinants of viral 
kinetics in early COVID-19 disease. 
Rate of viral clearance (as 
for primary endpoint) 
 
Days 0-5  
To determine optimal dosing regimens 
through pharmacometric assessment for 
antiviral drugs with evidence of efficacy 
(e.g. Nirmatrelvir/ritonavir, Ensitrelvir etc) 
 
Days 0-5  
 
Characterise viral rebound of studied 
treatment arms in comparison to 
contemporaneous controls (e.g. no study 
drug arm, positive control) 
After stopping treatment 
for at least 24 hours (or 5 
days if no drug is given or a 
single dose monoclonal 
antibody is given) rebound 
is defined as a 
oropharyngeal eluate viral 
density estimate >1000 
genomes per ml for at 
least 1 timepoint (average 
2 swabs), after >2 
consecutive days of 
average daily viral density 
estimate less than 100 
genomes per ml 
 
Days 0-14* 
To compare rates of fever clearance and 
rates of symptom resolution with respect 
to no treatment 
 
The following comparisons 
will be made: 
 Time to resolution of 
fever  
Days 0-28 

 
 
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 Area Under the Curve of 
recorded temperature 
 Time to resolution of 
symptoms 
Tertiary 
Characterise the relationship between viral 
clearance and hospitalisation 
(hospitalisation for clinical reasons) 
Hospitalisation for clinical 
reasons up to day 28 
Days 0-28 
Characterise the relationship between viral 
clearance, randomisation arm and other 
measures (covariates)  and development 
of post-acute COVID-19 (i.e. long COVID) 
Score on post-acute 
COVID-19 (i.e. long COVID) 
questionnaire at day 120 – 
modified COVID-19 
Yorkshire Rehabilitation 
Scale (C19 YRSm) 
Day 120 
*If a patient develops symptoms outside the planned swabbing schedule of D0-D5, D7 and D14, an extra swab 
can be performed up until D28. 
5. STUDY DESIGN  
The study is a randomised, open label, controlled adaptive platform trial that will be conducted in low-risk 
patients with COVID-19, recruited from outpatient COVID-19/ Acute Respiratory Infection (ARI) clinics or 
through other approved facilities, or from inpatient isolation facilities, or by patient self-referral to the study 
site, that is previously healthy patients 18 to 60 years old with early symptomatic COVID-19 and without co-
morbidities (see appendix 4). The study is being performed in Thailand, Brazil, Nepal and Laos. 
 
After obtaining fully informed consent, we will recruit adult patients with early symptomatic COVID-19 (less 
than 4 days (96 hours) since the reported onset of symptoms), who are positive by a SARS-CoV-2 lateral flow 
antigen test (identifying those with higher starting viral densities (20-22)) OR a positive PCR test for SARS-CoV-
2 within the last 24hrs with a Ct value of less than 25 (all viral targets). Patients will be included who can be 
followed up reliably for 120 days.It is expected that vaccination coverage will continue to increase during the 
study period as well as the cumulative number of natural infections.  
 
The primary pharmacodynamic measure in this study is the rate of viral clearance (expressed as the slope of a 
fitted regression to the linear segment of the serial standardized oropharyngeal sample qPCR densities from 
day 0 to day 5) following treatment (5). Each site will include a no antiviral treatment control arm consisting 
of patients not receiving any antiviral treatment, although local hospital supportive treatment will remain 
unchanged for the patients including antipyretics, anti-tussives, antihistamines, vitamins etc and other 
required medications, in the clinical judgement of the treating Physician.  
 
5.1. Interventions 
Intervention arms will be of three types: 
A) Small molecule drugs: The list of intervention drugs is Nitazoxanide, , Nirmatrelvir/Ritonavir (the positive 
control), and Hydroxychloroquine . We are adding in Metformin and Atilotrelvir/Ritonavir. The interventions 
will be chosen in order of priority, as well as local feasibility at sites (availability of drugs, local EC and regulatory 
approvals). Additional repurposed and newly available drugs can be added to the list. A number of drugs have 
been assessed and removed from this platform study. These include Ivermectin, Remdesivir, Favipiravir, 
Molnupiravir, Ensitrelvir, Fluoxetine, and a combination of Molnupiravir and Nirmatrelvir/Ritonavir. 
B) Monoclonal antibodies such as sotrovimab, other monoclonal antibodies may become available and 
included later. Evusheld and Regeneron have been assessed and removed from the platform study. 

 
 
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C) Dose finding study of Nirmatrelvir/Ritonavir, the following combinations of doses will be used (either from 
PAXLOVID or a high quality generic version)  
1. Nirmatrelvir 300mg + Ritonavir 100mg twice daily for 5 days (standard dose and positive (+ve) control) 
2. Nirmatrelvir 300mg + Ritonavir 50mg twice daily for 5 days 
3. Nirmatrelvir 150mg + Ritonavir 50mg twice daily for 5 days 
4. Nirmatrelvir 300mg alone twice daily for 5 days 
At any given time in the study, it is possible that not all intervention arms are available. Randomisation is 
explained further below. Ratios will be uniform across each stage of randomisation and will be at least 20% in 
the control arm in each stage.  
Randomisation will be continuously monitored by MORU. A positive SARS-CoV-2 lateral flow antigen test will 
be used as the main inclusion criteria. A positive lateral flow test result implies a relatively high viral load at 
the start of the study intervention (20-22). In order to assess viral clearance dynamics accurately over time 
initial high viral densities are required. In non-vaccinated patients, seronegativity implies there will be limited 
host control of the infection initially and was previously strongly correlated with higher viral loads (17), 
although this also depends on the variant.  
 
We aim to identify interventions that accelerate viral clearance by a minimum of 20% (corresponding 
approximately to a reduction of 2 days in the mean time to viral clearance). Any intervention drug that shows 
an acceleration of viral clearance, defined as a greater than 90% probability of accelerating viral clearance by 
more than 20%, or if there is evidence of accelerated viral clearance from other studies (e.g. Molnupiravir, 
Nirmatrelvir/ritonavir), will be selected for inclusion in a nested pharmacokinetic-pharmacodynamic study. In 
this nested study, frequent blood sampling will allow assessment of the relationships between plasma drug 
concentrations and viral clearance. The design of the pharmacokinetic study depends on the known 
pharmacokinetic properties of each drug. In each case no more than 10 blood samples (20mL) will be taken. 
For interventions not selected for the intense pharmacokinetic-pharmacodynamic study above, drug level 
samples at D3, D7 or D14 may be tested to determine a dose-response relationship. Any intervention arm that 
meets the futility endpoint (less than 10% probability of accelerating viral clearance by more than 20%) will 
be dropped from the study. New arms can be added at any time during the trial. Decisions concerning success 
and futility will be made sequentially at the pre-specified interim analysis to be conducted after 50 patients 
are enrolled, and thereafter after every 25 patients to ensure control of type 1 and type 2 error (Figure 5). The 
nested intensive PK-PD substudy will be performed on all arms of the dose finding sub study and in the other 
arms will be triggered if the probability that viral clearance is accelerated by more than 20% goes above 90%, 
or if there is evidence of accelerated viral clearance from other studies (e.g. Molnupiravir, 
Nirmatrelvir/ritonavir). A non-intensive PK-PD analysis can be conducted where determination of a dose-
response relationship is required (e.g. heterogeneity in the effect). 

 
 
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Figure 5. Schematic representation of the stopping rules as of January 2023  
 
5.2. Randomisation 
There are two ways in which participants can be randomised (depending on availability of interventions). 
Simple randomisation involves randomising the participants once. All drugs currently available in the study 
may be included in this, including the dose finding doses. Factorial randomisation, if interventions are 
available and this is currently active, will involve randomising the participant to randomisation part A AND 
THEN part B, thus they may receive 2  separate interventions.  
 
 
Randomisation part A  
Enrolled patients are randomised to (i) a small molecule drug (see list below, not all options will be available 
at any given time), (ii) no study drug, or (iii) the positive control (e.g. currently standard dose 
Nirmatrelvir/ritonavir). 
 
The list of studied small molecule drugs includes: Nitazoxanide, , Nirmatrelvir/ritonavir (standard dose 
(300/100mg twice daily for 5 days) – positive control), Hydroxychloroquine, Metformin and 
Atilotrelvir/Ritonavir 
The list of additional doses for Nirmatrelvir/Ritonavir  
- 
Nirmatrelvir 300mg + Ritonavir 50mg twice daily for 5 days 
- 
Nirmatrelvir 150mg + Ritonavir 50mg twice daily for 5 days 
- 
Nirmatrelvir 300mg alone twice daily for 5 days.  
 
 
Randomisation part B (as a factorial design) 
If monoclonal antibodies are available at the site, enrolled patients are additionally randomised to (i) a 
monoclonal antibody (see list below) or (ii) no study drug.  

 
 
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The list of studied monoclonal antibodies includes: Sotrovimab and other monoclonal antibodies that become 
available. 
 
6. PATIENT IDENTIFICATION AND RECRUITMENT  
6.1. Study Patients  
Previously healthy adult patients with early symptomatic COVID-19. 
 
6.2. 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. 
 
6.3. 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 (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. 
 
7. STUDY SET-UP AND PROCEDURES 
Recruitment of patients will be from outpatient COVID-19/ ARI clinics or through other approved facilities, or 
from inpatient isolation facilities, or by patient self-referral to the study site. Patients with a positive SARS-
CoV-2 rapid 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 targets) will be enrolled in the study after providing fully informed written consent. In each 
study site there will be a designated research ward for study procedures. In accordance with local and national 
infection control guidelines the initial assessments will be conducted in a designated research ward set-up to 
manage COVID-19 patients. Patients will receive care in either an inpatient or outpatient setting, in accordance 
with local and national guidelines. All recruited patients will be visited at their home or place of residence, or 
be seen in the designated clinical trials unit or hospital ward. All personnel will wear appropriate personal 
protective equipment (PPE). For home visits a trained member of personnel will perform the swabbing or ask 
the patient to self-swab (and may ask the patient to give a saliva sample). 

 
 
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The rapid lateral flow antigen test will be performed by trained study personnel. Patients will be eligible for 
the trial if the test is positive within a specified period of time (detailed in a separate SOP based upon 
manufacturer’s guidelines). A positive band appearing rapidly is correlated with a higher viral load in the swab 
sample (personal communication, Prof. Tim Peto). A digital photograph of the test result may be taken to allow 
for future analysis. The exact details of this will be detailed in the separate work instruction.  
 
Participants will be asked if they have been in the study before and whether any relatives have been in the 
study. After enrolment into the study, the patient will be randomised once for simple randomisation or twice 
for factorial design randomisation (randomisation part A and part B; if interventions are available). Further 
details of the randomisation procedures are given below (see section 7.6.1). An oropharyngeal swab will be 
obtained in duplicate by the study team using a standard operating procedure (SOP) after a full explanation is 
provided to the patient. Swabs will be taken in duplicate again prior to receiving the study drug. The patient 
may have further swabs between 6 – 18 hours after the initial swabs post dose, either by study personnel or 
by self-swabbing. To minimise patient discomfort, all SARS-CoV-2 qPCRs will be performed on eluates from 
standard oropharyngeal swabs, taken in duplicate (22-26). In addition, patients may be asked to have an extra 
set of daily swabs done by study peronnel or self-swabbing or by giving a sample of saliva during the first 5 
days of the trial (see section 7.1). The patient will undergo a physical examination and blood sampling for 
routine haematology and biochemistry and other baseline investigations (see Section 7.5). For oral study 
drugs, the first dose will be administered and observed at the research ward/ hospital. Subsequent doses will 
be administered by the ward personnel in hospital if the patient is an inpatient, at the patient’s home, or 
current residence, supervised by study personnel (if multiple doses, then one of the doses per day will be 
observed). In case a study drug requires parenteral administration, this will be provided under supervision by 
the study personnel in the research ward, or hospital, or the patient’s home.  
 
7.1.  Virological sampling 
Serial oropharyngeal swabs will be taken in duplicate (one swab each tonsil) at least once per day, and up to 
twice per day (4 swabs total) by the study team or by self-swabbing (25) according to the sample schedule. 
Patients need to consent to at least once a day swabbing. One set of swabs will be taken from the back of the 
throat (oropharynx; tonsillar fossa ) by trained study personnel according to the SOP abiding by strict PPE 
measures. Patients may also be asked to have an extra second set of daily swabs done by self-swab according 
to a set of given instructions.,or by study personnel over the first 5 days. They will be informed of the details 
by the study personnel. Each swab will be placed in 3mL of viral transport medium (VTM) (Thermofisher 
M4RT®), snapped off and sealed. In addition, some patients may be asked to give a sample of saliva, detailed 
in a set of separate instructions. The volume of saliva will be standardised. The purpose of self-swabbing/ 
saliva collection is to assess and validate methods of determining the viral density in the oropharynx in a less 
intrusive manner, or supplement the results from the oropharyngeal swabs to improve the characterisation 
of the viral clearance. As discussed later, the faster clearance of the virus over time means the later swabs 
(day 7) are less useful in terms of determining clearance than earlier in the study. Swab 6 and 10 will have 
been removed but swab 7 and 14 will remain to better characterise any viral rebound. As such the study will 
determine rate until day 5, and not day 7 as previous, and better characterisation of the earlier slope, with 
extra samples should be beneficial. If these results are informative, they may subsequently be included in the 
SAP for endpoint analysis. At least once daily sampling will be performed by the study personnel who will place 
the swabs in the transport medium, and document the time. The samples will be kept cool, and subsequently 
stored at -80°C as detailed in the SOP. Transport times will be recorded, as well as the time at which the swab 
is frozen at -80°C. Viral genomes from the throat swabs will be quantitated by RT-qPCR, according to published 
methods (28). Each observed value will be recorded along with the RNAseP log10 density (representing human 
cell numbers). The exact details of the analysis are given in the SAP (29, 30). The measurements for the patient 
over time will be used to estimate the rate of viral clearance under a Bayesian hierarchical linear mixed effects 
model. The concentration of urea in the VTM will also be measured and compared with the serum urea 
concentration in the baseline biochemistry sample. This comparison enables determination of the 

 
 
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extracellular fluid content in the eluate volume of the oropharyngeal samples. The urea concentration in 
throat fluid is the same as in serum, so that the dilution factor of the throat sample in the VTM fluid can be 
easily calculated (31). Blood will also be taken for quantitative virology and other baseline assessments (see 
Section 7.5). All samples positive for SARS-CoV-2 on qPCR will be sequenced using Next Generation Sequencing 
(NGS), or canonical variant mutation analysis will be used to determine the virus genotype, in order to 
determine the effect of viral genetics on viral load and response to treatment.  
7.2. Recruitment  
Potential patients with a positive SARS-CoV-2 test obtained during routine screening, or those with symptoms 
in keeping with COVID-19, even if they do not have the results of their SARS-CoV-2 test, or have not been 
tested yet, may be contacted by the research group. Alternatively, they may contact the research group for 
participation in the study. Each will be provided with a written participant information sheet.    
7.3. Screening and Eligibility Assessment 
Eligibility assessment will occur at the point of screening. If, based on the inclusion and exclusion criteria, the 
patient is eligible and willing to complete the full study, they will be included provided informed consent is 
obtained. 
7.4. Informed Consent 
Written and verbal versions of the Participant Information and Informed Consent will be presented to the 
patients detailing the exact nature of the study; what it will involve for the patient; the implications and 
constraints of the protocol; and the known side effects of the medicines under evaluation and any risks 
involved in taking part. It will be stated clearly that the patient is free to withdraw from the study at any time 
for any reason without prejudice to future care, and with no obligation to give the reason for withdrawal. 
The patient will be allowed as much time as required to consider the information as long as they remain eligible 
and within the time-frame for recruitment into the study, and the opportunity to question the Investigator or 
other independent parties to decide whether they will participate. Written Informed Consent will then be 
documented by a patient dated signature and dated signature of the person who presented and obtained the 
Informed Consent. The person who obtained the consent must be suitably qualified and experienced and have 
been authorised to do so by the site PI. A copy of the signed Informed Consent will be given to the patient. 
The original signed form will be retained at the study site. 
7.5. Baseline Assessments 
A physical exam, vital signs, symptom review and basic demographics will be recorded. Temperature will be 
recorded 12 hours later either by the patient or study personel. Oropharyngeal viral swabs will be taken by 
the study personnel in duplicate (swabs will be taken at two timepoints prior to study drug being administered) 
(and possibly a saliva sample see section 7.1). A total of 20 ml of venous blood for study testing will be taken 
at this point. Administration of the therapeutic may be delayed until the results of the FBC and Biochemistry 
will be available (although these will ideally be available within 1 hour of sample collection i.e. before 
randomisation), to determine if there is any contraindication. If these bloods are not available in this 
timeframe, then the patient can be safely enrolled, randomised, and given their first dose, and can be excluded 
prior to their next dose if laboratory abnormalities resulting in a contraindication are present. If an FBC and 
Biochemistry has been taken in the previous 24hrs, the results of these can be used to determine whether 
there is a contraindication. 
Laboratory tests at baseline 
 
Blood sample for  
o Full blood count (FBC) and differential count 

 
 
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o Biochemistry (including U&Es, creatinine, 
LFTs and LDH) 
o Fibrinogen, Ferritin, TNF/IL-6/IL-1 
o Serology (antibody responses) 
o Stored sample 
o Drug level 
o Host genotyping to assess determinants of 
the therapeutic response 
 
Oropharyngeal swab in duplicate (and possibly a 
saliva sample see section 7.1) 
 
ECG (this is not a requirement) 
 7.6  Days of study 
7.6.1 Randomisation D0 
After enrolment, the patient may be randomised once for simple randomisation or twice for factorial design 
randomisation using an online randomisation application. The number of arms at a site can be limited by the 
approval and availability of the study drug at that site. Randomisation to the no antiviral treatment control 
arm (no intervention) will be fixed at a minimum of 20% throughout the study. The randomisation ratios will 
be uniform for all available interventions in each stage of randomisation. The drug allocations are not blinded 
for the patient for practical reasons. For patients randomised to an active drug, the first treatment dose (hour 
0) will be supervised by study team after a viral swab (and possibly a saliva sample see section 7.1) is taken 
again for qPCR (taken in duplicate) (see appendix 1 for schedule of activities). The patient will then be observed 
for a minimum of 1 hour in the ward. Further swabs (taken either by the study personnel or self-swabbing) 
may be taken at hours 6-18 after initial swabs post dose. A second temperature will be recorded by the patient 
or the study personnel.  
For the therapeutic arms for which intensive PK has been triggered, and for the dose finding arms, patients 
will stay for extra blood tests for drug monitoring levels, according to the schedule in the drug-specific 
appendix. For further details of the intensive PK schedules for the individual therapeutics please see the 
appendix 2. 
7.6.2 Day 1- day 5  
The following variables will be assessed daily: 
 
Eligibility check, and assessment of treatment (taking of medications taken will be observed by the 
study personnel and the time recorded. In participants who are outpatients, for medications taken 
more than once daily, the patient will record the time non-observed doses are taken).  
 
Oropharyngeal swabs for qPCR will be taken in duplicate (and possibly a saliva sample see section 7.1) 
by the study personnel at least once by the study personnel (time taken recorded by the study 
personnel), with the option of further swabs being taken by the study personnel or by the participant 
(self-swabbing). 
 
Temperature recorded at least twice daily by study personnel or participant (information collected in 
a diary and reviewed by the study personnel daily). This is important to determine if the treatments 
affect how febrile the patient is, or the overall effect on their temperature. 
 
Study personnel/ patient completes a brief symptom questionnaire each day. 
 
Vital signs will be measured by the study personnel. 
 
Blood samples will be taken (ideally day 3) for antibody levels and for later pharmacokinetic analyses 
(pre- or post-dose depending on the therapeutic in question) and FBC and biochemistry, to assess 
potential drug adverse effects.  
 

 
 
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7.6.3 
Day 6, 7 and 14 
 
Eligibility check, and assessment of treatment (taking of medications taken will be observed by the 
study personnel and the time recorded. In participants who are outpatients, for medications taken 
more than once daily, the patient will record the time non-observed doses are taken).  
 
Temperature recorded twice daily by study personnel or participant (information collected in a diary 
card and reviewed by the study personnel daily). This is important to determine if the treatments 
affect how febrile the patient is, or the overall effect on their temperature. 
 
Patient/study personnel will complete a brief symptom questionnaire. This is important to 
determine how treatments effect the patient’s symptoms. 
 
All patients  will have oropharyngeal swabs taken in duplicate (and possibly a saliva sample see section 
7.1) either at home (if feasible) or at the research ward EXCEPT on D6 when they will not be swabbed. 
These extra swabs are to better capture viral rebound should this occur, as has been described with 
certain antivirals. D7 swabs, although no-longer used for determining the rate of clearance, are useful 
for characterising rebound (which according to certain definitions can occur within 2 days of stopping 
a medication), or detecting mutants. The patient will be reviewed in person on this day anyway for 
bloods, and the swabs can be done without inconvenience.  
 
Blood samples will be taken (at D7 and D14) for antibody levels and for later pharmacokinetic analyses 
(pre- or post-dose depending on the therapeutic in question) and FBC and biochemistry, to assess 
potential drug adverse effects.  
 
The exact timepoints of swabs used to characterise viral rebound will be defined in the SAP. The 
current definition is: After stopping treatment for at least 24 hours (or 5 days if no drug is given or a 
single dose monoclonal antibody is given) rebound is defined as a oropharyngeal eluate viral density 
estimate >1000 genomes per ml for at least 1 timepoint (average 2 swabs), after >2 consecutive days 
of average daily viral density estimate less than 100 genomes per ml. 
 
Study personnel/patient will also complete a brief symptom questionnaire, vital signs (EXCEPT on day 
6) and follow up temperature will be measured by the patient or study personnel. 
7.6.4 Day 28 assessment   
The day 28 follow-up assessment will be through a telephone call or a visit to check whether the patient 
recovered uneventfully for whether there was progression to more severe illness or need for hospitalisation 
for clinical reasons. A brief symptom questionnaire will also be completed. This final assessment will have an 
allowed window -2/ +7 days based upon calculation from Day 0. 
7.6.5 Day 120 assessment   
The day 120 follow-up assessment will be through a telephone call or visit to determine if the patient has any 
ongoing symptoms i.e. post-acute COVID-19. This final assessment is performed using the C19 YRSm, and will 
have an allowed window -10/ +30 days based upon calculation from Day 0. The severity of symptoms will be 
assessed following the standard C19 YRSm.   
Patients will either complete the assessment over the phone, or be given the questionnaire in advance to read 
the answers out to one of the study team over the phone. 
7.7 Intensive pharmacokinetic sampling 
For those study drugs in the dose finding sub study, or that are shown to be effective antivirals in other studies  
or meet the success criteria of the study (defined as a greater than 90% probability of accelerating viral 
clearance by more than 20%), we will then conduct intensive pharmacokinetic (PK) sampling for further 
patients who are enrolled into that arm. The exact sampling schedule will depend on the study drug 
characteristics (see appendix 2), but in general the patient will stay at the ward for the remainder of the day 
to have further blood tests performed. A cannula will be inserted so that blood can be drawn without the need 

 
 
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for repeated venepuncture. A further blood test will be performed the next day, either at the ward or at their 
home if feasible. The volume of blood from this will not exceed 20 mls.  
For any intervention not selected for the intense pharmacokinetic-pharmacodynamic study above, drug level 
samples at D3, D7 or D14 may be tested to determine a dose-response relationship. PK-PD analysis at D3, D7 
or D14 can be conducted where determination of a dose-response relationship is required (e.g. heterogeneity 
in the effect or unusual clearance characteristics). 
7.8 Management of patients who become ill  
During the study, although this is unlikely, the patient may deteriorate clinically from their COVID-19 or may 
develop a new intercurrent illness or potentially a side-effect related to the study medication.   
All patients who develop difficulty with activities of daily living or complain of shortness of breath will be 
assessed initially by the study personnel and their oxygen saturation measured and, if necessary, brought to 
the clinic research physician for further assessment. Based on this assessment, they may be referred to 
hospital, re-examined the next day, or asked to update the research team by mobile phone frequently on their 
well-being. The physician may decide to repeat study oropharyngeal swabs in duplicate if symptoms of COVID-
19 recur, for the duration of the illness, to characterise symptomatic viral rebound. 
If a patient is referred to hospital, a clinical assessment will be made by the hospital physician and a diagnosis 
made. The decision to stop study drug will depend on that diagnosis and be made between the hospital team 
and the study PI.  
The hospital physicians will have the responsibility for patient care but the research team will continue to 
follow the progress of the patients in hospital. Treatment for COVID-19 severe enough to warrant 
hospitalisation will follow national guidelines. For those patients where treatment is changed (i.e. a new 
treatment is started for clinical reasons) an extra set of swabs in duplicate (and possibly a saliva sample see 
section 7.1) should be collected prior to the initiation of the new treatment (i.e. 2 sets of swabs will be taken 
in duplicate). This will only occur if the patient is within the first 7 days of the study. 
The D0, D3, D7 and D14 blood samples will be tested for FBC and biochemistry (e.g. U&Es, LFTs) to assess for 
drug-related adverse effects or abnormalities which require a potential dose adjustment or stopping the 
therapeutic or clinical intervention. The responsibility for evaluating and acting upon the results of blood tests 
will belong to the study team at the local site. They will use their clinical judgement in the assessment of the 
patient, further tests and onwards referral. At any point of the study, extra laboratory tests may be conducted 
on the patient if felt to be clinically indicated by the research team, based on symptoms or previous laboratory 
abnormalities. 
7.9 Sample Handling and Retention 
Samples will be transferred to designated testing facilities, where they will undergo testing in accordance with 
best practice laboratory measures and safety procedures.  
Oropharyngeal swabs (and possibly a saliva sample see section 7.1) will be processed using validated 
quantitative Real-Time quantitative Polymerase Chain Reaction (qPCR) to detect SARS-CoV-2, according to the 
study SOP. A urea measurement will be measured on each and compared to the baseline blood concentration. 
Swabs will be tested in duplicate. 
The samples will be retained as per University of Oxford and local site regulations. Consenting patients may 
rescind their consent up until the completion of the study. Unless requested the samples collected prior to 
date of withdrawal will be retained for study analysis. 

 
 
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Samples, including those for PK, may be transferred to MORU or other designated testing facilities outside the 
site country, with appropriate material transfer agreements (MTA) and associated approvals prior to 
shipment. 
 
8 
 DISCONTINUATION/WITHDRAWAL OF PATIENTS FROM STUDY 
Patients may choose to stop treatment and/or study assessments but may remain on study follow-up. Patients 
may also withdraw their consent, meaning that they wish to withdraw from the study completely. In the case 
of withdrawal from both treatment and active follow up the following options for a tiered withdrawal from 
the study would apply a) Patients withdraw from the study but permit data and samples obtained up until the 
point of withdrawal to be retained for use in the study analysis. No further data or samples would be collected 
after withdrawal, b) Patients withdraw from active follow-up and further communication but allow the trial 
team to continue to access their medical records and any relevant hospital data that is recorded as part of 
routine standard of care; i.e., CT-Scans, blood results and disease progression data etc.  
 
In addition, the Investigator may discontinue a patient from the trial treatment at any time if the Investigator 
considers it necessary for any reason including, but not limited to: 
 
Pregnancy 
 
Ineligibility (either arising during the study or retrospectively having been overlooked at screening) 
 
Significant protocol deviation 
 
Significant non-compliance with treatment regimen or trial requirements 
 
An adverse event which requires discontinuation of the trial medication or results in inability to 
continue to comply with trial procedures 
 
Disease progression which requires discontinuation of the trial medication or results in inability to 
continue to comply with trial procedures  
The reason for discontinuation and/or withdrawal will be recorded in the Case Report Form. qPCR data from 
patients withdrawn from the study will still be analysed if at least three distinct timepoints are available for 
the estimation of a clearance slope. The sample size is adaptive so there is no need to replace withdrawn 
patients. 
Consenting patients may rescind their consent up until the completion of the study. Unless requested, data 
and samples collected prior to the date of withdrawal will be retained in the study database and analysis. 
8.1 Definition of End of Study 
The end of study is the date of the 120 day follow up visit of the last enrolled patient. 
 
9 
SAFETY REPORTING  
9.1 Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a patient to whom a medicinal product 
has been administered, including occurrences which are not necessarily 
caused by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a patient to an investigational 
medicinal product which is related to any dose administered to that patient. 

 
 
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The phrase “response to an investigational medicinal product” means that a 
causal relationship between a trial medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the trial 
medication qualify as adverse reactions. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing 
hospitalisationş 
 results in persistent or significant disability/incapacity 
 consists of a congenital anomaly or birth defect. 
Other “important medical events” may also be considered serious if they 
jeopardise the patient or require an intervention to prevent one of the above 
consequences. 
NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were 
more severe. 
Hospitalisation is defined as an unplanned, formal inpatient admission, even 
if the hospitalisation is a precautionary measure for continued observation. 
The patient must be admitted overnight, a short stay of several hours to 
receive treatment is not considered hospitalisation. If a patient is admitted 
overnight or longer for social/economic or isolation reasons and is otherwise 
medically stable, this does not constitute a SAE. Other examples of visits to a 
hospital facility that are not considered hospitalisation are: Emergency room 
visits, outpatient surgery, pre-planned or elective procedures for a pre-
existing condition (as long as that condition has not deteriorated while on trial 
treatment or brought forward because of worsening symptoms) and for the 
purpose of this study, being hospitalised for COVID-19 isolation. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of the trial 
treatments, based on the information provided. 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, the 
following note of clarification is provided: “Severe” is often used to describe intensity of a specific event, 
which may be of relatively minor medical significance. “Seriousness” is the regulatory definition supplied 
above. 
Any pregnancy occurring during the clinical trial and the outcome of the pregnancy should be recorded and 
followed up for congenital abnormality or birth defect, at which point it would fall within the definition of 
“serious”. 
 
9.2 Causality 
The relationship of each adverse event to the trial medication must be determined by a medically qualified 
individual according to the following definitions: 

 
 
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Definitely related:  
There is clear evidence to suggest a causal relationship and other possible contributing 
factors can be ruled out. 
Probably related:   
There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
Possibly related:     
There is some evidence to suggest a causal relationship (e.g. because the event occurs 
within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g. the patient’s clinical 
condition, other concomitant treatments). 
Unlikely to be related: There is little evidence to suggest there is a causal relationship (e.g. the event did not 
occur within a reasonable time after administration of the trial medication), or there is 
another reasonable explanation for the event (e.g. the patient’s clinical condition, 
other concomitant treatment). 
Not related:  
 
There is no evidence of any causal relationship. 
 
9.3 Procedures for Recording Adverse Events 
A symptom questionnaire will be performed daily until D5 with a final follow-up assessment on D28 to aid in 
the identification of adverse events. The participant will be assessed on day 120 for post-acute COVID-19 but 
after day 28 study adverse events will not be recorded. The severity of adverse events will be assessed 
following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0:   
1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal. 
AEs occurring in patients from enrolment and during trial participation that are observed by the Investigator 
or reported by the patient with severity grade of 3 (severe) or higher will be recorded on the CRF, whether or 
not attributed to trial medication. 
When drug combinations are assessed, the team will separately record all clinical AEs (grade of 1 or higher) 
for those given the combination (e.g. molnupiravir and nirmatrelvir/ritonavir), as well as those being given the 
same drugs individually (e.g. molnupiravir or nirmatrelvir/ritonavir). This will be important to monitor the 
safety and tolerability of combinations in direct comparison to the individual drugs. 
The following information will be recorded: description, date of onset and end date, severity, assessment of 
relatedness to trial medication, other suspect drug or device and action taken. Follow-up information should 
be provided as necessary. 
AEs considered related to the trial medication as judged by a medically qualified investigator or the Sponsor 
will be followed either until resolution, or the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient severity to 
require the patient’s removal from treatment. A patient may also voluntarily withdraw from treatment due to 
what he or she perceives as an intolerable AE. If either of these occurs, the patient must undergo an end of 
trial assessment and be given appropriate care under medical supervision until symptoms cease, or the 
condition becomes stable. 
 
9.4 Grading of laboratory abnormalities 
Abnormal laboratory findings detected during the study or are present at baseline and worsen following the 
taking of study medication will be reported as AEs or SAEs. If found to be abnormal the values will be graded 
according to the CTCAE v5.0. AEs and SAEs of severity grade 3 or higher will be recorded in the CRF and will be 
followed up until grade 2 or below, returned to baseline, or deemed to be permanent. For laboratory results 

 
 
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that are not available in the CTCAE v5.0, the site investigator should make a determination as to whether or 
not the laboratory abnormality is clinically significant. If the site investigator believes a laboratory abnormality 
is clinically significant, it should be reported as an adverse event and a grade should be identified to the best 
of their ability. 
 
9.5 Reporting Procedures for Serious Adverse Events 
All SAEs detected by the site investigator must be reported to the PLATCOV safety team within 24 hours of 
site awareness. The Serious Adverse Event CRF documenting the SAE should be emailed to 
PLATCOVsafetyteam@tropmedres.ac. The PLATCOV safety team will inform the DSMB within 10 days of initial 
notification of the SAE and keep the DSMB updated as needed. 
Further reports should be submitted, if required, until the SAE is resolved, is deemed stable/ permanent or 
results in death. A final status should be determined for any SAEs ongoing at the study end date.  
The site PI must also report the SAEs to the local ethics committee and the regulatory authority in accordance 
with local requirements. 
 
9.5.1 Expectedness 
Expectedness will be determined according to the Investigators’ Brochure/Summary of Product 
Characteristics.  
9.5.2 SUSAR Reporting 
All SUSARs occurring within the study will be reported by the site PI to the relevant Competent Authority and 
to the local Ethics Committee and other parties as applicable. For fatal and life-threatening SUSARs, this will 
be done no later than 7 calendar days after MORU is first aware of the reaction. Any additional relevant 
information will be reported within 8 calendar days of the initial report. All other SUSARs will be reported 
within 15 calendar days. 
Site PIs will be informed of all SUSARs for the relevant IMP that occur at any of the PLATCOV study sites. 
9.6 Data Safety Monitoring Board (DSMB) 
An independent Data Safety and Monitoring Board (DSMB) will be set up consisting of qualified volunteers 
with the necessary knowledge of clinical trials. The DSMB will receive summary reports from MORU as defined 
per charter or per ad-hoc request, prior to each meeting. All data reviewed by the DSMB will be in the strictest 
confidence. A DSMB charter will outline its responsibilities and how it will operate.  
 
An interim report will be prepared by the Trial Statistician for the pre-specified interim analysis. In case of 
safety concerns, additional information or formal interim analyses can be requested by the DSMB.  
The DSMB will meet formally at the following timepoints: 
 
before the study starts 
 
after the first 50 patients have been accrued into the study (10 per arm) 
 
At additional time-points as indicated by the DSMB after their review, if deemed necessary 
All DSMB recommendations will be communicated to site PIs. The site PI will be responsible for submitting the 
written DSMB summary reports with recommendations as applicable to local/ national ethics committees and 
other applicable groups. 
 

 
 
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10 STATISTICS AND ANALYSIS 
 
10.1 Overview of adaptive study design and overall approach 
This is a platform trial that will evaluate multiple antiviral treatments for COVID-19. The sample size is adaptive 
with multiple planned interim analyses. By specifying an adaptive sample size, we can more rapidly identify 
treatments that work and possibly remove treatments that do not work. Clinical trials with adaptive designs 
are increasingly being used in research, including in such successful and prominent COVID-19 studies as the 
RECOVERY study. In addition, the FDA and EMA supply guidance on studies with these designs1. They do not 
have fixed sample sizes, as do conventional RCTs. The number of patients recruited depends on the results 
(i.e. they are adaptive). The benefits of an adaptive sample size are increased efficiency and ethical 
considerations (i.e. they can stop ineffective arms earlier, identify effective arms earlier, and limit numbers in 
ineffective arms compared to fixed sample number 
studies). Because of these advantages this type of study 
is likely to become more prevalent, but it is important 
that the study is well-designed in advance, that the 
adaptive design is appropriate for the overall study 
design,and has mechanisms in place to control type I 
error.  
 
The main pharmacodynamic endpoint is the rate of viral 
clearance, estimated from serial qPCR measurements in 
each patient (4). There is considerable inter-individual 
variability in clearance rates which are first order and 
predominantly monoexponential, although there is some 
evidence of a biexponential component. The measured 
end point is the slope of the the initial log linear decline 
in qPCR estimated viral densities (Figure 6). The clearance 
rate is correlated with both disease progression and the 
presence of symptoms. As this is a multi-centre trial, 
populations may differ between sites with respect to key covariates. Therefore, the main analytic approach 
will be to fit a hierarchical Bayesian model to the serial qPCR measurements (using default weakly informative 
Bayesian priors to aid model fitting), whereby the baseline viral loads (intercept) and the first-order clearance 
rates (slope of initial decline) can vary between sites and between individuals. The viral clearance slope is also 
dependent on the randomised study arm. Stopping an intervention arm for futility or success, triggering an 
intensive PK-PD nested sub-study, may be decided using the posterior probabilities that the arm results in an 
increased slope (increase set as 20%, following the results of the first interim analysis). The PK-PD nested sub-
study may be also triggered if there is evidence of accelerated viral clearance from other studies (e.g. 
Molnupiravir, Nirmatrelvir/ritonavir). 
 
10.2 Results of the first interim analysis 
As pre-specified in the SAP, the first interim analysis, triggered once data from the first 50 patients were 
available, was presented to the Trial Steering Committee and the DSMB. This analysis showed that the positive 
control arm (REGN-CoV-2) had a substantially larger effect on viral clearance than anticipated, with over 50% 
increase in viral clearance relative to the negative control arm (Figure 7). In addition, the intra-individual 
variation in viral load estimation was greater than anticipated, resulting in larger uncertainty around effect 
sizes. For these reasons, we changed the threshold effect size defining futility and success from 5% increase 
                                                          
1 https://www.fda.gov/media/78495/download 
https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-methodological-issues-confirmatory-
clinical-trials-planned-adaptive-design_en.pdf 
Figure 6 qPCR viral densities in oropharyngeal samples over 
time, showing time of likely symptom onset 
relative to viral densities and study days 

 
 
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in viral clearance to 12.5% increase in the viral clearance and subsequently to 20%. Under this threshold, we 
would need an average of 50 patients randomised to an intervention that has no effect on viral clearance to 
demonstrate futility. For therapeutics which may potentially be used in prophylaxis, where a lesser antiviral 
effect may be required to be clinically useful, a different success threshold, and maximum number of patients, 
may be described in the SAP for the analysis.  
 
Figure 7 Data from the first interim analysis (first 50 patients recruited into the study). 
 
10.3 Bayesian hierarchical model of viral clearance 
At each interim analysis we will fit a series of Bayesian hierarchical (mixed effects) model to the serial viral 
load measurements (modelled directly on the Ct scale). The main linear model will take the following form: 
yk,i,t ~ Student(α0 + αk + αi + (β0 + βi + βk + βT(i))t , sigma2, dof) 
where yk,i,t is the observed log10 viral load for individual i at time t from site k (two values per timepoint), and 
T(i) is the randomised arm assigned to individual i. Sigma2 is the measurement error (residual error). The error 
model is a t-distribution with degrees of freedom inferred from the data (dof). The slope of viral clearance 
decomposes into 4 terms: the population mean slope β0; the site random effect βk; the individual random 
effect βi; and the treatment effect (fixed across sites and individuals) βT(i). The intercept term (baseline viral 
load) decomposes into 3 terms: the population intercept α0; the site random effect αk; and the individual 
random effect αi. All comparisons are made relative to the no antiviral treatment control arm, so we set βcontrol 
= 0. Adjustment will be made for human RNaseP concentration. The model will treat viral load corresponding 
to CT values of 40 as left censored. An equivalent non-linear model (allowing for an initial increase in viral load, 
followed by a linear decrease) will also be fitted to the data as a sensitivity analysis. 
The SAP has further details of the analysis. 
 

 
 
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10.4  Time varying effects 
Characterising and identifying time varying effects not specified in the main model is important for two 
reasons: 
 
Monoclonal antibodies (type B- see study design section) - where the efficacy can be reduced in 
infections with spike protein mutant SARS-CoV-2 strains. Therefore, it is possible that a waning effect 
is observed over time justifying early stopping. 
 
New interventions which are added later on during the trial cannot be compared directly to all data 
from the control arm without accounting for possible differences in population over time (as an 
epidemic evolves, included populations may differ in a single site over time). 
We will use descriptive approaches to detect time-varying effects (residual plots over time, mean slopes in 
control individuals over time). If substantial time-varying effects are observed, we will add a smooth time 
varying spline component to the linear model. The base model will not include this for simplicity. 
 
10.5 Sample size estimation, randomisation and statistical considerations for the Bayesian group 
sequential design 
 
The platform study has two main objectives: 
 
Identify interventions that are unlikely to be of clinical benefit (i.e. demonstrate futility) 
 
Identify interventions that could have clinical benefit and determine optimal dosing (from PK-PD 
studies) for phase 3 evaluations.  
The required sample size depends on how stringent the thresholds are that define futility or success. Before 
the trial started we used simulation to determine the probability thresholds that result in control of the type 
1 error at 10% and control of the type 2 error at 20% using as a minimum effect size a 5% increase in viral 
clearance. Following the first interim analysis at 50 patients, the minimum threshold was changed to 12.5%. It 
was subsequently increased to 20%. 
For the following interim analyses, the decisions made for a treatment arm T are as follows: 
 
Stopping for futility: if Probability(βT > 0.20 * β0) < 0.1 
 
Stopping for success/Triggering intensive PK-PD nested sub-study: if Probability(βT > 0.20 * β0) > 0.9 
The first interim analysis was carried out after 50 patients were enrolled. We will then carry out interim 
analyses every 25 patients. The initial thresholds for futility and success were chosen after simulating 6000 
trials with all combinations of futility thresholds in the set {0.05, 0.1, 0.2} and success thresholds in the set 
{0.8, 0.9, 0.95, 0.99} (12 combinations in total, 500 simulations per combination). The maximum sample size 
was set at 400 patients in total with 6 arms (5 intervention arms and 1 control arm). Out of the 5 interventions, 
1 was effective with an effect size of 10% and the other 4 were ineffective (no increase in slope). Type 1 error 
for a particular combination of futility and success thresholds was calculated as the average number of times 
any of the ineffective arms were declared effective divided by the number of decisions (note this the per 
decision type 1 error not the family wide error rate which is dependent on the number of arms). The type 2 
error was calculated as the number of times the effective arm was declared ineffective or no decision was 
reached by 400 patients. Appendix 3 shows how type 1 and type 2 error varies across choices of thresholds. 
The thresholds we have chosen allow us to control type 1 errors at 10% and type 2 errors at 20%.  
For these futility and success thresholds, the simulations demonstrate the number of patients randomised per 
arm in order to reach a decision is:  
 
50 patients (average; median is 30) for each efficacious intervention (effect size of 10% increase in 
viral clearance) means approximately 60 patients for an effect size of 20% increase in viral clearance, 
as per the current futility/ success threshold. However, a maximum number of 200 patients per arm 

 
 
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may be required, although further recruitment can occur after consultation with the DSMB or TSC, if 
it is felt that more precision of the result is beneficial. In the case that a stopping rule is not met before 
this number we will stop recruitment to an arm at 200 patients (excluding comparator arms e.g. 
negative and positive controls. This means more than 200 patients may be enrolled into the positive 
control at the time- i.e. more than 200 patients may be enrolled to the positive control at the time e.g 
nirmatrelvir/ritonavir (current positive control at the time of writing). 
 
 40 patients (average; median is 25) for each inactive intervention (effect size of 0). 
Therefore, supposing there were 5 interventions of type A in the platform, and assuming that only 1 of the 5 
were in fact effective, we would need on average a total of 50 + 4*40 = 210 patients randomised to 
interventions of type A (approximately 66% of the total sample size: a minimum of 20% of samples are 
randomised to the negative control and thus ~13% of patients are randomised to each intervention arm and 
the positive control arm). This implies a total of ~320 patients for the first set of interventions identified (this 
does not include any intensive PK sub-studies). 
This study is open-label and so a centralised server-based randomisation system will be used. Only designated 
study personnel will be authorised to access the webapp for patient allocation. The webapp will be password 
protected. All randomisation activities will be traced within the webapp and attributed to a timestamp along 
with the anonymised patient study code, age and sex. 
 
10.6 Sample size for the intensive PK-PD sub-study 
All drugs in the dose finding sub study and any drugs with evidence of accelerated viral clearance from other 
studies (e.g. Molnupiravir, Nirmatrelvir/ritonavir) or which meet the success endpoint (>90% probability that 
clearance is accelerated by more than 20% relative to control) will be included in an intensive PK-PD study. 
The sample size calculation for each sub-study will be drug dependent and will use the information regarding 
the variability in clearance in the intervention arm versus the variability in clearance in the control arm (i.e. it 
will be determined by the results). Larger observed variability in the intervention arm would be expected if an 
active intervention had variation in exposures that corresponded to variation around the near maximal effect 
concentration (eg EC95).  
We will use a PK simulation-based approach where we will simulate predicted drug AUC values for patients 
given the characteristics of the patients in each site (weight and sex) and use the observed variability in viral 
clearance rates to estimate the necessary sample size to infer a dose-response relationship whereby a 10% 
increase in AUC resulted in a 10% increase in the slope of viral clearance with 80% power and 5% type 1 error. 
10.7 Change to sampling schedule 
The initial sample schedule was based on simulations of data from untreated individuals in 2020. Since then 
there have been a number of new variants, new treatments and the greater knowledge of viral dynamics from 
patients randomised into the study. These results demonstrate that over time, the rate of viral clearance has 
increased and viral half-life has decreased (see Figure 8 below (32)). The result of faster clearance over time 
has been more undetectable viral loads at later timepoints between D0 and D7 i.e. D6 and D7. In addition, 
there appears to be a second slower phase to clearance, which is less affected by effective therapeutics (thus 
later timepoints can even dilute the observed antiviral effect). Updated simulations have shown that the ideal 
duration of sampling is until day 4 or 5 and we have conservatively changed the endpoint to be clearance up 
to day 5.  

 
 
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Figure 8 Clearance half-lives over time for the ineffective arms in PLATCOV showing an increased rate of clearance. 
 
10.8 Final analysis of primary outcome 
The final analysis will fit a series Bayesian hierarchical linear and non-linear models to the serial log10 viral load 
measurements (copies per mL). The primary estimates of interest are the relative changes in the rate of viral 
clearance for the intervention arms (including the positive control arm) compared to the no study drug arm. 
These will be reported as their mean posterior estimates along with credible intervals. All analyses will be 
done using R using the package rstan along with bespoke software. All analysis code is openly available via a 
GitHub repository: https://github.com/jwatowatson/PLATCOV-SAP. Anonymised viral load data and key meta 
data (e.g. site, strata, randomised allocation) will be made available at publication of results.  
 
11 DATA MANAGEMENT 
11.1 Access to Data 
Direct access will be granted to authorised representatives from the University of Oxford and any host 
institution for monitoring and/or audit of the study to ensure compliance with regulations. Outcome data and 
treatment assignment data will be made available for analysis in real time.  
 
11.2 Data Handling and Record Keeping 
Clinical study data will be recorded on CRFs and entered on to a password-protected database by the local 
study PI, research nurse or designee. The study database will be built in MACRO EDC, a clinical data 
management system that is compliant with ICH GCP and FDA 21 CFR Part 11 and will be hosted in a secure, 
access-restricted server in MORU. The study database will include internal quality checks to identify data that 
appear inconsistent, incomplete, or inaccurate. 
Measures will be taken to ensure non-disclosure of information that is potentially harmful to patients. Paper 
records (for example, patient identifiable information for the purposes of follow-up, the screening logs and 
signed ICFs) will be kept in locked cabinets; electronic data will only be accessible to personnel with user 
accounts and passwords. The database contains an audit trail that keeps record of changes to data and user 

 
 
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activity within the database. All electronic data will be stored on secure servers that are backed up daily, with 
weekly off-site storage.  
Patient records at site will, taking into account the ability of the sites, be stored in binders in the secured 
access-limited room or scanned and stored electronically. The records will be retained for at least five years 
following completion of the study, or according to local site regulation. The study database will be retained 
indefinitely. 
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). 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
The study will be conducted in accordance with relevant regulations and standard operating procedures. 
The study will be conducted in compliance with this protocol, International Conference on Harmonization 
(ICH) Guidelines for Good Clinical Practice (GCP) and any applicable regulatory requirement(s). Monitoring will 
be overseen by the MORU Clinical Trials Support Group (CTSG) according to a prespecified risk-based 
monitoring plan to ensure compliance to the study protocol and applicable guidelines and regulations. 
Biological specimens will be processed, stored and shipped in accordance with MORU SOPs. 
Data validation will be performed to identify errors or discrepancies and thus ensure completeness, validity 
and accuracy of data.  
 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in patients who would be unlikely to progress to severe illness. The investigated 
medications may benefit the patient; i.e. shorten the duration of symptoms or decrease their severity, but are 
unlikely to have a significant adverse effect on the patient’s illness and subsequent health, including when 
drugs are used in combination where there may potentially be more side effects (this is not expected) but also 
greater benefit in terms of shortening illness and decreasing severity. Assessing drug combinations may be 
important in preventing the development of drug resistance, and may be beneficial to those with a greater 
likelihood of severe illness (i.e. the wider population). No drug intervention has been shown to be 
unequivocally beneficial at this point in the illness, in this population, and clinical equipoise exists between 
the interventions and the no antiviral treatment (although local supportive treatment will be fully provided 
including antipyretics (e.g. paracetamol), anti-tussives, antihistamines, vitamins etc and any treatments 
clinically indicated by the Physician looking after the patient. Funds will be set aside to cover hospital costs in 
the unlikely event of a drug adverse reaction. 
Women who are pregnant, actively trying to become pregnant, or breast feeding will be excluded from this 
study as it is not known if any of the treatments being tested will have additional benefits that would outweigh 
any risks associated with pregnancy/breast feeding. 
 
13.1 Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the current revision of the 
Declaration of Helsinki.  
 
13.2 Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 

 
 
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13.3 Approvals 
The protocol, informed consent form and participant information sheet will be submitted to OxTREC and local 
ethics committees for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all amendments 
to the original approved documents. 
 
13.4 Patient Confidentiality 
The study personnel will ensure that the patients’ anonymity is maintained. The patients will be identified only 
by a patient ID number on all study documents and any electronic database, with the exception of the CRF, 
where patient initials may be added. The name and any other identifying detail will NOT be included in any 
study data electronic file. All documents will be stored securely and only accessible by study personnel and 
authorised personnel. The study will comply with the Data Protection Act 2018, which requires that personal 
data must not be kept as identifiable data for longer than necessary for the purposes concerned. 
 
13.5 Expenses  
Patients will be financially compensated for their time in the study, in accordance with local EC guidance and 
approval.   
 
13.6 Risk 
All of the treatments being tested initially (see Appendix 2 for study drugs) are generally well tolerated with 
the main adverse effects related to gastrointestinal symptoms (abdominal pain, diarrhoea, nausea and 
vomiting). In the case of intravenously/subcutaneously administered treatments there may be discomfort, 
bleeding or bruising of the skin at the site of needle puncture. Further information regarding specific side 
effects for each of the drugs used in the study can be found in Appendix 2. These are usually mild and settle 
without the need for medical intervention.  
The risks associated with blood withdrawal during the study include discomfort, occasional bleeding or 
bruising at the site of needle puncture, and very rarely infection. The risks associated with nose and throat 
swabbing are limited to some slight discomfort. 
The risks associated with the interaction of two study drugs during randomisation or with the combination of 
molnupiravir and nirmaterlvir/ritonavir are low. The drugs are not known to interact and participants will be 
monitored for adverse events. 
 
13.7 Benefits 
It is not yet known if any of the treatments being tested will have additional benefits for the patient in the 
management of COVID-19. Although an individual patient may not personally benefit, this study should help 
future COVID-19 patients by discovering treatments that work in early disease and ruling out those do not. 
Remuneration will be provided to the patients for the period they are enrolled in the study. Patients will be 
reimbursed for costs associated with traveling to the study site and loss of work time. The amount will be 
determined per local allowed guidelines and ethics committee policies . 
 
13.8 Reporting 
The PI shall submit an Annual Progress Report to OxTREC on the anniversary of the date of approval of the 
study. In addition, the PI shall submit an End of Study Report to OxTREC within 12 months of completion of 
the study. 

 
 
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13.9 Finance and insurance 
13.9.1 Funding: ACT- Accelerator 
This trial is funded by the COVID-19 Therapeutics Accelerator (CTA), managed with MORU through the 
Wellcome Trust. CTA is a philanthropic collaboration supporting efforts to research, develop and bring 
effective treatments against COVID-19 to market quickly and accessibly. CTA and Wellcome Trust have had no 
role in the design of this study and will not have any role during its execution, analyses, interpretation of the 
data, or decision to submit the results.  
 
13.9.2 Insurance:  
The University has a specialist insurance policy in place which would operate in the event of any patient 
suffering harm as a result of their involvement in the research (Newline Underwriting Management Ltd, at 
Lloyd’s of London).   
13.10 Data ownership 
The data generated in this study belongs to the study group as a whole. The final database will be shared 
amongst the site PI and key members of the research team.  
The database may be shared with researchers not directly involved in this study but only after the main paper 
has been published and in accordance with MORU guidelines on data sharing. The database will only be shared 
if future publications are not compromised. The criteria for authorship will be consistent with the international 
guidelines (http://www.icmje.org/#author). 
 
13.11 Publication policy 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any 
other publications arising from the study. Authors will acknowledge that the study was funded by by the 
COVID-19 Therapeutics Accelerator (CTA). Authorship will be determined in accordance with the International 
Committee of Medical Journal Editors (ICMJE) guidelines and other contributors will be acknowledged.  
The results of the study will be summarised in lay language, in both English and the language(s) commonly 
spoken at the study sites, and disseminated to key stakeholders, user communities and patients. 
 
 

 
 
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14 REFERENCES 
 
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transmissibility of COVID-19. Nat Med. 2020;26(5):672-5. 
3. 
Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, Niemeyer D, Jones TC, Vollmar P, 
Rothe C, Hoelscher M, Bleicker T, Brünink S, Schneider J, Ehmann R, Zwirglmaier K, Drosten C, Wendtner 
C. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020; 588 (7839):E35.  
May;581(7809):465-469.  
4. 
Hillen T, Contreras C, Newby JM. Personalized Virus Load Curves of SARS-CoV-2 Infection medRxiv 
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5. 
Watson JA, Kissler SM, Day NPJ, Grad YH, White NJ. Characterizing SARS-CoV-2 Viral Clearance Kinetics 
to Improve the Design of Antiviral Pharmacometric Studies. Antimicrob Agents Chemother. 
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6. 
Gastine S, Pang J, Boshier FAT 2, Carter SJ, Lonsdale DO, Cortina-Borja M, Hung IFN, Breuer J, Kloprogge 
F, Standing JF. Systematic review and patient-level meta-analysis of SARS-CoV-2 viral dynamics to model 
response to antiviral therapies. medRxiv preprint doi: https://doi.org/10.1101/2020.08.20.20178699 
7. 
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 
2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 323(11):1061-1069. 
8. 
RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, 
Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell 
LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. 
Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020 
NEJMoa2021436. doi: 10.1056/NEJMoa2021436. 
9. 
Abani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, et al. Casirivimab and imdevimab in patients 
admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. 
The Lancet. 2022;399(10325):665-76. 
10. Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGN-COV2, a Neutralizing 
Antibody Cocktail, in Outpatients with Covid-19. New England Journal of Medicine. 2020;384(3):238-51. 
11. Néant N, Lingas G, Le Hingrat Q, Ghosn J, Engelmann I, Lepiller Q, Gaymard A, Ferré V, Hartard C, Plantier 
JC, Thibault V, Marlet J, Montes B, Bouiller K, Lescure FX, Timsit JF, Faure E, Poissy J, Chidiac C, Raffi F, 
Kimmoun A, Etienne M, Richard JC, Tattevin P, Garot D, Le Moing V, Bachelet D, Tardivon C, Duval X, 
Yazdanpanah Y, Mentré F, Laouénan C, Visseaux B, Guedj J; French COVID Cohort Investigators and 
French Cohort Study groups. Modeling SARS-CoV-2 viral kinetics and association with mortality in 
hospitalized patients from the French COVID cohort. Proc Natl Acad Sci U S A. 2021 Feb 
23;118(8):e2017962118. doi:10.1073/pnas.2017962118. PMID: 33536313. 
12. Boschi C, Colson P, Bancod A, Moal V, La Scola B. Omicron Variant Escapes Therapeutic Monoclonal 
Antibodies (mAbs) Including Recently Released Evusheld®, Contrary to 8 Prior Main Variant of Concern 
(VOC). Clinical Infectious Diseases. 2022. 
13. Zhou H, Tada T, Dcosta BM, Landau NR. Neutralization of SARS-CoV-2 Omicron BA. 2 by therapeutic 
monoclonal antibodies. Biorxiv. 2022. 
14. Hill A, Khoo S, Boffito M, Back D. Should we switch to a 50-mg boosting dose of ritonavir for selected 
protease inhibitors? J Acquir Immune Defic Syndr. 2011;58(5):e137-8. 
15. Singh RSP, Toussi SS, Hackman F, Chan PL, Rao R, Allen R, et al. Innovative Randomized Phase I Study and 
Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir. Clin 
Pharmacol Ther. 2022;112(1):101-11. 
16. Butler CC, Hobbs FR, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus usual 
care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse 
outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. The Lancet. 
2023;401(10373):281-93. 

 
 
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17. Raveendran A, Jayadevan R, Sashidharan S. Long COVID: an overview. Diabetes & Metabolic Syndrome: 
Clinical Research & Reviews. 2021;15(3):869-75. 
18. Kissler SM, Fauver JR, Mack C, Tai C, Shiue KY, Kalinich CC, et al. Viral dynamics of SARS-CoV-2 infection 
and the predictive value of repeat testing. medRxiv. 2020:2020.10.21.20217042. 
19. Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero A, Ruiz-Castillo P, et al. The 
effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with 
non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. 
EClinicalMedicine. 100720. doi: 10.1016/j.eclinm.2020.100720. 
20. Pekosz A, Parvu V, Li M, Andrews JC, Manabe YC, Kodsi S, Gary DS, Roger-Dalbert C, Leitch J, Cooper CK. 
Antigen-Based Testing but Not Real-Time Polymerase Chain Reaction Correlates With Severe Acute 
Respiratory Syndrome Coronavirus 2 Viral Culture. Clin Infect Dis. 2021 Jan 20: ciaa1706. doi: 
10.1093/cid/ciaa1706. Epub ahead of print. PMID: 33479756. 
21. Kohmer N, Toptan T, Pallas C, Karaca O, Pfeiffer A, Westhaus S, Widera M, Berger A, Hoehl S, Kammel M, 
Ciesek S, Rabenau HF. The Comparative Clinical Performance of Four SARS-CoV-2 Rapid Antigen Tests and 
Their Correlation to Infectivity In Vitro. J Clin Med. 2021;10(2):E328. doi: 10.3390/jcm10020328. PMID: 
33477365. 
22. Rastawicki W, Gierczyński R, Juszczyk G, Mitura K, Henry BM. Evaluation of PCL rapid point of care antigen 
test for detection of SARS-CoV-2 in nasopharyngeal swabs. J Med Virol. 2021 Jan 6. doi: 
10.1002/jmv.26765.  
23. To KK, Tsang OT, Leung WS, Tam AR, Wu TC, Lung DC, et al. Temporal profiles of viral load in posterior 
oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an 
observational cohort study. Lancet Infect Dis. 2020;20(5):565-74. 
24. Sri Santosh T, Parmar R, Anand H, Srikanth K, Saritha M. A Review of Salivary Diagnostics and Its Potential 
Implication in Detection of Covid-19. Cureus. 2020;12(4):e7708. 
25. Williams E, Bond K, Zhang B, Putland M, Williamson DA. Saliva as a Noninvasive Specimen for Detection 
of SARS-CoV-2. J Clin Microbiol. 2020;58(8). 
26. Thompson MG, Ferber JR, Odouli R, David D, Shifflett P, Meece JK, et al. Results of a pilot study using self-
collected mid-turbinate nasal swabs for detection of influenza virus infection among pregnant women. 
Influenza Other Respir Viruses. 2015;9(3):155-60.  
27. van Wesenbeeck L, Meeuws H, D'Haese D, Ispas G, Houspie L, Van Ranst M, et al. Sampling variability 
between two mid-turbinate swabs of the same patient has implications for influenza viral load 
monitoring. Virol J. 2014;11:233. 
28. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel 
coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25(3). 
29. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for 
Patients with Severe Covid-19. N Engl J Med. 2020;382(24):2327-36. 
30. Piralla A, Daleno C, Pariani E, Conaldi P, Esposito S, Zanetti A, et al. Virtual quantification of influenza A 
virus load by real-time RT-PCR. J Clin Virol. 2013;56(1):65-8. 
31. Kaulbach HC, White MV, Igarashi Y, Hahn BK, Kaliner MA. Estimation of nasal epithelial lining fluid using 
urea as a marker. J Allergy Clin Immunol. 1993;92(3):457-65. 
32. Wongnak P, Schilling WH, Jittamala P et al. Temporal changes in SARS-CoV-2 clearance kinetics and the 
optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a 
randomised, controlled, adaptive platform study (PLATCOV). The Lancet Infectious Diseases. 2024 Apr 
24.  

 
 
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Appendices 
15 Appendix 1: Schedule of activities  
 
Procedures 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D14 
D28 
(-2/ +7) 
 
D120 
(-10/+30) 
If new Tx/ 
symptoms  
Pre-
1st 
dose 
H0 
H1 
H6-
18 
Screening incl. 
Lateral 
Flow 
Ag test and 
urine 
pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
information 
captured (inc 
symptoms, 
physical exam,  
ECG 
(optional)) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
Symptom 
checklist 
 
 
X1 
 
X  
X  
X  
X  
X  
X 
X  
X  
X  
 
 
Observed dose 
 
X1 
 
 
X1 
X1 
X1 
X1 
X1 
X1 
 
 
 
 
 
Observation 
post dose 
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature*  
 
 
X 
 
X  
X  
X  
X  
X  
X  
X  
X  
   
 
 
C19 YRSm 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Virology  
Oropharyngeal 
swabs**  
X  
X  
 
X*** 
X  
X  
X  
X  
X  
 
X  
 X 
   
 
X 
Possible extra 
swabs 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Bloods  
FBC+diff  
 X2 
  
 
 
   
   
 X  
   
   
  
X  
X 
   
 
 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 42 of 74 
Biochemistry 
(including 
U&Es, 
LFTs 
LDH)  
X2 
  
 
 
   
  
X  
   
   
  
X  
X 
   
 
 
Fibrinogen/ 
FDP  
 X  
  
 
 
   
   
 X  
   
   
  
X  
X 
   
 
 
Ferritin  
 X  
  
 
 
   
   
 X  
   
   
  
X  
X 
   
 
 
TNF/IL-6/IL-1  
 X  
  
 
 
   
   
 X  
   
   
  
X  
X 
   
 
 
Serology 
and 
stored sample 
X   
  
 
 
   
   
 X  
   
   
  
X  
X 
   
 
 
Drug level  
X  
  
 
 
  
  
X  
  
  
  
X  
X 
  
 
 
Host 
genotyping 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
* Performed at least twice a day. For those taking drugs which are more than once per day, the patient will also 
record the time the dose was taken for any non-observed doses. 
** Taken in duplicate at least once a day, up to twice per day, either by the study team or as a self-swab. Time 
swab done recorded. Some patients may be asked to give a saliva sample as well (see section 7.1) 
***May be taken by the study personnel or self-swabbing, 6-18 hours after H0. 
X1Depends on dosing schedule of the drug (see appendix 2). The first dose will be given at the designated trial 
facility. For drugs where further doses are required, at least one dose per day will be observed by the study team. 
The time the drug is taken will be recorded by the study team. 
X2 Results will be used to detect laboratory abnormalities included in the exclusion criteria (see appendix 4 
exclusion criteria) 
The final column, If new Tx/symptoms, refers to if the treatment is changed while the patient is within the 1st 7 
days of the study, or if new symptoms develop between day 7 and day 28 (see section 7.8 Management of patients 
who become ill). 
Note: PK sampling schedules for determination of antiviral drug level are mentioned in Appendix 2. 
 

 
 
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16 Appendix 2: Study drugs  
The maximum duration of treatment is 7 days so many of the toxicity concerns related to chronic dosing are 
not relevant to this short course treatment 
 
 

 
 
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16.1 Nitazoxanide 
Rationale 
Nitazoxanide is a broad-spectrum antiprotozoal and antiviral drug first discovered in the 1980s. It has an 
excellent safety profile, the only contraindication to nitazoxanide being a hypersensitivity reaction to 
nitazoxanide. Nitazoxanide has demonstrated broad-spectrum in vitro antiviral activity including against SARS-
CoV-2. There are also reports from trials suggesting benefit and given the low cost, safety, tolerability and 
availability of this drug, it would be an attractive candidate in the prevention and treatment of COVID-19, if 
shown to have benefit in this illness. Nitazoxanide has in vitro activity against the novel coronavirus SARS-CoV-
2, which causes coronavirus disease (COVID-19). The EC50 on Vero E6 cells (the concentration to decrease the 
cytopathic effect of the virus by 50%) was reportedly 2.12µM (1). Nitazoxanide has a molar mass of 
307.283g/mmol, and as such 2.12µM corresponds to a concentration of 0.65mg/L.  
Although the above study on SARS-CoV-2 used nitazoxanide, the active metabolite tizoxanide inhibits 
influenza, respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, 
dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in vitro (2). Nitazoxanide 
was able to protect 90% of mice from death in a lethal challenge model of Japanese Encephalitis (3). The exact 
mechanism by which nitazoxanide exhibits its antiviral effects are uncertain, but augmented host responses 
as opposed to direct antiviral effects are postulated. Nitazoxanide is able to increase interferon responses in 
HCV/HIV coinfected individuals (4). 
A double-blind randomised placebo-controlled trial of nitazoxanide in acute uncomplicated influenza found a 
significant reduction in duration of symptoms in the 600mg BD nitazoxanide group, but not the 300mg BD one 
(5). Additionally, viral titres were significantly decreased in the 600mg BD nitazoxanide group. Another study 
using the same doses in cases of severe respiratory infection caused by all respiratory viruses, did not show 
an effect (6). Nitazoxanide is being assessed in clinical trials in COVID-19, and published results suggest an 
increased time to viral clearance, although this result may be confounded by differences in initial viral loads 
(7). 
Composition & dose 
One 
tablet 
of 
nitazoxanide 
as 
ALINIA® 
tablets 
contain 
500 
mg 
of 
nitazoxanide 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021497s001,021498s004lbl.pdf). 
Nitazoxanide will either be obtained by the sponsor or the local teams from a reliable manufacturer.  
High dose nitazoxanide is given as 1.5 g bd.  
The dose in this trial is: 1.5g PO twice daily for 7 days (taken with food). 
Pharmacokinetic characteristics 
Following oral administration of nitazoxanide, the drug is rapidly hydrolysed to its active constituent, 
tizoxanide, and then conjugated to produce active tizoxanide glucuronide; nitazoxanide is not detected in 
plasma and > 99% of tizoxanide is 
bound 
to 
proteins. 
The 
bioavailabilities of tizoxanide and 
tizoxanide 
glucuronide 
are 
increased 2-fold with food. The 
mean Tmax of tizoxanide, is 2.5h 
with a half-life of 1 to 2h (8).  The 
mean Tmax of the tizoxanide 
glucuronide is 4 to 6h. A dose of 
1g 
PO 
BD 
of 
nitazoxanide 
produces a Cmax of 24mg/ml of 
tizoxanide 
and 
26.4mg/ml 

 
 
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tizoxanide glucuronide and the half-lives increase to 6.4 and 3.5 hours, respectively. Tizoxanide is excreted in 
the urine, bile and faeces, and tizoxanide glucuronide is excreted in urine and bile (its concentration is x10 
that of plasma).  
Pharmacokinetic sampling schedule: (only if there is evidence of accelerated viral clearance) 
All patients will need to be admitted for 12 hours for intense sampling. The timings may be the following but 
the number and timing are subject to change:  
Pre-dose D0H0, then 
1, 2, 3, 4, 6, 9, 12 and 24h 
Note that blood will be taken on D3 and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations.      
Toxicity  
Nitazoxanide is a safe and well-tolerated drug. Reported toxicities include: 
Gastrointestinal disorders: diarrhoea, gastroesophageal reflux disease  
Nervous System disorders: dizziness  
Respiratory, thoracic and mediastinal disorders: dyspnoea  
Skin and subcutaneous tissue disorders: rash, urticaria  
Risks related to nitazoxanide are very low. This is a very safe and generally well tolerated medication but 
adverse reactions relating to the central nervous system (headache and rare reports of dizziness), the 
gastrointestinal system (abdominal pain and nausea and rare reports of diarrhoea and gastro-oesophageal 
reflux), and genitourinary system (urine discolouration) have been described as well as post-marketing cases 
of dyspnoea, skin rash and urticaria. In one study, side effects of nitazoxanide did not differ from those of the 
placebo when used for the treatment of giardiasis, and does not cause side effects when used in healthy adults  
(9). This lack of significant side-effects is seen in doses up to 4g in humans. The LD50 of various animals is 
10g/Kg. A study of 365 patients with AIDS receiving nitazoxanide 500-1500mg twice daily for a median 
duration of 62 days (1-1528 days) concluded that “No safety issues were identified at doses up to 3000 mg/day 
or for long durations of treatment” (10). These risks will be mitigated by excluding participation if people have 
had a previous serious adverse reaction to nitazoxanide.  
Nitazoxanide may be used after the first trimester of pregnancy with severe symptoms of cryptosporidiosis. 
Adverse events have not been observed in animal reproduction studies although human data are not available. 
It is not known whether nitazoxanide enters into breast milk, and the manufacturer suggests balancing risk of 
exposure to the infant and benefit to the mother. We will exclude pregnant women and women breastfeeding 
from this study and ask female patients of child-bearing age to undergo a pregnancy test and take precautions 
not to become pregnant (contraception). Those who do become pregnant will be followed up. However, given 
the lack of evidence of harmful effects and its use later in pregnancy, the risk to a foetus seems low. The 
mitigating factors of a pregnancy test and advising contraception will make the likelihood of pregnancy within 
the trial and potential risk, even lower. 
Contraindications and cautions 
Known hypersensitivity. The Pharmacokinetics of nitazoxanide in patients with compromised renal or hepatic 
function have not been studied. 
Relevant Drug interactions 
None 
 

 
 
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Acute Respiratory Illness. Clin Infect Dis. 2019;69(11):1903-11. 
7. Rocco PRM, Silva PL, Cruz FF, Junior M, Tierno P, Moura MA, et al. Early use of nitazoxanide in mild 
Covid-19 disease: randomised, placebo-controlled trial. Eur Respir J. 2021. Jan 14:2003725. doi: 
10.1183/13993003.03725-2020.  
8. Stockis A, Deroubaix X, Lins R, Jeanbaptiste B, Calderon P, Rossignol JF. Pharmacokinetics of 
nitazoxanide after single oral dose administration in 6 healthy volunteers. Int J Clin Pharmacol Ther. 
1996;34(8):349-51. 
9. Stockis A, Allemon AM, De Bruyn S, Gengler C. Nitazoxanide pharmacokinetics and tolerability in man 
using single ascending oral doses. Int J Clin Pharmacol Ther. 2002;40(5):213-20. 
10. Rossignol JF. Nitazoxanide in the treatment of acquired immune deficiency syndrome-related 
cryptosporidiosis: results of the United States compassionate use program in 365 patients. Aliment 
Pharmacol Ther. 2006;24(5):887-94. 
 
 
 
 
 
 
 
 
 
 
 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 47 of 74 
16.2 Nirmatrelvir/ritonavir (e.g. PAXLOVID™) 
Rationale 
PAXLOVID™ is a therapeutic combination of 2 compounds, Nirmatrelvir and ritonavir, taken at the same time 
as separate pills. Nirmatrelvir (PF-07321332) is an oral covalent 3CL protease inhibitor of SARS-CoV-2 and 
ritonavir is an inhibitor of HIV-1 and HIV-2 protease. Ritonavir inhibits cytochrome P450A and CYP2D6 which 
inhibits the metabolism of nirmatrelvir. 
Coronoviruses contain two proteases, main protease – Mpro (also known as 3CL protease – 3CLpro) and 
papain-like protease. Pfizer developed a SARS-CoV Mpro inhibitor in 2002 (PF-00835231) which demonstrated 
in vitro and in vivo activity against  SARS-CoV-2 (1). Other studies also found successful in vitro inhibition of 
SARS-CoV-2 replication in derived alveolar basal epithelial cells expressing ACE2 (2) and human bronchial 
epithelial cells (3). This compound had insufficient bioavailability so the oral version PF-07321332 was 
developed (4). 
A Phase 2/3 EPIC-HR randomised double blind control trial from Pfizer looked at non-hospitalised patients at 
risk of progressing to severe illness. Intervention was ritonavir and nirmatrelvir started within three or five 
days of symptom onset. Primary endpoint was COVID-19-related hospitalisation or all cause death up to day 
28.  For those receiving PAXLOVID™ within 3 days, 3/389 (0.7%) were hospitalised with zero deaths., compared 
to the placebo 27/385 hospitalised with 7 deaths, p<0.0001. For treatment within 5 days, 6/607 (6.7%) were 
hospitalised with no deaths, compared to 41/612 (with 10 deaths) in the placebo group (p<0.0001) (5). 
Composition & dose 
Administered as 300MG of nirmatrelvir (two 150MG tablets) with one 100 MG tablet of ritonavir given twice 
daily for 5 days. 
Nirmatrelvir/ritonavir will either be obtained by the sponsor or the local teams from a reliable manufacturer 
(including high-quality generics manufacturers).  
Pharmacokinetic characteristics 
Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic 
concentrations and longer half-life of nirmatrelvir. This supports a twice daily administration.  Nirmatrelvir 
(when given with ritonavir) is eliminated renally, with a half-life of 6.05 hours, peak concentration is at 3 hours.  
Ritonavir is metabolised in the liver, with a half-life of 6.15 hours, peak concentration is at 3.98 hours. 
Pharmacokinetic sampling schedule:  
The timings may be the following but the number and timing are subject to change: 
Pre-dose D0H0, then 
1, 2, 3, 4, 6, 9, 12 and 24h post dose 
Note that blood will be taken on D3 and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations. 
Toxicity 
Repeat-dose toxicity studies up to 1 month duration of nirmatrelvir in rats and monkeys resulted in 
no adverse findings. Ritonavir can cause retinal toxicity with long term use (6), although this is not relevant for 
the short-term use in the study. Ritonavir alone does not cause any issues related to HIV drug-resistance.  
Contraindications 
In our study, nirmatrelvir/ritonavir is contraindicated in:  

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 48 of 74 
hypersensitivity to nirmatrelvir/ritonavir or any of its ingredients, including ritonavir. 
co-administration with drugs highly dependent on CYP4503 A. 
co-administration with potent CYP450 3A inducers 
More details regarding concomitant medication can be found at: 
https://www.covid19-druginteractions.org/checker 
https://crediblemeds.org/ 
https://compendium.ch/fr/Patient - this is a Swiss website dealing with drug interactions 
https://www.bnf.org/products/bnf-online/ - available only in the UK 
Cautions 
Caution should be given in patients with pre-existing liver disease/hepatitis or live enzyme abnormalities.  
Dose reduction for renal impairment (eGFR ≥ 30 to <60 mL/min) is 150MG nirmatrelvir and 100 MG ritonavir. 
Drug Interactions 
Contraindicated with drugs that are highly dependent on CYP3A for clearance or are potent CYP3A inducers 
(see above). There are no theoretical drug interactions in combination molnupiravir. 
References 
1.   Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, et al. Discovery of a novel 
inhibitor of coronavirus 3CL protease as a clinical candidate for the potential treatment of COVID-19. 
BioRxiv. 2021:2020.09. 12.293498. 
2.  de Vries M, Mohamed AS, Prescott RA, Valero-Jimenez AM, Desvignes L, O’Connor R, et al. A 
comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a 
potential new treatment for COVID-19. Journal of Virology. 2021;95(10):e01819-20. 
3.  Barilli A, Visigalli R, Ferrari F, Di Lascia M, Riccardi B, Puccini P, et al. Organic Cation Transporters (OCTs) 
in EpiAirway™, a Cellular Model of Normal Human Bronchial Epithelium. Biomedicines. 2020;8(5):127. 
4.  Owen DR, Allerton CM, Anderson AS, Aschenbrenner L, Avery M, Berritt S, et al. An oral SARS-CoV-2 
Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021:eabl4784. 
5. Mahase E. Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company 
reports. British Medical Journal Publishing Group; 2021. 
6.  Tu Y, Poblete RJ, Freilich BD, Zarbin MA, Bhagat N. Retinal toxicity with ritonavir. International journal 
of ophthalmology. 2016;9(4):640. 
 
 
 
 
 
 
 
 
 
 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 49 of 74 
16.3 Nirmatrelvir/ritonavir (e.g. PAXLOVID™) dose finding 
Rationale 
Finding the optimal dose of Ritonavir to boost Nirmatrelvir to the levels required for a significant clinically 
beneficial effect, while balancing the side-effects of Ritonavir-induced dysgeusia and drug-drug interactions, 
could increase the number of patients able to access Nirmaltrelvir.   
Nirmatrelvir/Ritonavir (e.g. PAXLOVID™) is one of the two main licensed treatments for COVID-19. The other 
is molnupiravir. PAXLOVID™ is licensed in numerous countries across the world. Despite clinical efficacy 
demonstrated in the pre-registration phase III studies (1), and it being widely considered the most effective 
COVID-19 medication, several important drawbacks prevent its widespread use. Amongst these are drug-drug 
interactions from the Ritonavir component, which prevents many of the highest risk individuals most at need 
from accessing the medication (2). Additionally, a bad taste, or dysgeusia, from Ritonavir affects patient uptake 
and reduces adherence.  
Other important limitations include the high cost (c.$500/ course) and concern regarding viral rebound. More 
recently, in a vaccinated population of normal and high-risk patients, PAXLOVID™ did not demonstrate clinical 
efficacy over placebo, reflecting most likely the overall reduction of severe outcomes in COVID-19 in an 
increasingly immune population. Despite this, recent modelling suggests that increased use of PAXLOVID in 
the USA could avert large numbers of hospitalisations and save $57billion USD even in low COVID-19 
transmission scenarios. Thus, addressing barriers to uptake of antivirals against COVID-19 has health and 
economic benefits to societies as a whole (3). 
In the urgent context of the pandemic, the dose of Ritonavir chosen to boost the Nirmatrelvir was the upper 
end of the range used to boost other protease inhibitors (e.g. HIV)- 100mg BD. This made sense- guaranteeing 
maximal boosting and Nirmatrelvir levels, but dose-finding studies with lower dose Ritonavir were not 
conducted. We do not know if the maximal boosting effect could have been achieved with less, or whether 
the antiviral benefit could be achieved without Ritonavir. Many protease inhibitors are boosted equally well 
at lower doses of Ritonavir than 100mg BD e.g., saquinavir, fosamprenivir and darunavir are boosted equally 
well with a dose as little as 50mg/day (4). A phase I study in healthy volunteers did show rapid elimination, 
and low peak levels of Nirmatrelvir given without Ritonavir, although without a pharmacodynamic measure 
of efficacy. At a dose of 150mg (half the current dose of Nirmatrelvir used in PAXLOVID, the drug levels surpass 
the EC90 for several hours, which suggests that the drug will have some efficacy (see below figure) (5). 
Additionally, the well-established down-regulation of CYP3A enzymes with inflammation and infection (thus 
potentially meaning higher levels) means healthy volunteer studies may underestimate drug levels of CYP3A 
excreted drugs (6). 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 50 of 74 
 
Figure 2 Median plasma Nirmatrelvir concentration-time profiles (semi-logscales) for single-ascending dose 
and supratherapeutic exposure cohorts 
By determining the dose-response relationship of the Nirmatrelvir, regimens could be suggested which 
additionally reduce the dose of Nirmatrelvir, thereby decreasing the cost and allowing better access in poorer 
nations, or longer courses which may prevent rebound. The arrival of generic PAXLOVID through the Medicines 
Patents Pool (MPP) could hasten this reduction in cost. 
Composition & dose 
Patients will be randomised to PAXLOVID or a high-quality generic version in the following doses: 
 
Nirmatrelvir 300mg + Ritonavir 100mg twice daily for 5 days 
 
Nirmatrelvir 300mg + Ritonavir 50mg twice daily for 5 days 
 
Nirmatrelvir 150mg + Ritonavir 50mg twice daily for 5 days 
 
Nirmatrelvir 300mg alone twice daily for 5 days 
Nirmatrelvir/Ritonavir will either be obtained by the sponsor or the local teams from a reliable manufacturer 
(including high-quality generics manufacturers).  
Pharmacokinetic characteristics 
Ritonavir is administered with Nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic 
concentrations and longer half-life of Nirmatrelvir. This supports a twice daily administration.  Nirmatrelvir 
(when given with Ritonavir) is eliminated renally, with a half-life of 6.05 hours, peak concentration is at 3 
hours. Ritonavir is metabolised in the liver, with a half-life of 6.15 hours, peak concentration is at 3.98 hours. 
Pharmacokinetic sampling schedule 
The timings may be the following but the number and timing are subject to change: 
Pre-dose D0H0 
1, 2, 3, 4, 6, 9, 12 and 24h post dose. 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 51 of 74 
Note that blood will be taken on D3 and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations. 
Safety and toxicity 
PAXLOVID at a dose of 300mg Nirmatrelvir and 100mg Ritonavir BD has a well-established safety profile and 
has been given to more than 500 patients in PLATCOV alone. Reductions in the Nirmatrelvir or Ritonavir would 
be unlikely to worsen the existing safety profile. We are not using any doses higher than those currently 
licensed. Repeat-dose toxicity studies up to 1 month duration of Nirmatrelvir in rats and monkeys resulted in 
no adverse findings. Ritonavir can cause retinal toxicity with long term use, although this is not relevant for 
the short-term use in the study. Ritonavir alone does not cause any issues related to HIV drug-resistance.  
Contraindications 
In our study, Nirmatrelvir/Ritonavir is contraindicated in:  
hypersensitivity to Nirmatrelvir/Ritonavir or any of its ingredients, including Ritonavir. 
co-administration with drugs highly dependent on CYP4503 A. 
co-administration with potent CYP450 3A inducers 
More details regarding concomitant medication can be found at: 
https://www.covid19-druginteractions.org/checker 
https://crediblemeds.org/ 
https://compendium.ch/fr/Patient - this is a Swiss website dealing with drug interactions 
https://www.bnf.org/products/bnf-online/ - available only in the UK 
Cautions 
Caution should be given in patients with pre-existing liver disease/hepatitis or live enzyme abnormalities.  
Dose reduction for renal impairment (eGFR ≥ 30 to <60 mL/min) is 150MG Nirmatrelvir and 100 MG Ritonavir. 
Drug Interactions 
Contraindicated with drugs that are highly dependent on CYP3A for clearance or are potent CYP3A inducers 
(see above). There are no theoretical drug interactions in combination molnupiravir. 
References 
1. Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. Oral Nirmatrelvir for 
High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-408. 
2. Committee 
NC-TG. 
COVID-19 
Treatment 
Guidelines 
2024 
[Available 
from: 
https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-
products/ritonavir-boosted-nirmatrelvir--paxlovid-/paxlovid-drug-drug-interactions/. 
3. Bai Y, Du Z, Wang L, Lau EHY, Fung IC, Holme P, et al. Public Health Impact of Paxlovid as Treatment 
for COVID-19, United States. Emerg Infect Dis. 2024;30(2):262-9. 
4. Hill A, Khoo S, Boffito M, Back D. Should we switch to a 50-mg boosting dose of ritonavir for selected 
protease inhibitors? J Acquir Immune Defic Syndr. 2011;58(5):e137-8. 
5. Singh RSP, Toussi SS, Hackman F, Chan PL, Rao R, Allen R, et al. Innovative Randomized Phase I Study 
and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir. Clin 
Pharmacol Ther. 2022;112(1):101-11. 
6. de Jong LM, Jiskoot W, Swen JJ, Manson ML. Distinct Effects of Inflammation on Cytochrome P450 
Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for 
Pharmacogenetics. Genes (Basel). 2020;11(12). 

 
 
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16.4 Hydroxychloroquine 
Rationale 
Although hydroxychloroquine and chloroquine have shown anti-SARS-CoV-2 activity in vitro (1-4), 
hydroxychloroquine in hospitalised patients did not result in clinical benefit in two large randomised controlled 
trials (5,6). Although this is strong evidence that it is ineffective in late stage disease, the evidence earlier in 
the disease process is equivocal including in early treatment. Meta-analysis of RCTs in pre-exposure 
prophylaxis is in the direction of benefit. There is therefore substantial uncertainty whether 
hydroxychloroquine has significant antiviral activity against SARS-CoV-2 in humans, and importantly for new 
pandemics, when vaccines and treatments may not be available. 
 
Composition and dose 
The 
reference 
form 
of 
hydroxychloroquine 
is 
the 
Sanofi 
product, 
Plaquenil® 
(https://www.medicines.org.uk/emc/product/1764/smpc). 
Hydroxychloroquine will either be obtained by the sponsor or the local teams from a reliable manufacturer.  
One tablet of hydroxychloroquine sulphate contains 200 mg of hydroxychloroquine sulphate which is 
equivalent to 155 mg hydroxychloroquine base. Hydroxychloroquine will be given for 7 days. 
The dosing schedule of hydroxychloroquine is: 
Day 0 
2 tablets at time 0 
2 tablets 12 hours later, then 
Days 1 – 6 
2 tablets per day 
That is a total of 800 mg of hydroxychloroquine sulphate (salt) on the first day of treatment and 400 mg of 
hydroxychloroquine sulphate as a maintenance dose. The doses will be given with food to reduce gastric upset. 
Pharmacokinetic characteristics 
Hydroxychloroquine is generally well-absorbed, reaches a Cmax at a mean of ~2-3 hours, and following 
distribution and a multiexponential disposition profile, has a long terminal elimination half-life of ~54 days (5). 
The disposition of hydroxychloroquine in healthy volunteers is shown in Figure 3 (6).  
Pharmacokinetic sampling schedule: (only if there is evidence of accelerated viral clearance) 
All patients will need to be admitted for 12 hours for intense venous blood sampling around the loading dose.  
The timings may be the following but the number and timing are subject to change: 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 53 of 74 
Pre-dose D0H0, then 
1, 2, 3, 4, 6, 9, 12 and 24h post dose 
Note that blood will be taken on D3 and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations.  
 
Toxicity  
Studies recruiting 2,795 participants using hydroxychloroquine in COVID-19 have confirmed the safety of this 
drug (7). Hydroxychloroquine is well-tolerated and has been used for many years to treat patients with 
rheumatological diseases. The toxicity associated with long term use e.g. retinal disease, myopathy is not seen 
with short term use. 
The most common side effects include dyspepsia, nausea, vomiting, headache and blurred vision; the latter is 
dose related and usually transient but patients should be warned about driving and operating machinery. 
Postural hypotension may occur in patients with a fever. 
Cardiac toxicity 
Hydroxychloroquine (and chloroquine) cause dose related QRS and QT prolongation but these are only 
clinically important in: 
Overdose (4) 
those with pre-existing QT prolongation 
patients with QT prolonging diseases e.g. myxoedema, ischaemic heart disease, hypokalaemia 
patients on QT prolonging drugs. 
The large randomised controlled trials in COVID-19 (RECOVERY and SOLIDARITY) did not find an excess of 
arrhythmias in patients receiving high dose hydroxychloroquine. 
More details regarding concomitant medication can be found at: 
https://www.bnf.org/products/bnf-online/ - available in the UK 
https://www.uptodate.com/drug-interactions/?source=responsive_home#di-druglist – this requires a 
subscription 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 54 of 74 
https://compendium.ch/fr/Patient - A Swiss website which deals with drug interactions 
https://crediblemeds.org/ 
Skin  
These include: 
exacerbation of psoriasis (case reports) 
acute generalised exanthematous pustulosis (AGEP) that may be associated with fever and neutrophilia and 
resolves with discontinuation of the offending drug 
itching / prickly sensation that is more common in dark skinned individuals 
Contraindications 
In our study, hydroxychloroquine is contraindicated in:  
those with known hypersensitivity to hydroxychloroquine or other 4-aminoquinolines (e.g. amodiaquine) 
patients with pre-existing retinopathy of the eye  
severe liver disease, severe renal disease, epilepsy, porphyria and myasthenia gravis are relative 
contraindications but such patients would not be enrolled in this trial 
Cautions 
Long term use of hydroxychloroquine has caused hypoglycaemia in type II diabetes. Diabetic individuals will 
not be recruited. 
Patients with a history of unexplained syncope and/ or family history of sudden unexplained cardiac death, 
should have an ECG is performed and should be enrolled only if the Bazett QTc <430 ms in males and <450 ms 
in females. 
We will conduct ECGs in all patients randomised into the hydroxychloroquine arm and exclude those if the 
Bazett QTc <430 ms in males and <450 ms in females. Relevant drug interactions 
Antacids may reduce absorption of hydroxychloroquine so it is advised that a 4-hour interval be observed 
between hydroxychloroquine sulphate and antacid dosing 
References 
1. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of 
chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. 
2. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized 
Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020. 
 
3. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the 
recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. 
4. White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and 
treatment: A critical analysis of chloroquine andhydroxychloroquine clinical pharmacology. PLoS Med 
2020; 17: e1003252. 
5. RECOVERY group, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, et al. Effect of Hydroxychloroquine 
in Hospitalized Patients with Covid-19. N Engl J Med. 2020;383(21):2030-40. 
6. Consortium WHO Solidarity Trial, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, 
et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 
2020; 384(6):497-511. 
7. Sarah M Lofgren, Melanie R Nicol, Ananta S Bangdiwala, Katelyn A Pastick, Elizabeth C Okafor, et al., 
Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19, Open Forum 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 55 of 74 
Infectious 
Diseases, 
Volume 
7, 
Issue 
11, 
November 
2020, 
ofaa500, https://doi.org/10.1093/ofid/ofaa500 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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16.5 Atilotrelvir/ritonavir 
Rationale 
Atilotrelvir (GST-HG171) is an oral covalent 3CL protease inhibitor of SARS-CoV-2. It is taken with Ritonavir, a 
protease inhibitor that inhibits cytochrome P450A and CYP2D6. This in turn inhibits the metabolism of 
atilotrelvir allowing a longer half-life. 
Atilotrelvir has broad-spectrum activity against the variants of SARS-CoV-2, including Beta, Delta, Omicron 
B.1.1.529, Omicron BA.4, BA.5 variants. For wild type the IC50 was 3.0. In an invitro head-to-head comparison 
with Nirmatrelvir, atilotrelvir was found to have 5-10 fold higher potency in a cytopathic effect assay (1). 
H11-k18-hACE2 mice were challenged intra-nasally with wildtype SARS-CoV-2 virus, and treated with 
atilotrelvir, Nirmatrelvir or a control. Atilotrelvir reduced the viral copies of the three genes (ORF1ab, N gene 
and S gene) for 1.7, 2.1, and 1.3 log more than Nirmatrelvir (1). 
A phase 1 study was performed in 78 enrolled subjects. The drug was well tolerated, with no reports of serious 
adverse events (SAEs) or AEs that led to withdrawal after dosing. There were 5 drug related grade 2 AEs 
(consisting of hypertriglyceridemia, low white blood cell count and hypoglycaemia). A dose of 150MG 
atilotrelvir and 100MG Ritonavir BD was chosen based on the population PK modelling (2). 
A randomised, double-blind, placebo-controlled phase 2/3 trial was carried out in China. The trial included 
adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Participants were randomised 
1:1 to receive atilotrelvir (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 
days. Primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days. Clinical 
recovery was defined as a score of 0 out of 11 COVID-19 related symptoms for at least 2 consecutive days. 
Patients who received atilotrelvir showed shortened median time to sustained recovery of clinical symptoms 
compared to the placebo group (13 days vs 15 days P = 0.031). There was a significant difference in LS mean 
change in SARS-CoV-2 viral load from baseline to day 4. Adverse event incidence was similar in both groups, 
there was one SAE in the atilotrelvir arm and two in the placebo arm (3). 
Composition & dose 
The dose is –  150mg atilotrelvir plus 100mg Ritonavir – both taken twice a day for 5 days. 
Pharmacokinetic sampling schedule 
The timings may be the following but the number and timing are subject to change: 
Pre-dose D0H0 
1, 2, 3, 4, 6, 9, 12 and 24h post dose. 
Note that blood will be taken on D3 and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations. 
Pharmacokinetic characteristics 
Half-life of atilotrelvir 150mg when given with Ritonavir 100mg is 3.84 hours. The concentration at 12-h post-
administration is 816.1 ng/mL. 
Common adverse effects 
In the phase 2/3 placebo controlled clinical trial, The incidence of adverse events was similar in the atilotrelvir 
(320/617, 51.9%) and placebo (298/610, 48.9%) group. The most common AE in both arms was 
hypertriglyceridemia. Drug-related adverse events were reported for 222 (36.0%) of 617 patients in the 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 57 of 74 
atilotrelvir plus Ritonavir group and 182 (29.8%) of 610 patients in the placebo group. All of them were non-
serious, most of grade 1/2, and more than half resolved by the end of the study (3). 
Contraindications 
Hypersensitivity.  Contraindicated with drugs that are highly dependent on CYP3A for clearance or are potent 
CYP3A inducers (see below) 
Drug Interactions 
Contraindicated with drugs that are highly dependent on CYP3A for clearance, such as -  
 
Alpha1-adrenoreceptor antagonist: alfuzosin 
 
Antianginal: ranolazine 
 
Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine 
 
Anti-gout: colchicine 
 
Antipsychotics: lurasidone, pimozide, clozapine 
 
HMG-CoA reductase inhibitors: lovastatin, simvastatin 
 
PDE5 inhibitor: sildenafil when used for pulmonary arterial hypertension (PAH) 
 
Sedative/hypnotics: triazolam, oral midazolam 
 
Contraindicated in drugs that are potent CYP3A inducers such as 
 
Anticancer drugs: apalutamide 
 
Anticonvulsant: carbamazepine, phenobarbital, phenytoin 
 
Antimycobacterials: rifampin 
 
Herbal products: St. John’s Wort (hypericum perforatum) 
 
References 
1. Zhang G MJ, He H, Xu K, Zhou J, et al. Discovery of GST-HG171, A Potent and Selective Oral 3CL 
Protease Inhibitor for the Treatment of COVID-19. SM J Infect Dis. 2023;6(9). 
2. Zhang H, Zhou J, Chen H, Mao J, Tang Y, Yan W, et al. Phase I study, and dosing regimen selection for 
a pivotal COVID-19 trial of GST-HG171. Antimicrobial Agents and Chemotherapy. 2024;68(1):e01115-
23. 
3. Lu H, Zhang G, Mao J, Chen X, Zhan Y, Lin L, et al. Efficacy and safety of GST-HG171 in adult patients 
with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial. 
Eclinicalmedicine. 2024;71. 
 
 
 
 
 
 
 
 
 
 

 
 
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16.6 Sotrovimab 
Rationale 
Sotrovimab (VIR-7831) is an Fc-engineered IgG1 human monoclonal antibody developed from a parental 
antibody isolated from a survivor of the SARS outbreak in 2003 (1). Sotrovimab targets a highly conserved 
epitope in the SARS-CoV-2 spike protein at a region that does not compete with angiotensin-converting 
enzyme 2 binding.  
In-vitro testing has shown that sotrovimab is able to retain activity against alpha, beta, gamma, delta and 
kappa variants, and even omicron pseudotyped virus encoding the then most prevalent haplotype of the 
Omicron spike. The same study showed that Syrian Golden hamsters infected with wildtype SARS-CoV-2 had 
significantly decreased total viral load and infectious virus levels with sotrovimab (2). 
A multicentre randomized, double-blind, multicentre, placebo-controlled, phase 3 study tested sotrovimab on 
non-hospitalised patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for disease 
progression. Symptom onset was within 5 days, median age was 53. Primary efficacy outcome was all-cause 
hospitalization longer than 24 hours for acute illness management or death through day 29. Primary outcome 
was significantly reduced with sotrovimab (6/528 – 1%) compared to placebo (30/529 – 6%) by 79%  (95% CI, 
50% – 91%; P<.001) (3). 
N.B. – REGN-COV2 (the initial positive control monoclonal antibody) was shown in vitro studies to fail to 
neutralise omicron (4), although the in-vivo significance of this is yet to be determined. 
Composition & dose 
Recommended dose is 500MG sotrovimab administered as a single intravenous infusion over 60 minutes.  
Patients should be monitored for at least 1 hour after administration. 
0.9% Sodium Chloride of 5% dextrose for injection, one vial of sotrovimab is 500MG/8ML. 
Pharmacokinetic characteristics 
The mean systemic clearance is 125 mL/day, and the median terminal half-life is approximately 49 days. The 
geometric mean maximum plasma concentration (Cmax) after a 1-hour sotrovimab intravenous infusion to be 
117.6 mcg/mL, and the geometric mean Day 29 concentration to be 24.5 mcg/mL. 
Toxicity 
Serious hypersensitivity reactions, including anaphylaxis, have been reported with administration of 
sotrovimab. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur during 
infusion, immediately discontinue administration and initiate appropriate medications and/or supportive care. 
Contraindications 
Hypersensitivity  
Cautions 
Renal impairment is not expected to impact the pharmacokinetics of sotrovimab since monoclonal antibodies 
with molecular weight >69 kDa do not undergo renal elimination. The effect of hepatic insufficiency is 
unknown.  The effect of other covariates (e.g., sex, race, body weight, disease of severity on the 
pharmacokinetics is also unknown. 
Pharmacokinetic schedule: only if there is evidence of accelerated viral clearance  
As a type B intervention (positive control), intensive pharmacokinetic sampling will not be conducted on 
those receiving sotrovimab. 

 
 
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Drug Interactions 
No formal drug interaction studies have been performed with sotrovimab. Sotrovimab is not renally 
excreted or metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions with concomitant 
medications that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are 
unlikely. 
References 
1.  Pinto D, Park Y-J, Beltramello M, Walls AC, Tortorici MA, Bianchi S, et al. Cross-neutralization of SARS-
CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020;583(7815):290-5. 
2.  Cathcart AL, Havenar-Daughton C, Lempp FA, Ma D, Schmid M, Agostini ML, et al. The dual function 
monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against 
SARS-CoV-2. bioRxiv. 2021. 
3.  Gupta A, Gonzalez-Rojas Y, Juarez E, Casal MC, Moya J, Falci DR, et al. Effect of the Neutralizing SARS-
CoV-2 Antibody Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial. 
medRxiv. 2021. 
4.  Wilhelm A, Widera M, Grikscheit K, Toptan T, Schenk B, Pallas C, et al. Reduced neutralization of SARS-
CoV-2 omicron variant by vaccine sera and monoclonal antibodies. MedRxiv. 2021. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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16.7 Metformin 
Rationale 
Metformin is one of the most widely used drugs to treat type 2 diabetes mellitus since being approved in the 
UK in 1958 and the USA in 1995. It is a biguanide and works by decreasing intestinal glucose absorption, 
improving peripheral  glucose uptake, lowering fasting plasma insulin levels and increasing insulin sensitivity. 
This results in a reduction of blood glucose concentrations without causing overt hypoglycaemia (1). 
More recently it has been suggested as a treatment for COVID-19. It acts through several mechanism – it 
causes AMP-activated protein kinase (AMPK) activation, inhibition of mTOR pathway preventing immune 
hyperactivation and increases cellular pH to interference with viral endocytic cycle (2). 
There has been In vitro evidence of metformin significantly inhibiting SARS-CoV-2 growth in cell culture 
models. IC50 values from dose-variation studies in infected cells were found to be 0.4 in Calu3 cells and 1.43 
mM in Caco2 cells (3). 
There have been several clinical trials assessing the effectiveness of metformin against COVID-19. All of the 
following clinical trials had populations that were overweight or obese. A small trial by Ventura-López et al. in 
Mexico compared 10 patients taking placebo with 10 taking a dose of 620MG of metformin glycinateBD for 
14 days. The patients were hospitalized with severe COVID-19 (median BMI = 28.54). There was no difference 
in number of days hospitalized, however metformin decreased number of days until undetectable viral load 
(4). 
The COVID-OUT trial gave 1500MG of immediate release metformin OD for 14 days to non-hospitalised 
patients. The metformin was given as an increasing dose over 6 days. 663 received metformin and 660 
received the control (median BMI = 30). Metformin did not prevent the composite endpoint of hypoxemia, ED 
visit, hospitalization, or death. However, benefit was seen when hypoxaemia was removed aOR = 0.58 (95% 
CI, 0.35 to 0.94) (5). 
Another aspect of the COVID-OUT trial looked at long COVID (post-COVID condition). Long COVID was defined 
as a formal diagnosis being given by a medical provider (median BMI 29.8). There were 562 in the placebo arm 
and 564 in the metformin arm. Metformin reduced long COVID incidence by 41% (6). 
The TOGETHER trial gave at risk patients 750 MG of metformin BD for 10 days (94% had a BMI of >30). 215 
were randomised to the metformin arm and 203 to placebo. In the metformin arm there was no reduction in 
hospitalisations due to COVID-19 and no difference in viral clearance at day 7 (7). 
Composition & dose 
The metformin dose will be 500MG metformin modified release, three times per day for 5 days.  
Pharmacokinetic characteristics 
Metformin is not metabolised, it is excreted unchanged in the urine. It has a half life of approximately 6.5 
hours and a Tmax of 7 hours for the modified release formulation (8). 
Common adverse effects 
Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite, metallic taste in mouth  
Contraindications 
Severe renal impairment, hypersensitivity to metformin, acute or chronic metabolic acidosis (including 
diabetic ketoacidosis). 

 
 
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Drug Interactions 
Insulin, 
sulfonylureas, 
meglitinides, 
corticosteroids, 
carbonic 
anhydrase 
inhibitors 
 
References 
1. Wang YW, He SJ, Feng X, Metformin: a review of its potential indications. Drug design, development 
and therapy. 2017 Aug 22:2421-9. 
2. Scheen AJ. Metformin and COVID-19: from cellular mechanisms to reduced mortality. Diabetes & 
metabolism. 2020 Nov 1;46(6):423-6. 
3. Parthasarathy H, Tandel D, Siddiqui AH, Metformin suppresses SARS-CoV-2 in cell culture. Virus 
research. 2023 Jan 2;323:199010. 
4. Ventura-López C, Cervantes-Luevano K, Aguirre-Sánchez JS Treatment with metformin glycinate 
reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial. 
Biomedicine & Pharmacotherapy. 2022 Aug 1;152:113223. 
5. Bramante CT, Huling JD, Tignanelli CJ, Randomized trial of metformin, ivermectin, and fluvoxamine for 
Covid-19. New England Journal of Medicine. 2022 Aug 18;387(7):599-610. 
6. Bramante CT, Buse JB, Liebovitz DM. Outpatient treatment of COVID-19 and incidence of post-COVID-
19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-
group, phase 3 trial. The Lancet Infectious Diseases. 2023 Oct 1;23(10):1119-29. 
7. Reis G, Silva EA, Silva DC, Effect of early treatment with metformin on risk of emergency care and 
hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial. The 
Lancet Regional Health–Americas. 2022 Feb 1;6. 
8. Metformin hydrochloride 500 mg Prolonged-release Tablets - Summary of Product Characteristics 
(SmPC) -(emc) [Internet]. Medicines.org.uk. 2024 [cited 2024 Aug 5]. Available from: 
https://www.medicines.org.uk/emc/product/14339/smpc/print 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 Appendix 3: Sample size simulations 
Sample size projections were done via simulation. Each simulation used a pharmacodynamic model of viral 
clearance (4) that was fitted to prospectively collected viral load data in 46 individuals. For simplicity, we 
assumed there was no site dependent effects. 
Interim analyses were performed after 50 patients were enrolled and then for every subsequent 25 patients. 
In the simulation, out of the 5 interventions 4 were ineffective (no increase in viral clearance) and 1 was 
effective (10% increase in viral clearance). Figures 9 & 10 show the type 1 and 1-type 2 errors for different 
choices of stopping rule thresholds, respectively. 
 
Figure 9 Estimated type 1 error 
  

 
 
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Figure 10 Estimated power (1-type 2 error) 
 
 
 
 

 
 
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18 Appendix 4: Exclusion criteria 
The exclusion criteria in the Master Protocol are expanded upon here. The exclusion criteria in bold below 
have a corresponding section in this appendix where more details are given. The patient may not enter the 
study if ANY of the following apply: 
 
Taking any concomitant medications or drugs† 
 
Presence of any chronic illness/ condition requiring long term treatment, or other significant 
comorbidity  
 
Laboratory abnormalities discovered at screening  
 
For females: pregnancy, actively trying to become pregnant, or lactation 
 
Contraindication to taking, or known hypersensitivity reaction to any of the proposed therapeutics  
 
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. 
 
1. Taking any concomitant medications or drugs 
The study will exclude all patients taking regular drugs including herbal drugs for the treatment of COVID-19, 
but some patients may take over the counter drugs or other vitamin and herbal supplements if considered 
safe in the judgement of the site investigator upon screening assessment. Patients should be counseled to 
end and avoid all non-essential medications during study participation. In certain circumstances where a 
patient is on a regular medication, which does not reflect an excluded underlying illness, and in the decision 
of the study PI is not likely to interfere with the study outcomes, or predispose the patient to any increased 
risk, a decision can be made to enrol. In all cases, the risks/ benefits of this decision should be documented, 
as well as the person(s) making the decision. 
Drug interactions change rapidly as new data become available. If in any doubt, please refer to some of the 
web sites below: 
https://www.covid19-druginteractions.org/checker 
https://crediblemeds.org/ 
https://compendium.ch/fr/Patient - this is a Swiss website dealing with drug interactions 
https://www.bnf.org/products/bnf-online/ - available only in the UK 
https://www.uptodate.com/drug-interactions/?source=responsive_home#di-druglist – this requires a 
subscription 
 
2. Presence of any chronic illness/ condition requiring long term treatment, or other significant 
comorbidity 
The protocol excludes almost all individuals with a chronic illness of any severity and those with an illness that 
requires long term treatment.  
BMI ≥ 35 kg/m2 
Diet controlled diabetes mellitus 

 
 
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Reduced kidney function – eGFR < 70 mls/min/1.73m2* 
Any known underlying liver disease, HIV infection and other immunocompromised condition. 
Asplenia 
Any underlying bleeding disorder e.g. haemophilia, von Willibrand’s disease  
Suffering with any other disease which in the opinion of the investigator poses undue risk to the potential 
patient 
*eGFR for males is calculated based on the Chronic Kidney Disease Epidemiology Collaboration (Andrew S 
Levey, Lesley A Stevens et al. 2009) 
https://qxmd.com/calculate/calculator_251/egfr-using-ckd-epi 
 
3. Laboratory abnormalities discovered at screening  
These are: 
haemoglobin < 8 g/dL 
platelet count < 50,000/uL 
ALT > x 2 ULN  
total bilirubin > 1.5 x ULN 
eGFR < 70 mls/min/1.73m2 
 
4. Contraindication to taking, or known hypersensitivity reaction to any of the proposed therapeutics: 
Where a contraindication is mentioned in the above sections, or an above contraindication incorporates drug-
specific contraindications below, it is not repeated again in this section, unless further information is given 
which warrants some repetition. For a complete list of drug-specific contraindications please see the section 
for that drug in Appendix 2. 
To repeat, a known hypersensitivity reaction to ANY of the proposed therapeutics below (even if the patient 
were to be randomised to a different treatment arm or control) is an exclusion criterion from entering into 
the study. 
The following are relevant contraindications (i.e. in potentially eligible patients): 
Nitazoxanide 
No additional contraindications 
Sotrovimab 
No additional contraindications 
Atilotrelvir/Ritonavir 
No additional contraindications 
Metformin 
No additional contraindications 
Nirmatrelvir/Ritonavir 
No additional contraindications 

 
 
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Nirmatrelvir/Ritonavir dose finding 
No additional contraindications 
Hydroxychloroquine 
No additional contraindications 
References for exclusion criteria 
1. Andrew S Levey, Lesley A Stevens, Christopher H Schmid, Yaping Lucy Zhang, Alejandro F Castro, 
Harold I Feldman, John W Kusek, Paul Eggers, Frederick Van Lente, Tom Greene and J. Coresh (2009). 
"A new equation to estimate glomerular filtration rate." Annals of Internal Medicine 150: 604-612. 
2. Williamson, E. J., A. J. Walker, K. Bhaskaran, S. Bacon, C. Bates, C. E. Morton, H. J. Curtis, A. Mehrkar, 
D. Evans, P. Inglesby, J. Cockburn, H. I. McDonald, B. MacKenna, L. Tomlinson, I. J. Douglas, C. T. 
Rentsch, R. Mathur, A. Y. S. Wong, R. Grieve, D. Harrison, H. Forbes, A. Schultze, R. Croker, J. Parry, F. 
Hester, S. Harper, R. Perera, S. J. W. Evans, L. Smeeth and B. Goldacre (2020). "Factors associated with 
COVID-19-related death using OpenSAFELY." Nature 584(7821): 430-436. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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19 Appendix 5: Amendment History 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued 
Author(s) of 
changes 
Details of Changes made 
1 
3.0 
11 July 2022 
Professor Sir 
Nicholas J White and 
Dr William Schilling 
1. 
Co-investigators changed 
2. 
Sponsor address changed. 
3. 
Synopsis: removed “Study Patient” 
row 
4. 
Selection 
criteria 
changed 
throughout 
5. 
Synopsis: 
Clarified 
in 
“Planned 
Sample Size” that no fixed sample 
size 
6. 
Synopsis: Changed “Planned Study 
Period” from “2 years” to “3 years” 
7. 
Synopsis: Updated “interventions” 
information of type A and B 
throughout 
8. 
Synopsis: 
Updated 
“Control” 
throughout 
9. 
Synopsis: 
Updated 
“Rational” 
throughout 
10. Objectives and/or endpoint wording 
changed throughout 
11. Section 
“3 
Background 
and 
rationale”: Updated information of 
small molecule medications and 
updated to reflect current global 
vaccine and COVID-19 situation 
including omicron variant. 
12. Section “3.1 Proposal”: Emphasis of 
why this type of trial is most suited 
and clarification of the expected 
outcome of the interim analysis. 
13. Section “5 Study design”: Updated 
information about the places to 
recruit the participants, site and 
current study design. 
14. Section “5.1 Interventions”: Pick the 
winner no longer applies, language 
changed to reflect addition of small 
molecule drugs and updated Figure 4  
15. Section 
“7 
Study 
set-up 
and 
procedures”: 
Updated 
study 
procedures. Swabs will be done in 
duplicate before receiving the first 
dose of the intervention (or if on no 
intervention arm). 
16. Section “7.1 Virological sampling”: 
Clarification that duplicate means 
one swab on each tonsil, increased 
viral 
transport 
medium 
(VTM), 
updated the laboratory procedures 
and added saliva collection process 
in some participants 

 
 
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17. Section “7.5 Baseline assessments”: 
if the results haven’t returned the 
participant can be given the first 
dose then excluded later if there are 
laboratory 
abnormalities. 
The 
procedures are also updated. 
18. Section “7.6.1 Randomisation D0”: 
Updated the ratio of randomisation 
as no antiviral treatment will be 
fixed at “at least 20%” throughout 
the study and the randomisation 
ratios will be uniform for all available 
interventions. 
19. Section “7.6.2 Day 1 - day 7”: 
Updated the procedures during day 
1- day 7 
20. Section 
“7.7 
Intensive 
pharmacokinetic 
sampling”: 
Explained more details about the 
study 
drugs 
for 
intensive 
PK 
sampling. 
21. Section 
“7.8 
Management 
of 
patients 
who 
become 
ill”: 
If 
treatment arm is changed, duplicate 
swabs will be taken again prior to 
any new treatment. 
22. Section 
“9.1 
Definition/Serious 
Adverse Event (SAE)”: Removed “and 
not otherwise receiving medical 
treatment” 
23. Section 
“10.1 
Overview 
of 
adaptive study design and overall 
approach”: 
Added 
new 
information. 
24. Section “10.2 Results of the first 
interim analysis”: This new section 
and Figure 6 have been added. 
25. Section “10.3 Bayesian hierarchical 
model 
of 
viral 
clearance”: 
Statistical explanation has been 
updated. 
26. Section “Estimating the optimal 
structural model for clearance rate”:  
Deleted. No-longer required as the 
methodology has been validated. 
27. Section 
“10.5 
Sample 
size 
estimation, 
randomisation 
and 
statistical considerations for the 
Bayesian group sequential design”: 
Information have been updated. 
28. Section “10.7 Final analysis of 
primary outcome”: Linear and non-
linear models are being used, 
package rstan is being used instead 

 
 
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of rstanarm. Analysis code available 
from github, link was given. 
29. Section “13 Ethical and regulatory 
considerations”: 
Clarification 
of 
what treatment will be given to no 
antiviral treatment arm. 
30. Section “13.7 Benefits”: Maximum 
amount per patient (£400 GBP) has 
been removed. 
31. Section “14 References”: References 
have been updated. 
32. Section “15 Appendix 1 Schedule of 
activities”: 
“If 
new 
treatment” 
column and explanation below the 
table have been added/updated. 
33. Section “16 Appendix 2 Study 
drugs”: 
 Hydroxychloroquine, 
lopinavir/ritonavir, 
miglustat, 
nitazoxanide 
and 
nebulized 
unfractionated 
heparin 
(UFH): 
Reference order updated.  
 Remdesivir: Changed for more up 
to date information with more 
references.  
 Ivermectin: Dosing table changed 
for higher mg of tablets and 
reference order updated. 
 REGN-COV2: Dose changed from 
1,200 mg to 600 mg of casirivimab 
and 1,200 mg to 600 mg of 
imdevimab and reference order 
updated. 
 Favipiravir: Introduction changed 
for more up to date information 
including references. 
 Molnupiravir, 
nirmatrelvir/ritonavir 
(PAXLOVID™), 
sotrovimab, 
fluoxetine, 
fluvoxamine 
and 
AZD7442 (evusheld): Monograph 
added (Section 16.10 – 16.15). 
34. Section “18 Appendix 4 Exclusion 
criteria”:  
 Update information to comply 
with the exclusion criteria 
 Added line to include herbal drugs 
in regular drugs 
 Added line of the decision of the 
study 
PI 
whether 
to 
enrol 
participants 
taking 
regular 
medications.  
 Add in the list of the most severe 
comorbidities, and include HIV and 
other 
immunocompromised 
condition.  

 
 
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 Changed the BMI from ≥ 30 to ≥ 
35 kg/m2. 
 Changed the eGFR limit of 
exclusion from <80 to <70 
mls/min/1.73m2 
 Added 
contraindications 
for 
hydroxychloroquine 
(prolong 
QTc), 
molnupiravir, 
nirmatrelvir/ritonavir 
(PAXLOVID™), 
sotrovimab, 
fluoxetine, 
fluvoxamine 
and 
AZD7442 (evusheld). 
 Added that study may be done as 
an inpatient or an outpatient 
throughout. 
35. Administrative changes 
2 
4.0 
17 August 
2022 
Professor Sir 
Nicholas J White and 
Dr William Schilling 
1. Funder: 
Update 
funder 
name 
including grant reference number  
2. Section 
“1: 
Synopsis”: 
Updated 
“Planned Sample Size” by adding 
expected total participant and study 
countries 
3. Section 
“1: 
Synopsis”: 
Updated 
“interventions” information of type A 
4. Section 
“3 
Background 
and 
rationale”: Added information about 
‘viral rebound’ and clarify more about 
assessment  
5. Section “5.1 Interventions”: Added 
“Ensitrelvir and a combination of 
Molnupiravir 
and 
Nirmatrelvir/Ritonavir” in type A and 
“Evusheld” in type B 
6. Section “7.6 Days of Study”: Added 
Day 
10 
activities 
to 
capture 
asymptomatic viral rebound and 
safety concern for viral rebound 
7. Section “7.8 Management of patients 
who 
become 
ill”: 
Added 
new 
procedure to determine the viral 
rebound which is important with 
certain antivirals (e.g. Paxlovid) and 
may impact effectiveness of these 
against onward viral transmission. 
8. Section “9.3 Procedures for recording 
adverse 
events”: 
Added 
safety 
evaluation for combination drugs 
9. Section “10.5 Sample size estimation, 
randomisation 
and 
statistical 
considerations for the Bayesian group 
sequential design”: Added tentative 
sample size (60 patients) in each arm 
for an effect size of 12.5% increase in 
viral clearance 
10. Section “11.2 Data handling and 
record 
keeping”: 
Extended 
the 

 
 
PLATCOV_Master protocol_V7.0_07Aug24                                       CONFIDENTIAL                                       Page 71 of 74 
retention of the records to “at least 
five years” 
11. Section “15 Appendix 1 Schedule of 
activities”:  
 Added column “D10”  
 Changed column title from “If new 
treatment” 
to 
“if 
new 
treatment/symptoms” 
 Clarified the definition of “if new 
treatment/symptoms” 
12. Section “16 Appendix 2 Study drugs”: 
 Molnupiravir: Updated section 
“drug interaction”  
 Nirmatrelvir/ritonavir 
(e.g. 
PAXLOVID™): 
Updated 
section 
“drug interaction”  
 Ensitrelvir: 
Added 
monograph 
(Section 16.16). 
13. Section “18 Appendix 4 Exclusion 
criteria”: Added contraindications for 
ensitrelvir and molnupiravir and 
nirmatrelvir/ritonavir combination 
14. Administrative changes 
3 
5.0 
23 May 23 
Professor Sir 
Nicholas J White and 
Dr William Schilling 
1. Updated investigators 
2. Changed designation of investigators 
3. Changed age cut off to 60 from 50 
4. Added maximum sample size per 
intervention arm to 120 (excluding 
controls) 
5. Increased total enrolment number 
from 1,500 to 3,000. 
6. Increased duration of study from 3 to 
6 years 
7. Increased participant enrollment to 
120 days 
8. Added assessment at day 120 using 
modified COVID-19 Yorkshire 
Rehabilitation Scale (C19 YRSm) to 
measure for symptoms of post-acute 
COVID-19 (long COVID) and added day 
120 C19 YRSm to schedule of activities 
9. AEs will only be assessed up until day 
28, not day 120. 
10. SARS-CoV-2 antibody RDT has been 
removed. 
11. Medications no longer in the trial have 
been removed (included all 
information given in the appendices 
regarding them). 
12. Categories of interventions relabelled 
13. Viral clearance cut-off increased from 
12.5 to 20% 
14. Added schematic to explain stopping 
rules as of January 2023. 
15. Added factorial randomisation 
16. ECG now listed as optional 

 
 
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17. Virological rebound characterisation 
will be defined in SAP. 
18. Included justification for drug 
combination. 
19. Removed drugs that are not being 
used in trial at present 
20. Statement that risk of combination 
drugs interacting is low 
21. Added name of funder 
22. Updated references 
23. Administrative changes e.g. grammar 
errors corrected, updated spelling 
from American English to English 
English (randomisation) 
4 
6.0 
04 Oct 23 
Professor Sir 
Nicholas J White and 
Dr William Schilling 
1. Explained can increase number in 
intervention past 120 if DSMB or TSC 
agree 
2. Added in new interventions and 
removed old ones (Evusheld removed, 
Hydroxychloroquine and Fluoxetine 
added) 
3. Wording of the primary endpoint 
clarified. 
4. Two secondary endpoints added: viral 
rebound and symptom/ fever 
resolution. 
5. Changes made to sample schedule, 
now swabbing day 0 to day 5 once or 
twice per day to characterise viral 
clearance, and on day 6, 7, 10 and 14 
to characterize viral rebound. This is 
based on data simulations 
6. Minor changes made to make rationale 
and proposal more up-to-date and 
clearer 
7. Added ensitrelvir to list of drugs with 
evidence of antiviral effects from other 
studies 
8. 
Clarified 
that 
interventions 
not 
selected for intense PK-PD may have 
blood tests on days 3, 7 and 14 for 
determination 
of 
dose-response 
relationship 
9. Added possibility of patient self-
swabbing 
10. Re-described viral clearance curve as 
biexponential 
11. Explained that success threshold and 
maximum number of patients may be 
changed for therapeutics which may 
potentially be used in prophylaxis 

 
 
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12. Description added of the sample size 
calculation for intensive PK-PD sub-
study 
13. Diagram included showing half-life 
decrease over time 
14. New drugs added to appendices 
15. Significant comorbidities causing 
exclusion removed 
16. Contraindications added to new 
interventions 
17. Window of follow-up for D120 
assessment increased from -/+ 5 days 
to -10/+30 days. 
5 
7.0 
07 Aug 24 
Professor Sir 
Nicholas J White, Dr 
William Schilling and 
Dr. Simon Boyd 
1. Added new investigators, Dr. Ellen and 
Dr. Seers. 
2. Set limit of maximum participants per 
arm at 200. 
3. Increased number of participants to be 
enrolled in total across sites to 3800 
and updated the maximum number in 
Figure 5. 
4. Atilotrelvir/Ritonavir and Metformin 
added. 
5. Dose finding for ritonavir boosted 
nirmatrelvir added. 
6. Interventions no longer in use 
removed (Ensitrelvir, Molnupiravir, 
Combination of Molnupiravir and 
Nirmatrelvir/ritonavir (Paxlovid), 
Fluoxetine). 
7. Added two new abbreviations 
8. Background and rationale have been 
updated with more recent references 
and new Figure. 
9. Removed mention of comparative 
study between Molnupiravir and 
Nirmatrelvir/ritonavir (Paxlovid) as 
already done. 
10. Clarification of study sites. 
11. Allowed temperature to be 
measured multiples times per day. 
12. Additional swab added at 6-18 hours 
post baseline swabs. 
13. Added vital signs measurement to 
day 1–5. 
14. Removed oropharyngeal swabs and 
vital signs measurement on day 6. 
15. Added possibility of extra swabs days 
1-5 and removed all activities on day 
10 to schedule of activities (section 
7.6.2). 
16. New drugs including dose finding 
added to the Appendix and old drugs 
removed. 

 
 
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17. Allowed other time points to be 
added/taken away in the intense 
pharmacokinetic study. 
18. Contraindications added to new 
interventions. 
19.Changed “staff” to “personnel” for 
continuity. 
20. Minor grammar changes.