An International, Investigator Initiated and Conducted, Pragmatic Clinical Trial to Determine Whether 40mg Atorvastatin Daily Can Improve Neurocognitive Function in Adults With Long COVID Neurological Symptoms
Phase: PHASE3
Conditions: Neurocognitive Impairment, Mild
Sponsor: The George Institute

 
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An international, investigator initiated and conducted, pragmatic clinical trial to 
determine whether 40mg atorvastatin daily can improve neurocognitive function in 
adults with long COVID neurological symptoms 
 
STUDY PROTOCOL 
Version 12 May 2021 
 
 
CONTACT DETAILS 
STRONGER Central Coordinating Centre 
The George Institute for Global Health 
University of New South Wales 
Level 5, 1 King St 
Newtown NSW 2042 Australia 
Tel   +61 2 8052 4500 
Fax   +61 2 8052 4501 
Email: STRONGER@georgeinsitute.org.au 
 
 
 
 
 
 
This protocol has been developed by the STRONGER Steering Committee and its contents are the intellectual 
property of this group.  It is an offence to reproduce or use the information and data in this protocol for any 
purpose other than this study without prior approval from The George Institute for Global Health. 
 
 

 
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Investigator Agreement 
I have read the following protocol: 
 
Protocol Title: Statin TReatment for COVID-19 to Optimise NeuroloGical recovERy (STRONGER) 
 
Version and Date: Version 2.0, 12 May 2021 
I have read this protocol and associated procedure manuals and agree that it contains all the necessary details 
for carrying out the study.  I will conduct the study as outlined herein and will complete the study within the 
time designated. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of the study.  I will discuss this material with them to ensure that they are fully informed 
regarding the study intervention and the conduct of the study. 
 
 
 
 
Name of Investigator (Printed) 
 
 
 
 
 
Investigator’s Signature 
 
Date (Day / Month / Year) 
 
 
 
Name of Institution (Printed) 
 
 
 
Prof Craig Anderson 
Chief Investigator 
 
 
12 May 2021 
 
Signature 
Prof Mark Woodward 
Principal Trial Statistician 
 
 
12 May 2021 
 
Signature 
 
 
 

 
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Contents 
Investigator Agreement ...................................................................................................................................................... 2 
Contents .............................................................................................................................................................................. 3 
Glossary of Abbreviations & Terms ..................................................................................................................................... 6 
1 
Version History ........................................................................................................................................................... 7 
2 
Administrative Information ........................................................................................................................................ 7 
2.1 
Registration................................................................................................................................................................7 
2.2 
Funding ......................................................................................................................................................................7 
2.3 
Study Management & Oversight ..............................................................................................................................7 
2.3.1 
Central Coordinating Centre ............................................................................................................................8 
2.3.2 
Drug Distribution Centre .................................................................................................................................8 
2.3.3 
Steering Committee .........................................................................................................................................8 
2.3.4 
Data & Safety Monitoring Board .....................................................................................................................8 
3 
Protocol Synopsis ....................................................................................................................................................... 9 
4 
Introduction ............................................................................................................................................................. 10 
5 
Research Question/Aims .......................................................................................................................................... 13 
6 
Methods ................................................................................................................................................................... 13 
6.1 
Study Design ........................................................................................................................................................... 13 
6.2 
Study Setting ........................................................................................................................................................... 13 
6.3 
Recruitment ............................................................................................................................................................ 13 
6.4 
Eligibility Criteria..................................................................................................................................................... 14 
6.4.1 
Inclusion Criteria ........................................................................................................................................... 14 
6.4.2 
Exclusion Criteria ........................................................................................................................................... 14 
6.5 
Informed Consent .................................................................................................................................................. 15 
6.6 
Schedule of Evaluations ......................................................................................................................................... 16 
6.7 
Visit Summary ......................................................................................................................................................... 18 
6.7.1 
Preliminary Screening ................................................................................................................................... 18 
6.7.2 
Visit 1 – Screening, Baseline & Randomisation ........................................................................................... 18 
6.7.3 
Visit 2 – 6 Weeks (± 1 Week) – Telephone .................................................................................................. 19 
6.7.4 
Visit 3 – 6 Months (± 1 Month) – Clinic........................................................................................................ 20 
6.7.5 
Visit 4 – 12 Months (± 1 Month) – Telephone ............................................................................................. 20 
6.7.6 
Visit 5 – End of Study 18 Months (± 1 Month) – Clinic ............................................................................... 20 
6.8 
Assessment Details ................................................................................................................................................. 21 
6.8.1 
Screening Questionnaire ‘SPHERE’............................................................................................................... 21 
6.8.2 
Blind MoCA .................................................................................................................................................... 21 
6.8.3 
Cognitive Assessments .................................................................................................................................. 22 
6.8.4 
Other Health Assessments ........................................................................................................................... 24 
6.9 
Sub-Study – Neurodegenerative Markers & MRI ................................................................................................. 25 
6.9.1 
Neurodegenerative Markers ........................................................................................................................ 25 
6.9.2 
MRI Scanning ................................................................................................................................................. 25 
6.10 
Communications with Health Care Providers ....................................................................................................... 26 
7 
Study Treatment & Adherence ................................................................................................................................. 26 
7.1 
Study Treatment ..................................................................................................................................................... 26 
7.2 
Blinding ................................................................................................................................................................... 26 
7.3 
Treatment Adherence ............................................................................................................................................ 26 
7.4 
Management of Possible Treatment Related Side-Effects .................................................................................. 26 
7.5 
Permanent Discontinuation of Study Treatment ................................................................................................. 27 

 
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8 
Concomitant Medications ........................................................................................................................................ 27 
9 
Study Withdrawal ..................................................................................................................................................... 27 
10 
Co-Enrolment of Participants into Other Studies ..................................................................................................... 28 
11 
Statistical Methods ................................................................................................................................................... 28 
11.1 
Sample Size ............................................................................................................................................................. 28 
11.1.1 
Sub-Study Sample Size .................................................................................................................................. 28 
11.2 
Assignment of Intervention ................................................................................................................................... 28 
11.3 
Statistical Analysis .................................................................................................................................................. 28 
12 
Outcomes ................................................................................................................................................................. 29 
12.1 
Primary Outcome ................................................................................................................................................... 29 
12.2 
Key Secondary Outcome ........................................................................................................................................ 29 
12.3 
Other Outcomes ..................................................................................................................................................... 29 
12.4 
Safety Outcomes .................................................................................................................................................... 29 
13 
Safety........................................................................................................................................................................ 29 
13.1 
DSMB....................................................................................................................................................................... 29 
13.2 
Definitions & Reporting ......................................................................................................................................... 29 
13.2.1 
Adverse Events .............................................................................................................................................. 30 
13.2.2 
AESI ................................................................................................................................................................ 30 
13.2.3 
SAEs ................................................................................................................................................................ 30 
13.2.4 
Suspected Unexpected Serious Adverse Reactions .................................................................................... 30 
13.2.5 
SAE Reporting Period .................................................................................................................................... 31 
14 
Study Drug Management ......................................................................................................................................... 32 
14.1 
Manufacturer & Packaging .................................................................................................................................... 32 
14.2 
Labelling .................................................................................................................................................................. 32 
14.3 
Distribution & Resupply ......................................................................................................................................... 32 
14.4 
Storage .................................................................................................................................................................... 32 
14.5 
Drug Dispensing & Accountability ......................................................................................................................... 32 
14.6 
Disposal & Destruction........................................................................................................................................... 32 
15 
Data Management & Quality Assurance .................................................................................................................. 33 
16 
Monitoring & Auditing .............................................................................................................................................. 33 
16.1 
Monitoring .............................................................................................................................................................. 33 
16.2 
Auditing ................................................................................................................................................................... 33 
17 
Regulatory & Ethical Considerations ........................................................................................................................ 33 
17.1 
Regulatory & Ethical Compliance .......................................................................................................................... 33 
17.2 
Protocol Amendments ........................................................................................................................................... 34 
17.3 
Informed Consent .................................................................................................................................................. 34 
17.4 
Confidentiality ........................................................................................................................................................ 34 
17.5 
Post-Study Care ...................................................................................................................................................... 34 
17.6 
Reimbursement ...................................................................................................................................................... 35 
18 
Document Retention ................................................................................................................................................ 35 
19 
Publications Policy & Data Sharing ........................................................................................................................... 35 
20 
Appendices ............................................................................................................................................................... 36 
20.1 
Appendix 1 – SPHERE Questionnaire .................................................................................................................... 36 
20.2 
Appendix 2 – SDMT ................................................................................................................................................ 37 
20.3 
Appendix 3 – RAVLT-D ........................................................................................................................................... 38 
20.4 
Appendix 4 – OTMT A ............................................................................................................................................ 39 
20.5 
Appendix 5 – OTMT B ............................................................................................................................................ 40 

 
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20.6 
Appendix 6 – D-KEF-CWIT ...................................................................................................................................... 41 
20.7 
Appendix 7 – SF ...................................................................................................................................................... 42 
20.8 
Appendix 8 – PHQ-9 ............................................................................................................................................... 43 
20.9 
Appendix 9 – PSQI .................................................................................................................................................. 44 
20.10 
Appendix 10 – GAD-7 ............................................................................................................................................. 46 
20.11 
Appendix 11 – EQ-5D-5L ........................................................................................................................................ 47 
20.12 
Appendix 12 – Blind MoCA .................................................................................................................................... 49 
20.13 
Appendix 13 – Sleep Diary ..................................................................................................................................... 50 
20.14 
Appendix 14 – NPS SAMS ....................................................................................................................................... 51 
21 
References ................................................................................................................................................................ 53 
 
 
 

 
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Glossary of Abbreviations & Terms 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
CCC 
Central Coordinating Centre 
cGMP 
Current Good Manufacturing Practices 
COVID-19 
Coronavirus Disease 2019 
CRP 
C Reactive Protein 
D-KEF-CWIT 
Delis-Kaplan Executive Functioning System “Stroop” Colour-Word Interference Test 
dMRI 
Diffusion-Weighted Magnetic Resonance Imaging 
DSMB 
Data & Safety Monitoring Board 
EC 
Ethics Committee 
eCRF/CRF 
Electronic Case Report Form – also referred to as IBM Clinical Development or database 
eGFR 
Estimated Glomerular Filtration Rate 
EQ-5D-5L 
EuroQoL 5-Dimensional 5-Level Questionnaire 
FDA 
Food & Drug Administration 
FOD 
Fibre Orientation Distribution 
GAD-7 
General Anxiety Disorder 7 Questionnaire 
GP 
General Practitioner 
HDL 
High-Density Lipoprotein  
HR 
Heart Rate 
HRQoL 
Health-Related Quality of Life 
ICH-GCP 
International Conference on Harmonisation guidelines for Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LDL 
Low-Density Lipoprotein  
Long COVID 
Signs/symptoms ≥12 weeks after infection with COVID-19, not otherwise explained 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging  
NHMRC 
National Health & Medical Research Council 
NPS 
National Prescribing Service 
OTMT-A & B 
Oral Trail Making Test A & B 
PCR 
Polymerase-Chain-Reaction 
PHQ-9 
Patient Health Questionnaire-9 
PISCF 
Participant Information Sheet & Consent Form 
PROBE 
Prospective, Randomised, Open-Label, Blinded Endpoint 
PSQI 
Pittsburgh Sleep Quality Index 
RAVLT-D 
Rey Auditory Verbal Learning Test – Delayed Recall 
SAE 
Serious Adverse Event 
SAMS 
Statin-Associated Muscle Symptoms 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SC 
Steering Committee  
SD 
Standard Deviation 
SDMT 
Symbol Digit Modalities Test 
SF 
Semantic Fluency 
SPHERE 
Somatic & Psychological Health Report 
STAREE 
Statins in Reducing Events in the Elderly 
STRONGER 
Statin TReatment for COVID-19 to Optimise NeuroloGical recovERy 
SUSAR 
Suspected Unexpected Severe Adverse Reaction 
TGA 
Therapeutic Goods Administration 

 
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Abbreviation 
Definition 
TGI 
The George Institute for Global Health 
ULN 
Upper Limit of Normal 
1 Version History 
Version Number 
Version Date 
Summary of Revisions 
1 
20 April 2021 
Original 
2 
12 May 2021 
Section 2.3.2 – Update pharmacy for study drug 
Section 3 – Further details added to inclusion and exclusion criteria 
Section 6.4 – Further details added to Inclusion criteria 
Section 6.6. – Further details added to Schedule of Evaluations 
Section 6.7.2 – Clarification and update of procedures at Visit 1 – Screening, 
Baseline and Randomisation 
Section 6.7.4 - Further details added to Visit 3 - 6 months 
Section 6.7.6 - Further details added to Visit 5 – End of Study 18 months 
Section 6.8.1 - Further details added to the SPHERE questionnaire 
Section 6.8.2 - New assessment details added on the Blind MoCA 
Section 6.8.4 – Further details and clarifications added to Other Health 
Assessments 
Section 6.9.2 – Further details added to MRI scanning 
Section 6.10 – Clarifications and further details added to Communications 
with Health Care Providers 
Section 7.2 – Further details added on Blinding 
Section 7.4 – Further details added on NPS process 
Section 7.5 – Further details and clarifications added on Permanent 
Discontinuation of Study Treatment 
Section 8 – Further details and clarifications added to Concomitant 
Medications 
Section 10 – Further details and clarifications added to Co-enrolment of 
Participants in Other Studies 
Section 11.2 – New section added on Assignment of Intervention 
Section 13.1 – Further details and clarifications made to DSMB 
Section 14.1 – Updates added to 14.1 Manufacturer and Packaging 
Section 14.3 – Updates added to Distribution and Resupply 
Appendices – Updates added to Appendix 2- SDMT, Appendix 7 -SF, Appendix 
12 – Blind MoCA, Appendix 13 – Sleep Diary, and Appendix 14 – NPS SAMS 
 
2 Administrative Information 
2.1 
Registration 
Statin TReatment for COVID-19 to Optimise NeuroloGical recovERy (STRONGER) will be registered on 
Clinicaltrials.gov prior to enrolment of any participants. 
 
2.2 
Funding 
This study is funded by National Health & Medical Research Council (NHMRC) / Rare Cancers Rare Diseases 
and Unmet Need – Coronavirus Disease 2019 (COVID-19) (Medical Research Futures Fund RG203341). 
 
2.3 
Study Management & Oversight 

 
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STRONGER is an investigator initiated and conducted study managed by a Central Coordinating Centre (CCC) 
based at The George Institute for Global Health (TGI) in Sydney, Australia.  The study will be overseen by a 
Steering Committee (SC) comprised of international experts in the fields of neurology, infectious diseases, 
endocrinology, cardiovascular disease, public health, statistics, epidemiology and clinical trials. 
 
2.3.1 
Central Coordinating Centre 
The Central Coordinating Centre (CCC) is based at TGI and is comprised of a team of project staff who are 
responsible for the day-to-day management of the study, including but not limited to: data and project 
management, committee coordination, assistance with ethics committee and regulatory applications, 
preparation of protocol and procedures for training, monitoring of data quality and safety, adherence and 
compliance to protocol, applicable guidelines and regulations, preparation of study data for analysis and 
publication. 
 
2.3.2 
Drug Distribution Centre 
Study drug will be appropriately labelled, packaged and couriered to Australian trial participants by Syntro 
Health, Melbourne, Australia.  In Chile, comparable study medication obtained locally will be distributed to 
participants the pharmacy of the Clínica Alemana de Santiago and Facultad de Medicina Clínica Alemana, 
Universidad del Desarrollo, Santiago, Chile. 
 
2.3.3 
Steering Committee  
The Steering Committee (SC) is responsible for the execution of the study design, protocol, data collection and 
analysis plan, as well as publications.  The SC has the right to appoint new members and co-opt others to add 
to the integrity of the conduct of the study and analyses.  The SC will also include the primary grant holders 
and other experts. The members are: Prof Craig Anderson, Prof Sophia Zoungas, Prof Sharon Naismith, Prof 
Meng Law, Prof Karin Leder, Dr Ian Harding, A/Prof Ruth Peters, Prof Mark Woodward, and A/Prof Julian Elliott 
in Australia; and Dr Paula Muñoz Venturelli and Dr Ximena Stecher in Chile.  The SC will be chaired by Prof 
Craig Anderson. 
 
2.3.4 
Data & Safety Monitoring Board 
An independent Data & Safety Monitoring Board (DSMB) will be constituted.  This committee will receive data 
and will have the power to recommend to the SC potential modifications to study conduct including early 
discontinuation of the study based on a risk/benefit assessment of the study data.  The DSMB will also monitor 
the occurrence of serious adverse events (SAEs), adverse events (AEs) and adverse events of special interest 
(AESIs) throughout the study in order to monitor participant safety.   
 
 
 

 
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3 Protocol Synopsis 
Main Sponsor:  
The George Institute for Global Health (TGI) 
Trial Registration Number(s): 
STRONGER will be registered on 
Clinicaltrials.gov and ANZCTR 
Title of Study: Statin TReatment for COVID-19 to Optimise NeuroloGical recovERy (STRONGER) 
Study Duration: 3 years 
Clinical Phase: III 
Objectives:  To determine effectiveness of treatment with 40mg atorvastatin over 18 months on attenuating 
cognitive decline and neuroinflammatory biomarkers in adults with long COVID neurological symptoms.   
Number of planned participants: 410 
Study Design:  Prospective, randomised, open-label, blinded endpoint (PROBE) study of atorvastatin 40mg on top of 
standard care, in patients with long COVID neurological symptoms. 
Study Treatment: 40mg atorvastatin + standard care or standard care alone 
Inclusion Criteria: 
1. Age ≥18 years 
2. History of COVID-19 that is confirmed by a positive polymerase-chain-reaction (PCR) test 
3. Any ongoing neurological symptoms as a result of COVID-19 (e.g. problems with memory, concentration, sleep 
disturbance and fatigue) that are identified through administration of the checklist of symptoms on the Somatic 
and Psychological Health Report (SPHERE) questionnaire, or reported loss of smell (anosmia);29 
4. Able to fully participate in all procedures, including cognitive assessments 
5. Able and willing to provide written informed consent  
Exclusion Criteria: 
1. Evidence of dementia and/or significant cognitive impairment on screening (i.e. Blind Montreal Cognitive 
Assessment [MoCA] score <19/22)  
2. Severe co-morbid medical or psychiatric condition that prevents participation 
3. History of traumatic brain injury with loss of consciousness (>30 mins) within the last 2 years 
4. Ongoing long-term use for a clear indication (e.g. secondary cardiovascular prevention in high-risk individuals) 
or any contraindication (e.g. previous adverse reaction) of statin use 
5. Evidence of severe or significant liver disease, defined as any of the following: acute viral hepatitis; chronic active 
hepatitis; chronic active hepatitis; cirrhosis; or elevated biochemical function markers i.e. ALT or AST >3x the ULN 
or eGFR <30mL/min/1.73m2 
6. Creatine kinase (CK) levels > 2x upper limit of normal (ULN)  
7. Female of child-bearing potential that is unable or unwilling to use reliable method of contraception, 
breastfeeding, or planning a pregnancy 
8. For a sub-group of participants undergoing MRI – any contraindication to MRI due to metallic body parts or 
claustrophobia 
9. Medical history of a disorder that might, in the opinion of the attending clinician, put the participant at significant 
risk if they were to participate in the trial 
Outcome Measures: 
Primary – processing speed, assessed on the oral Symbol Digit Modalities Test (SDMT) 
Key Secondary – white matter free water measured on diffusion MRI brain imaging 
Other – other components of cognitive function; other health assessments; other MRI markers of cerebral white 
matter integrity, iron load, cerebral perfusion, and glutathione for oxidative stress; cost-effectiveness compared to 
standard care 
Safety – any SAEs, AEs or AESI including diabetes mellitus, myalgia, myositis, and biochemical abnormalities 
 
 
 

 
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4 Introduction 
COVID-19 Pandemic  
By early 2021, the COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2), had affected approximately 100 million people and caused over 1.8 million deaths, since it emerged 
in Wuhan, China in late 2019. The epidemiological pattern and clinical spectrum, pathogenesis, and 
complications in those infected with SARS-CoV-2 and diagnosed with COVID-19 in the acute phase have now 
been relatively well-described,1, 2 but there is uncertainty over its long-term health consequences.  However, 
there is increasing recognition that many patients have persistent symptoms, in particular ongoing impairment 
of cardiorespiratory, mobility, cognitive and psychological function.3 Although post-acute syndrome is well-
recognised in patients recovering from serious illness, particularly those requiring hospitalisation and 
admission to intensive care units, post-acute COVID-19 syndrome is not just observed in those who have had 
severe illness and were hospitalised.  Studies have shown that up to three-quarters of patients report at least 
one symptom several months after onset of the infection.  The most common symptoms of ‘long COVID’ are 
fatigue, muscle weakness, disturbed sleep, and anxiety/depression.  Approximately 5-10% of people report 
neurological symptoms, such as ‘brain fog’, headaches, poor concentration, and dizziness.4-8 
 
COVID-19 & The Brain  
Evidence suggests that the brain is often involved in COVID-19,8-13 as seen in other serious respiratory 
infections, such as influenza A, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory 
Syndrome.  Many SARS patients had altered concentration, memory, and mood, which often persisted long 
after their physical recovery. COVID-19 patients appear to suffer a similar range of symptoms, subtle cognitive 
deficits,10 and abnormalities on brain imaging.11  This is likely to be due to a complex interplay of mechanisms 
related to systemic inflammation (i.e. vasculitis and hypercoagulable states), immune processes, and direct 
viral invasion into the brain (Fig 1).  While the subset of patients with severe disease, those who require 
intensive care and mechanical ventilation, are at greatest risk of acute stroke and neurological complications, 
many with mild or absent respiratory symptoms complain of non-specific neurological symptoms, 
anxiety/depression, insomnia and fatigue, which persist beyond the acute infection. 
Figure 1: Neuro-Inflammation & COVID-19 
 
 
 

 
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COVID-19 Inflammation 
Inflammatory cytokines and C-reactive protein (CRP) were important markers of ongoing inflammation in 
SARS, even after viral clearance.  SARS-CoV-2 particles follow a similar pattern of spread via respiratory mucosa 
and other infected cells, to elicit a cascade of immune responses, sometimes with a detrimental cytokine 
storm.  Direct infection of the brain is not required for neurological sequelae: systemic inflammation and 
cytokine elevation have been shown to be linked to subsequent hippocampal atrophy and cognitive 
impairment in sepsis survivors.14  Late neurocognitive issues are likely after COVID-19 from: (i) direct non-
resolving low-grade inflammation or immune reactions in the brain (Fig. 1); and (ii) indirect cerebral injury 
from hypotension, hypoxia, and metabolic dysfunction from effects on the heart, lungs and other organs.  As 
in other injuries to the brain, full neurocognitive recovery may take several months or years after the initial 
COVID-19 diagnosis. More concerning is the potential for long-term consequences to brain health, in keeping 
with contemporary theories of accumulating exposures over the life-course for developing Alzheimer’s disease 
and other neurodegenerative conditions.15 
 
 
Brain Free Water & Cognition   
Local extracellular fluid changes in the brain, from microglial activation and cerebral small vessel disease, can 
be readily quantified using non-invasive multi-shell diffusion-weighted magnetic resonance imaging (dMRI) 
(Fig. 2) in standard clinical settings.  So-called ‘free water imaging’, is a sensitive marker of small vessel 
disease,16 cognitive impairment (especially decision-making performance and working memory)17 and 
dementia;18 tracks cognitive function over time;19 precedes overt white matter hyperintensities; and is a 
marker of vasogenic oedema, neuroinflammatory gliosis, and/or loss of neuropil or myelin.20   
 
 
 
Figure 2: a) Fibre orientation distribution (FOD) estimated on multi-shell diffusion-weighted imaging (dMRI); b) FOD and 
compartment models allow decomposition of intra-axonal diffusion, extra-axonal diffusion and trapped water to resolve 
complex crossing fibre maps; c) axial and sagittal MRI showing an area of the corpus callosal genu in a subject who received the 
neurosteroid allopregnanolone (allo) showing d) baseline FOD and e) post-allo FOD increased intra-axonal fibre density 
consistent with reduced brain oedema and inflammation, and white matter regeneration. These measures are similarly relevant
to the mechanisms of action of atorvastatin. 

 
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Statins & Inflammation   
Statins are medications commonly prescribed for the prevention of cardiovascular disease.  They inhibit 3-
hydroxy-3-methylglutaryl coenzyme A reductase, which controls the rate limiting step in cholesterol 
biosynthesis conversion to mevalonate.  However, statins also have non-lipid lowering effects that are 
attributed to mevalonate inhibition, which modify the activation of intracellular proteins21 and have an 
essential role for intracellular inflammatory signalling and pro-inflammatory cytokine responses (Fig. 3).  
Human cell culture experiments and animal models have shown that statins reduce the activation of these 
signalling proteins, which in turn reduces the expression of cytokines, chemokines, acute phase proteins, 
enzymes, and adhesion molecules.  Statins also affect leukocyte-endothelium interactions, modify T-
lymphocyte activity, activate natural killer cells, enhance phagocytosis, and inhibit neutrophil oxidative burst 
and superoxide production, as well as coagulation and thrombosis.   
 
Statins & Cognition 
Epidemiologic associations of statins and risk of dementia have been reviewed in recent publications, including 
an update of trials in the Cochrane library,15, 22-24 which show a lower risk of all-cause dementia and Alzheimer’s 
disease with statin use. However, variability across epidemiological studies and clinical trials appears related 
to the timing and exposure characteristics for statin therapy modulating the risks of cognitive decline and 
dementia.25  There is also evidence of heterogeneity in the effects across different statins, which is missed in 
clustering of epidemiologic association studies.26  Atorvastatin is highly lipophilic, which enables it to cross cell 
membranes including the blood brain barrier.27  Moreover, it has the greatest effect among the statins in 
reducing β-amyloid deposition in rodent models of Alzheimer's disease.28  Several important factors are, 
therefore, likely to influence the effects of statins in preventing cognitive decline and dementia: type, dose, 
length of exposure, and time of initiation within the life-course. These data are persuasive enough to justify 
clinical trials of statin therapy to reduce the risk and/or delay the progression of cognitive decline and 
degenerative dementia in at-risk individuals. Thus, given the critical role of the neurovascular unit in modifying 
the brain’s susceptibility to injury – regulation of cerebral blood flow, blood brain barrier permeability, trophic 
support and repair potential – the benefits of statins are more likely to be realised if commenced soon after 
any acute inflammatory insult.   
 
Summary  
Figure 3: Pleiotropic effects of statins in the context of infection. 

 
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Pleiotropic (i.e. lipid-independent) statin effects on suppressing proinflammatory microglia activity and β-
amyloid deposition, and promotion of endothelial function, are predicted to attenuate the medium and long-
term consequences of COVID-19 on brain health.  Thus, STRONGER aims to determine the clinical benefit of 
atorvastatin to attenuate cognitive decline and reduce (or stabilise) features of neuroinflammation as 
evidenced by cerebral white matter free water and other cerebral changes. 
 
5 Research Question/Aims 
Question: Does treatment with 40mg atorvastatin over 18 months attenuate cognitive decline and 
neuroinflammatory biomarkers in adults with long COVID neurological symptoms?   
Aims:  In 410 adults who report ongoing alteration of their memory, thinking, concentration or mood after 
COVID-19 diagnosis, this pragmatic clinical trial aims to determine the effects of standard-dose atorvastatin 
on improving neurological outcomes with sensitive measures of cognitive function and brain MRI. 
 
6 Methods 
6.1 
Study Design 
STRONGER is an international, investigator-initiated and conducted, multi-centre, prospective, randomised, 
open-blinded end-point (PROBE) study, with fixed time point for outcome assessments. Participants 
randomised to the intervention group will receive 40mg atorvastatin for up to 18 months.  
 
6.2 
Study Setting 
The study sites will be established at centralised research clinics located at: The Brain and Mind Centre of the 
University of Sydney; Alfred Medical Centre linked to Monash University, and a research clinic associated with 
Clínica Alemana Universidad del Desarrollo, Santiago, Chile. Additional sites may be set up as required. 
 
6.3 
Recruitment 
Participants will be recruited from the community in states of Victoria and New South Wales in Australia, and 
in the city of Santiago, Chile. Other states in Australia may participate if remote assessment is possible, and 
possibly other countries according to funding and regulatory requirements.  Recruitment strategies will 
include screening of various COVID-19 registries and advertising campaigns via social media, community, 
pharmacy and community practice sites.  Sources of existing registries/databases include: 
• 
St Vincent’s Hospital, New South Wales – the ADAPT study, total cohort of 167 patients to date.6 
• 
Royal Prince Alfred Hospital, New South Wales – Virtual (hospital-at-home), total cohort of ~1000 
patients to date. 
• 
Royal Melbourne Hospital & West Metro, Victoria – COVID-19 Care Pathway, total cohort of ~600 
patients across a catchment area covering ~25% of the Melbourne population 
• 
Monash University – NeuroCOVID database, ~20 participants to date 
• 
Monash Health, Melbourne – Hotel quarantine health monitoring program 
• 
TGI/UNSW ‘Join Us’ – an Australia-wide electronic research registry to recruit adults with chronic 
disease, including those with COVID-19, to participate in research and involves extensive media 
outreach. 
 

 
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Participants who meet the eligibility criteria will progress through a 2-stage screening process involving:  
a. a telephone call or online preliminary screening, and;  
b. an in-person (or remote on-line) more detailed clinical assessment to assess eligibility. 
 
If an individual is eligible, and after having provided informed consent, they will undergo a series of baseline 
clinical, blood and neuroimaging (a sub-group) assessments in a clinic (or remotely), before being randomised 
into the study.  Reasonable attempts will be made to include a study population with diverse characteristics 
to enhance the broader generalisation of the results.   
 
6.4 
Eligibility Criteria 
6.4.1 
Inclusion Criteria 
1. Age ≥18 years 
2. History of COVID-19 that is confirmed by a positive polymerase-chain-reaction (PCR) test 
3. Any ongoing neurological symptoms as a result of COVID-19 (e.g. problems with memory, 
concentration, sleep disturbance and fatigue) that is identified through administration of the checklist 
of symptoms on the Somatic and Psychological Health Report (SPHERE) questionnaire, or reported 
current loss of smell (anosmia) as a result of COVID-19;29 
4. Able to fully participate in all procedures, including cognitive assessments 
5. Able and willing to provide written informed consent 
 
6.4.2 
Exclusion Criteria 
1. Evidence of dementia and/or significant cognitive impairment on screening (i.e. Blind Montreal 
Cognitive Assessment [MoCA] score <19/22) 
2. Severe co-morbid medical or psychiatric condition that prevents participation 
3. History of traumatic brain injury with loss of consciousness (>30 mins) within the last 2 years 
4. Ongoing long-term use, or clear indication (e.g. secondary cardiovascular prevention in high-risk 
individuals) or contraindication (e.g. previous adverse reaction) for statin use 
5. Evidence of severe or significant liver disease, defined as any of the following: acute viral hepatitis; 
chronic active hepatitis; cirrhosis; or elevated biochemical function markers, i.e. alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN) or 
estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2  
6. Creatine kinase (CK) levels > 2x upper limit of normal (ULN)  
7. Female of child-bearing potential that is, unable or unwilling to use reliable method of contraception, 
breastfeeding, or planning a pregnancy 
8. For a sub-group of participants undergoing MRI – any contraindication to MRI due to metallic body 
parts or claustrophobia 
9. Medical history that might, in the opinion of the attending clinician, put the participant at significant 
risk if they were to participate in the trial 
 
 
 

 
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6.5 
Informed Consent  
Potentially eligible participants will be provided with basic information about the study at initial contact and 
the full participant information sheet and consent form (PISCF) will be provided via email or post on request.  
Remote consent will be collected either via telephone or via an online portal prior to commencement of the 
preliminary screening process.  Once preliminary screening criteria have been satisfied and the PISCF has been 
provided, prospective participants will be provided ample time to read and discuss with family/their doctor 
prior to a attending an in-person clinic visit for assessments.   
 
Participants who have provided remote consent and have agreed to attend the clinic for Visit 1, will be asked 
to attend the clinic in a fasting state to enable fasting blood tests to be collected.  At the clinic, they will be 
taken through the PISCF by research staff, any potential risks and benefits will be explained and opportunity 
to ask questions will be provided.  A copy of the consent to participate will be given to the participant and 
another stored on a password-protected and secured drive at each research clinic. Written informed consent 
must be obtained from all participants before conducting screening assessments in accordance with the 
International Conference on Harmonisation guidelines for Good Clinical Practice (ICH-GCP) and New South 
Wales Health Teletrial Standard Operating Procedures.  
 
The PISCF, signed by the participant and the authorised person conducting the consent process, must be the 
current Ethics Committee (EC)/Institutional Review Board (IRB) approved version.  An electronic or printed 
signed copy will be provided to the participant. 
In the case of a remote visit, and if a participant cannot provide an electronic signature, the participant will be 
asked to sign the informed consent in front of a witness and ask the witness to sign and date.  The signed PISCF 
will be mailed to the study team by the participant via a postage-paid envelope before the videoconference 
assessment.  The process of obtaining informed consent should be documented in the participant’s study 
records.   

 
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6.6 
Schedule of Evaluations 
Table 1: Schedule of Evaluations 
Visit Number 
0 
1 
2 
3 
4 
5 
Time (Weeks [w]/Months [m]) 
-1m to 0 
0 
6w 
6m 
12m 
18m 
Window Period 
- 
- 
±1w 
±1m 
±1m 
±1m 
Visit Type 
Online + Phone 
Clinic* 
Phone 
Clinic* 
Phone 
Clinic* 
Remote / Electronic Informed Consent 
X 
 
 
 
 
 
In-person Written Informed Consent 
 
X 
 
 
 
 
SPHERE Questionnaire  
X 
X 
 
 
 
 
Blind MoCA 
X 
 
 
 
 
 
Eligibility – Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Medical History, Demographics & Socio-Economic Status 
 
X 
 
 
 
 
Pregnancy Test – where required 
 
X 
 
 
 
 
Lifestyle – Smoking, Diet, Alcohol 
 
X 
 
X 
 
X 
History of Health Service Use for COVID-19/Visits to Medical Professionals 
 
X 
 
X 
 
X 
Anthropometrics – Height & Weight 
 
X 
 
 
 
X 
Blood Pressure, Heart Rate 
 
X 
 
X 
 
X 
Fasting 
Bloods 
Haematology/Electrolytes/Renal/Liver Function – full blood count, Na, K, urea, nitrogen, creatinine, eGFR, ALT, AST, CK 
 
X 
 
 
 
X 
Glucose/Lipids/Inflammation – glucose, total cholesterol, LDL, HDL, triglycerides, CRP 
 
X 
 
 
 
X 
Neurodegenerative Biomarkers – 220 participants 
 
X 
 
 
 
X 
Cognitive Assessments – SDMT, RAVLT-D, OTMT-A, OTMT-B, D-KEF-CWIT, SF 
 
X 
 
X 
 
X 
Health Assessments – PHQ-9, GAD-7, PSQI, EQ-5D-5L 
 
X 
 
X 
 
X 
Actigraphy plus Sleep Diary – 7-day Capture 
 
X 
 
X 
 
X 
Brain MRI – 220 participants 
 
X 
 
 
 
X 
Dispense Study Medication – treatment arm only 
 
X 
 
X 
X 
 
Study Medication Adherence & Accountability – treatment arm only 
 
 
X 
X 
X 
X 
Concomitant Medications  
 
X 
X 
X 
X 
X 
SAEs/AESIs 
 
 
X 
X 
X 
X 
*For participants who cannot attend the clinic, efforts will be made for visit assessments to be conducted remotely via tele-/videoconference. 
ALT – Alanine Aminotransferase 
AST – Aspartate Aminotransferase 
CK – Creatine Kinase 
CRP – C-Reactive Protein 
D-KEF-CWIT – Delis-Kaplan Executive Functioning System “Stroop” Colour-Word Interference Test   
GAD-7 – Generalised Anxiety Disorder-7  
HDL – High-Density Lipoprotein  
LDL – Low-Density Lipoprotein 
MoCA – Montreal Cognitive Assessment  
MRI – Magnetic Resonance Imaging  
PSQI – Pittsburgh Sleep Quality Index  
RAVLT-D – Rey Auditory Verbal Learning Test – Delayed Recall  
SDMT – Symbol Digit Modalities Test  
SF – Semantic Fluency  
SPHERE – Somatic and Psychological Health Report 

 
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eGFR – estimated Glomerular Filtration Rate 
EQ-5D-5L – EuroQoL 5-Dimensional 5- Level Questionnaire   
OTMT – Oral Trail Making Tests A & B 
PHQ-9 – Patient Health Questionnaire-9  

 
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6.7 
Visit Summary 
In-person visits will be supplemented with telephone interviews to check on a participant’s ongoing health 
status, adherence to study medication, and any AESIs/SAEs, as well as to provide support and appointment 
reminders.  If participants are unable to attend in-persons visits, Zoom based (or telephone) interviews will be 
undertaken to assess the various health measures, where possible. 
 
6.7.1 
Preliminary Screening 
Preliminary screening will be conducted via telephone or via an online portal to assess key inclusion and 
exclusion criteria that can be assessed remotely.  
 
6.7.2 
Visit 1 – Screening, Baseline & Randomisation 
After preliminary screening, potentially eligible participants who have provided remote consent will be invited 
to attend a morning appointment at a research clinic in a fasting state to complete the screening process and, 
if eligible, baseline assessments. (If required e.g. if results of blood tests are not available on the same day, 
the visit can be split across 2 days).   If participants are unable to attend these clinics and are otherwise eligible 
and willing to participate in the study, efforts will be made to conduct all assessments remotely.   
 
At the screening visit, the following assessments will take place: 
• 
Informed consent  
• 
Eligibility assessment 
• 
Review of participant’s demographics, socio-economic status and lifestyle – smoking, diet and alcohol 
intake 
• 
Review of participant’s medical history including health service use 
• 
Measurement of height and weight 
• 
BP and HR 
• 
Blood sample – following an overnight fast 
o Haematology/electrolytes/renal/liver function – full blood count, sodium, potassium, urea, 
nitrogen, creatinine, eGFR, ALT, AST, CK 
o Glucose/lipids/inflammation – glucose, total cholesterol, low-density lipoprotein (LDL), high-
density lipoprotein (HDL), triglycerides, CRP 
o Neurodegenerative biomarkers (sub-study group: 220 participants) 
• 
Cognitive Assessments 
o Symbol Digit Modalities Test (SDMT), Rey Auditory Verbal Learning Test – Delayed Recall 
(RAVLT-D), Oral Trail Making Test (OTMT) (A & B), Delis-Kaplan Executive Functioning System 
“Stroop” Colour-Word Interference Test (D-KEF-CWIT), Semantic Fluency (SF) 
o Cognitive assessments will be undertaken in a separate session within 7-10 days of the clinical 
assessment by research personnel with skills in cognitive measures. Personnel conducting 
cognitive assessments will be kept blind to the participants’ treatment allocation. Treatment 
allocation (randomisation) will be undertaken by the research coordinator using the study 
database following review of the participant’s routine blood tests.  
• 
Health Assessments 
o Patient health questionnaire 9 (PHQ-9), generalised anxiety disorder 7 (GAD-7), Pittsburgh 
sleep quality index (PSQI), EuroQoL 5-Dimensional 5-Level Questionnaire (EQ-5D-5L) 
• 
Provision of actigraphy watch and sleep diary 

 
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o Actigraphy watches and a sleep diary will be mailed to all participants for recording of their 
physical activity and sleep over a 7-day period in the next 2 weeks, and then returned by 
courier to a central office for downloading of data.  
• 
Brain MRI (sub-study group: 220 participants) 
• 
Randomisation – if eligible 
o After confirmation of eligibility, participants are randomised to receive standard care or study 
medication (atorvastatin 40mg) according a stratification scheme that involves (see Section 
11.2) country, time since the acute COVID-19 illness, age, current anosmia, and participation 
in the MRI/biomarker substudy ,.  
o Participants will only be informed of their treatment allocation once they have completed all 
baseline assessments, in order to reduce the risk of differential withdrawal between the two 
arms. 
• 
Dispense study medication – treatment arm only 
o Study medication will be dispensed in person or via courier in each country; if the latter, an 
SMS message will be sent by the participant to the regional research office to confirm receipt 
of study medication.  If no message is received, the office will contact the participant by 
telephone for confirmation. 
• 
Record of concomitant medications 
 
Visit 1 will take approximately 3-4 hours.  
 
All women of child-bearing potential must have a confirmed menstrual period and a negative highly sensitive 
pregnancy test 7 days or fewer before starting run-in medication and must use a highly effective method of 
contraception throughout their participation in the study. Highly effective contraceptive methods include 
hormonal contraception (oral, intravaginal, transdermal, injectable, implantable) or intrauterine device. These 
methods are not required in the case of bilateral tubal occlusion, vasectomised partner or true sexual 
abstinence (i.e. within line of the person’s preferred and usual lifestyle).  
 
A subset of participants (n=220) will be invited to participate in a sub-study involving: 
• 
the collection and storage of blood for future neurodegenerative biomarker studies, and 
• 
Brain MRI scanning (45 mins).  
These additional assessments will be undertaken either the same day or within the next 7-10 days of the 
baseline clinical assessment, according to booking availability.  See Section 6.10 for further information. 
 
6.7.3 
Visit 2 – 6 Weeks (± 1 Week) – Telephone  
The following will be assessed at the 6-week phone call: 
• 
Review of any SAE/AESIs since last visit 
• 
Adherence to study medication (participant-reported) – treatment arm only 
• 
Changes to concomitant medications 
 
 

 
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6.7.4 
Visit 3 – 6 Months (± 1 Month) – Clinic  
The following will be assessed at the 6-month clinic visit:  
• 
Review of any SAE/AESIs since last visit 
• 
BP and HR 
• 
Adherence to study medication (pill count) – treatment arm only 
• 
Changes to concomitant medications 
• 
Review health service use and lifestyle questions 
• 
Cognitive Assessments 
o SDMT, RAVLT-D, OTMT-A, OTMT-B, D-KEF-CWIT, SF 
o Cognitive assessments will be undertaken in a separate session within 7-10 days of the clinical 
assessment by a separate blinded research person with skills in cognitive measures. 
• 
Health Assessments 
o PHQ-9, GAD-7, PSQI, EQ-5D-5L 
• 
Download of actigraphy watch data 
• 
Collect sleep diary 
• 
Fasting blood tests – routine measures of haematology, biochemistry, renal function, lipids, glucose, 
and inflammatory markers  
• 
Dispense of study medication (to be sent via courier/mail) – treatment arm only 
 
This visit will take approximately 2-3 hours. 
 
6.7.5 
Visit 4 – 12 Months (± 1 Month) – Telephone 
The following will be assessed at the 12-month phone visit:  
• 
Review of any SAE/AESIs since last visit 
• 
Adherence to study medication (participant-reported) – treatment arm only 
• 
Changes to concomitant medications 
• 
Dispense of study medication (to be sent via courier/mail) – treatment arm only 
 
 
6.7.6 
Visit 5 – End of Study 18 Months (± 1 Month) – Clinic  
The following will be assessed at the 18-month End of Study clinic visit:  
• 
Review of any SAE/AESIs since last visit 
• 
Measurement of height and weight 
• 
BP and HR 
• 
Adherence to study medication (pill count) – treatment arm only 
• 
Changes to concomitant medications 
• 
Review medical history and lifestyle questions 
• 
Blood sample – following an overnight fast 
o Haematology/electrolytes/renal/liver function – full blood count, Na, K, urea, nitrogen, 
creatinine, eGFR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), CK 
o Glucose/lipids/inflammation – glucose, total cholesterol, low-density lipoprotein (LDL), high-
density lipoprotein (HDL), triglycerides, CRP 
o Neurodegenerative biomarkers (220 participants) 

 
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• 
Cognitive Assessments 
o SDMT, RAVLT-D, TMT-A, OTMT-B, D-KEF-CWIT, SF 
o Cognitive assessments may be undertaken in a separate session within 7-10 days of the clinical 
assessment and/or by a separate research person with skills in cognitive measures who 
remains blind to the treatment allocation. 
• 
Health Assessments 
o PHQ-9, GAD-7, PSQI, EQ-5D-5L 
• 
Download of actigraphy watch data 
• 
Collect sleep diary 
• 
Brain MRI with biomarkers (subset of 220 participants) 
 
This visit will take approximately 3-4 hours. 
 
6.8 
Assessment Details 
6.8.1 
Screening Questionnaire ‘SPHERE’ 
The SPHERE questionnaire will be administered at screening to assess for long COVID symptoms.  It is a 34-
item self-report questionnaire that was developed to assess symptoms of mental distress and persistent 
fatigue, with questions selected from other common scales. Participants respond to each of the items, 
choosing from one of three fixed options (‘sometimes/never’, ‘often’, and ‘most of the time’, which are coded 
0, 1, and 2, for calculating a sum score) to describe the frequency of their symptoms over the ‘past few weeks’.   
 
This study will use the original 34-item scale to identify any positive response to the three arms of SPHERE: 
anxiety-depression, somatic distress and persistent fatigue.  There is no score threshold for inclusion. 
 
People with anosmia will be included as this is a heterogeneous condition with uncertain relationship to 
olfactory neuronal circuitry and encephalitis, where neuroimaging and long-term follow-up are required.30 
 
6.8.2 
Blind MoCA 
The Blind MoCA will be administered at screening via telephone to assess for any significant cognitive 
impairment. The MoCA is a brief screening test for cognitive impairments that has been validated as a remote 
alternative to the full MoCA that can be administered over the telephone.   It is scored out of 22 with a cut-off 
of N <19 indicating significant cognitive impairment for which subjects will be excluded from participating in 
the study.

 
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6.8.3 
Cognitive Assessments 
Cognitive assessments will be administered between 9:30am and 12:30pm. Completion of all assessments will take approximately 40 mins. 
Name 
Format 
Purpose 
Assessment 
Scoring 
Normative Data 
Test-Retest Reliability 
SDMT 
Oral 
Assesses frontal lobe 
executive processing. 
Requires participants to match 
numbers to symbols according to 
a key, containing 9 abstract 
symbols each paired with a 
number.  Participants verbalise 
the correct number. 
The number of correct 
symbols within the allowed 
time, usually 90 seconds28   
There are Australian 
normative data available 
for the oral SDMT.29  
 
The oral SDMT demonstrates 
excellent test-retest reliability (an 
intraclass correlation coefficient 
of 0.89) and only has a small 
learning effect (Cohen’s d = 0.26) 
within a 1-week interval.30  
RAVLT-D 
Oral 
No difference in 
videoconferencing 
and face-to-face 
RAVLT–D have been 
reported.31 
Assesses memory and 
learning.32 
Requires participants to learn a 
15-item word list over 5 learning 
trials, followed by a distractor 
list, and short and long-delayed 
recall.   
Max score = 15 
Australian normative 
data is available in 
Carstairs, Shores and 
Myors (2012).33 
Test-retest reliability of the RAVLT 
has been reported, with the most 
reliable measures being the total 
number of words learned over the 
learning trials (r = 0.77), and 
performance on the retention trial 
of the learning list following the 
presentation and performance of 
the distractor list (r = 0.70).32 
OTMT-A & B 
Oral 
Provides information on 
visual search, scanning, 
speed of processing, 
mental flexibility, and 
executive functions. 
The OTMT is a sensitive 
measure of early cognitive 
decline in relation to 
vascular-related factors.34, 
35 
Part A – participant is asked to 
count from 1 to 25 as quickly as 
possible.  In Part B – participant is 
asked to progressively alternate 
between counting numbers up to 
13 and reciting letters of the 
alphabet up to L as quickly as 
possible.  
Scores relate to time for 
completion. 
The primary performance 
metric is the time in seconds 
required to complete each of 
the two parts of the test.   
Age-based norms (for 
ages 20 to 90) are 
available in Mrazik, 
Millis, and Drane 
(2010).36 
The OTMT-B demonstrated 
moderate test–retest reliability 
Scores showed significant 
agreement (intraclass correlation 
= .62, p < .0001), a significant 
correlation (Pearson r = .62, p < 
.0001), and similar mean scores 
(M = 41.85, SD = 32.55; M = 43.40, 
SD = 30.18) across 
administrations.37 

 
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Name 
Format 
Purpose 
Assessment 
Scoring 
Normative Data 
Test-Retest Reliability 
D-KEF-CWIT 
Oral 
A battery of 
neuropsychological tests 
designed to measure 
executive functions in 
children and adults, ages 
8–89. 
It is based on the Boston 
process approach38 which 
stipulates that there is a 
primary function that each 
test is designed to 
measure, but also that 
component functions 
contribute to performance 
on a particular test.39  
Four parts: colour naming, word 
reading, inhibition, and 
inhibition/switching.39  
Performance is measured by 
completion time on each of 
the four trials. In addition, 
colour naming and word 
reading times may be 
summed for a composite 
score representing 
component functions. Three 
contrast scores (inhibition vs. 
colour naming, 
inhibition/switching vs. 
combined colour naming and 
word reading, and 
inhibition/switching vs. 
inhibition) may be calculated 
to determine whether there 
is a disproportionate 
impairment in a higher-level 
function than the component 
function(s). 
Australian normative 
data not available. 
The majority of contrast measures 
demonstrated low reliabilities: of 
the 51 reliability coefficients 
calculated in the present study, 
none exceeded 0.7 and hence all 
failed to meet any of the criteria 
for acceptable reliability proposed 
by various experts in psychological 
measurement.40 
SF 
Category fluency to 
animals is valid and 
reliably assessed via 
videoconference 
compared to 
assessed via 
traditional face-to-
face assessment.41 
Assesses language 
processing. 
Requires the generation of as 
many ‘animal names’ in 1-
minute. 
Counting the number of 
correct unique semantic 
category items produced. 
Normative data is 
available in Chami et al. 
(2018)42 
Category fluency to animals 
demonstrated intraclass 
correlation coefficient = 0.98.43 
 

 
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6.8.4 
Other Health Assessments 
PHQ-9 & GAD-7 
• 
Brief and validated measures of the presence and severity of depression and generalised anxiety, 
respectively.42   
• 
PHQ-9 is a brief, self-administered, screening questionnaire for depression, which scores each of the 
nine DSM-V major depression criteria as ‘0’ (not at all) to ‘3’ (nearly every day).  It can be used to make 
a tentative diagnosis of depression in at-risk populations (e.g. those with coronary heart disease or 
after stroke), whereby participants who score ≥10 are likely to have clinically significant depression.   
o In this study, the PHQ-9 will be used as a continuous measure to monitor the severity of 
depression and response to treatment.   
o If a participant has scored >10 on Q9 of the PHQ-9, or positively responded to the final 
question 9 ‘thoughts that you would be better off dead, or of hurting yourself in some way’, 
a member of the study team will advise them to see their GP (or alternate health care 
professional as applies in the local context) and a letter will be sent to the treating doctor 
informing them of the result.   
• 
GAD-7 is a valid and efficient, brief tool for screening for generalised anxiety disorder and assessing 
its severity in clinical practice and research.43 A score of ≥10 represents a reasonable cut point for 
identifying cases of generalised anxiety. Cut points of 5, 10, and 15 might be interpreted as 
representing mild, moderate, and severe levels of anxiety GAD-7. 
PSQI 
• 
Designed to assesses overall sleep quality in clinical populations, covering 19 self-reported items 
across seven sub-categories: subjective sleep quality, sleep latency, sleep duration, habitual sleep 
efﬁciency, sleep disturbances, use of sleeping medication, and daytime dysfunction;44 with five 
additional questions rated by the respondent’s roommate or bed partner, if available.  
• 
Administration by self-report and it generally takes 5-10 mins to complete.  Scores >5 are generally 
indicative of poor sleep quality.  In this study, the PSQI will be analysed as a continuous measure. 
EQ-5D-5L 
• 
Measures HRQoL across five dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), each rated according to five levels, as well as providing an integrated utility score 
for calculating an overall score against population-based preference weights. 
Mobility & Sleep 
• 
Participants will also be invited for the home application of actigraphs and a completion of a sleep 
diary to monitor their sleep-wake and activity patterns over 7-days in the next 2 weeks according to 
established protocols.  These data will be analysed centrally to compute sleep efficiency, nocturnal 
awakenings, sleep timing, total sleep and activity time. The Sleep diary data are used to assist 
interpretation of actigraphy results in accordance with recommendations of the American Academy 
of Sleep Medicine. Actigraphy will also provide a measure of activity, as a proxy for physical activity. 
Both sleep and physical exercise may be important potential mediators of the primary outcome. 
 
 

 
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6.9 
Sub-Study – Neurodegenerative Markers & MRI 
The following assessments will occur in a subset of 220 participants. The assessments will take place at Visit 1 
and Visit 5. 
 
6.9.1 
Neurodegenerative Markers 
Bloods will be collected for measurement of apolipoprotein E, inflammatory and other neurodegenerative 
markers.  The bloods will be collected after an overnight fast (>8 hours) and drawn at 08:00-11:00am according 
to standardised procedures.  The blood will then be immediately centrifuged, and the plasma locally stored at 
-80°C within 2 hours of collection.  The bloods will be shipped at the end of the study for subsequent storage 
and analysis on a SIMOA immunoanalyser at the Department of Neuroscience (Alfred Hospital Precinct), 
Monash University, Melbourne, Australia. Key markers of neurodegeneration to be measured include Ptau-
181, neurofilament light chain (NfL) and Aβ42/40, and DNA extraction for apolipoprotein E genotype.  
Peripheral markers of oxidative stress and inflammatory markers relevant to neurodegeneration (IL-6, IL-1, 
NAD+, TNF-, hsCRP) will also be collected for subsequent exploratory analyses.  
 
6.9.2 
MRI Scanning 
MRI scanning will be undertaken on 3-Tesla clinical scanners at the Alfred Hospital (Melbourne, Australia), 
Brain and Mind Centre (Sydney, Australia), and the Clínica Alemana (Santiago, Chile).  Scan sessions will take 
approximately 45 minutes and will include acquisition of: 
• 
whole brain 3D T1-weighted, T2-weighted, and fluid-attenuated inversion structural images;  
• 
2D diffusion-weighted microstructural images;  
• 
3D pseudo-continuous arterial spin labelling perfusion images;  
• 
3D susceptibility-weighted images; and  
• 
magnetic resonance spectroscopy in the posterior cingulate.   
 
All scans will be acquired with the participant at rest, with no requirements for contrast or other injections, 
breath holds or other active engagement.  Participant screening and data acquisition will be performed by 
clinical radiographers at all sites.  Following local acquisition, all scans will be securely transferred in DICOM 
format, and housed on the Monash University XNAT imaging informatics server, Melbourne, Australia. 
 
According to standard procedures , where an abnormal finding is detected on the MRI scan that is deemed by 
the site radiologist to require clinical follow-up or monitoring (e.g. small cerebral aneurysm, plaque suspicious 
of multiple sclerosis, small meningioma), the participant will be notified and the report forwarded to the 
participant's primary care or other physician (i.e. in Australia, a general practitioner [GP]) unless a more urgent 
follow-up is necessary (e.g. primary or secondary tumour, cerebral aneurysm, arteriovenous malformation); 
in which case we arrange for a direct referral to a neurologist in addition to GP. In other countries, appropriate 
follow-up will be arranged in accordance with the local clinical pathways) . Asymptomatic incidental findings 
(e.g. small spot-like abnormalities in the cerebral white matter) that are not deemed to have clinical relevance 
are not reported back to participant; because there is variability in what different radiologists will include in 
their report and it can cause a lot of anxiety for participants without any commensurate benefit. 
 
 
 

 
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6.10 Communications with Health Care Providers 
The study team will communicate with GPs or alternate designated health care provider (according to local 
context) via telephone, mail or email (if available), at least three times throughout the study.   
1. Prior to participant participation. The study procedures will be briefly explained, including information 
about the study medication, and any concerns regarding participation will be sought.   
o If at the screening stage, a participant is ineligible for the study or a physical, mental or social 
health issue has been identified, the GP (or alternate health care provider) will also be advised 
particularly if further investigations or consultation with the participant may be required.  
2. When the participant is randomised to the study.  
3. At the end of the trial, regardless of whether the participants have dropped out or completed the trial, 
GP (or alternate health care providers) will be provided with their participants blood test results and 
interpreted neuropsychological test results. 
 
7 Study Treatment & Adherence 
7.1 
Study Treatment  
Participants who meet the eligibility criteria will be randomised to receive standard care or 6-monthly supplies 
of atorvastatin 40mg on top of standard care for a period of 18 months.    
 
7.2 
Blinding 
Study treatment is open-label. The randomisation allocation will be blinded to researchers conducting 
cognitive assessments and endpoint adjudicators. All participants, physicians and other study team members 
will be aware of participant treatment allocation.  However, participants will only be informed of their 
allocation after all the baseline assessments have been completed in order to reduce the risk of differential 
withdrawal between the two arms. 
 
7.3 
Treatment Adherence 
To maximise participant adherence to study medication, the following procedures will be implemented: 
• 
Participant education on the importance of taking study medication, including timing, storage, and 
what to do in the event of a missed dose; 
• 
Returned tablets will be counted and recorded by the study team; 
• 
Participants will be provided with contact details of the responsible researcher so that they can make 
contact if for any reason they are unable to continue their study medication or have missed multiple 
doses and are unsure whether to continue. 
 
7.4 
Management of Possible Treatment Related Side-Effects 
The following strategies (Table 2) can be employed for participants with side-effects deemed due to study 
medication and sufficiently severe to warrant a change of treatment. 

 
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Table 2: Strategies for change in treatment due to side-effects 
Clinical Scenario 
Strategy 
Clear contraindication to a statin 
Ineligible  
Mild symptoms of myalgia, 
nausea, dizziness 
Temporarily stop study medication.  If symptoms improve, restart study 
medication  – subject to investigator’s discretion.  If symptoms persist, study 
medication can be permanently stopped. 
Moderate-severe symptoms of 
abdominal pain or myalgia, 
with/without biochemical or 
haematological abnormalities 
Temporarily stop study medication. Factors to consider include renal 
impairment and other medications.  On improvement, consider re-challenging 
with study medication and review. If symptoms persist, study medication can be 
permanently stopped. 
If severe reaction, permanently cease study medication and begin appropriate 
alternate treatment in accordance with local guidelines. 
 
For possible or suspected Statin-Associated Muscle Symptoms (SAMS), the National Prescribing Service (NPS) 
process will be followed (see Appendix 14).  
 
7.5 
Permanent Discontinuation of Study Treatment 
Permanent discontinuation of study medication is not considered withdrawal from the study and participants 
should continue to complete all study assessments in accordance with the intention to treat (ITT) principle.  
Participants who have temporarily stopped study medication for any reason other than the above should be 
encouraged to restart study medication as soon as practically, and medically appropriate at the discretion of 
the investigator. 
 
The investigator must not deviate from the protocol, except when there is a contraindication, due to the 
participant’s condition or the participant is intolerant of the study medication, in these cases, the study 
medication should be temporarily stopped. Study medication should also be temporarily or permanently 
stopped if:  
▪ 
there is an SAE, which in the opinion of the investigator, is related to the study 
medication; and/or  
▪ 
the investigator assesses that it is in the participant’s best interest” 
 
8 Concomitant Medications 
Investigators are directed to consult the Product Information for atorvastatin for consideration of listed 
contraindications, special warnings and precautions.   
 
All concomitant medications taken by the participant at screening, baseline and during the study period will 
be recorded in their study files and entered in the electronic case report form (eCRF).  Further instructions 
about capturing these data will be provided in a procedure manual. 
 
9 Study Withdrawal 
If a participant wishes to withdraw or the study team/responsible investigator decides it is in the best interest 
of the participant to withdraw from further participation in the study, every effort should be made for the 
participant to report any SAEs to the study team that occur within 4 weeks of their last dose of study 
medication (as applies), and to attend an end of study visit prior to withdrawal. 
 

 
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10 Co-Enrolment of Participants into Other Studies 
Co-enrolment in another investigative drug intervention trial may be considered provided there is agreement 
between the steering committees of both trials that there are no contraindications or adverse impact on 
outcomes of either trial.   Participants who are enrolled in investigational device, lifestyle trial or observational 
cohort study, may be included into the STRONGER study at the discretion of the investigator. Co-enrolment of 
participants into this study is allowed where participants are informed, and there are strategies in place to 
avoid undue burden on them and/or duplication of research effort through co-operation with other research 
(trial/s) leaders. 
 
11 Statistical Methods 
11.1 Sample Size 
A sample of 410 patients will provide 90% power (α=0.05) to detect at least a 0.3 standard deviation (SD) effect 
size difference between groups, assuming equal group participation.  These calculations assume a modest 5% 
non-compliance and 5% dropout over 18-months of follow-up.  The SDMT age-adjusted mean score is 
estimated at 60 (SD = 13) at baseline (based on healthy control data).32  The effect is based on statin dementia 
prevention and multiple sclerosis trials, where achieved effect sizes of 0.3-0.4 are clinically meaningful and 
likely to confer public health benefits.45   
11.1.1 Sub-Study Sample Size 
For the sub-study, a sample size of 220 (110 per group) is estimated (α=0.05) to provide 80% power to detect 
effect sizes of relative differences of 5.0-6.5 (variance between groups/variance within groups) for the imaging 
endpoints, assuming a 20% drop out. 
 
11.2 Assignment of Intervention 
Participants will be registered and randomised via a secure web-based database. The randomisation will be 
stratified by the following factors: (i) country; (ii) time (<6 vs. ≥6 months since acute COVID-19 illness), (iii) age 
(<60 vs. ≥60 years), (iv) Current anosmia that has occurred in relation to COVID-19, and (v) participation in the 
MRI/biomarker substudy.  
  
11.3 Statistical Analysis 
The study follows the ITT principle for analysis. Baseline characteristics will be summarised by treatment 
group.  The primary endpoint of change on the SDMT score will be summarised by means (SD)/medians 
(interquartile range), with the treatment effect tested by a Wilcoxon test.  Continuous endpoints will be 
summarised by means/medians.  The primary analysis will be through logistic regression models adjusted for 
region, age and sex.  A sensitivity analysis will be undertaken with adjustment for baseline imbalances and 
clinically meaningful confounders.  Descriptive statistics will be provided for safety data, where SAEs and 
treatment discontinuation will be tabulated using standard terminology.  Heterogeneity of treatment on the 
primary endpoint will be assessed in pre-defined subgroups, such as age, time since COVID-19 diagnosis, 
baseline CRP levels, ethnicity, and prior cardiovascular risk.  Analyses will be specified a priori in a full 
statistical analysis plan.  A modelled cost-utility analysis using trial data (HRQoL, captured by EQ-5D-5L; drug 
costs; and health service utilisation costs, including AEs) will be conducted comparing use of atorvastatin and 

 
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standard care.  A 5-year time horizon will be undertaken, with analyses conducted in line with accepted 
Australian standards for use of economic evaluation in decision-making. 
12 Outcomes 
12.1 Primary Outcome 
The primary outcome is processing speed, assessed by the oral SDMT.   
 
12.2 Key Secondary Outcome 
The key secondary outcome is total white matter free water (dMRI) undertaken using data collected in 
standard procedures using multi-shell diffusion spectral imaging with fibre orientation and compartment 
modelling. SC members from Monash University have developed a novel computational framework to 
accurately characterise multi-shell diffusion spectral imaging signals from high b-values whilst retaining the 
capability of reliably resolving crossing fibres.  Three compartments are used to associate brain microstructure 
to the diffusion signal: an intra-axonal compartment, an extra-axonal compartment, and a third compartment 
representing the fraction of trapped water molecules with essentially negligible diffusion.   
 
12.3 Other Outcomes 
Various other components of cognition; other health assessments and MRI markers of white matter 
hyperintensity volume, enlarged peri-vascular space volume, total grey matter volume, white matter 
microstructure (fractional anisotropy), basal ganglia iron load and total cerebral perfusion, and spectroscopy-
derived glutathione as a marker of oxidative stress; cost-effectiveness compared to standard care. 
 
12.4 Safety Outcomes 
AEs, AESIs and SAEs. 
 
13 Safety 
13.1 DSMB  
The DSMB will review the safety, ethics and outcomes of the study. The DSMB is responsible for monitoring 
cognitive and safety outcomes for early dramatic benefits or potential harmful effects and provide reports to 
the SC on recommendations to continue or temporarily halt recruitment to the study.  The DSMB will be 
governed by a charter that will outline their responsibilities, procedures and confidentiality.  They will review 
unblinded data from the study at regular intervals during follow-up and monitor treatment adherence 
differences between the two groups, drop-out, and event rates. It is anticipated that the first data review will 
be conducted after the first 50 participants have achieved 6 months of follow-up, and 6- monthly reviews 
thereafter.  
  
13.2 Definitions & Reporting 

 
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13.2.1 Adverse Events  
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product at any dose and which does not necessarily have a causal relationship 
with this treatment.  Therefore, an AE can be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational 
medicinal product (IMP), whether or not it is considered related to the IMP. This definition includes 
intercurrent illnesses or injuries, and an exacerbation of a pre-existing condition.  
13.2.2 AESI 
The expected adverse reactions to the study medication that will be used in this study that are of special 
interest are listed below. To better assess participants’ tolerability to the study medications, the following 
AESIs and whether they are new or ongoing from baseline, will be reported in the eCRF at specified visits, 
regardless of severity and seriousness: 
• 
myalgia 
• 
nausea 
• 
elevation in blood glucose 
• 
elevation in creatinine kinase 
• 
abdominal pain 
• 
new-onset diabetes mellitus 
• 
rhabdomyolysis 
 
 
13.2.3 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
results in death 
• 
is life-threatening in the opinion of the attending clinician (i.e. the participant was at risk of death at 
the time of the event; it does not refer to an event that might hypothetically have caused death had 
it been more severe) 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation  
• 
results in persistent or significant disability or incapacity 
• 
results in congenital anomaly or birth defect (Note that females in the study are required to take 
effective contraception) 
• 
is an important medical event in the opinion of the attending clinician that is not immediately life-
threatening and does not result in death or hospitalisation, but which may jeopardise the patient or 
may require intervention to prevent one of the other outcomes listed above. 
AEs which do not fall into these categories are defined as non-serious.   
 
If treatment is discontinued as a result of any AE, serious or non-serious, the site study team will document 
all events leading to the discontinuation of treatment. 
 
If an SAE is unresolved at the conclusion of the study or if the participant withdraws early from the study, a 
clinical assessment will be made by the medical monitor as to whether continued follow-up of the SAE is 
warranted. 
 
13.2.4 Suspected Unexpected Serious Adverse Reactions 
An unexpected adverse reaction is an adverse reaction, the nature or severity of which is not consistent with 
the listed side effects in accordance with the applicable product information for atorvastatin.   

 
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A suspected unexpected serious adverse reaction (SUSAR) is any unexpected adverse reaction that at any dose 
meets the definition of an SAE. TGI will be responsible for reporting all SUSARs to regulatory authorities in 
accordance with country-specific requirements and in compliance with the International Conference on 
Harmonisation’s Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 
 
13.2.5 SAE Reporting Period 
All SAEs will be collected from the time the participant is enrolled in the study until the end of the final follow-
up visit. To ensure SUSAR reporting requirements are met, site investigators are required to report all SAEs in 
the study database within 24 hours of becoming aware of an event. 
 
 
 

 
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14 Study Drug Management 
14.1 Manufacturer & Packaging 
The study medication, atorvastatin, will be sourced from Syntro Health, Richmond, Australia, a community 
pharmacy that specialises in  direct to patient (DTP) services and clinical trials in particular. Atorvastatin 40mg 
has TGA and United States Food and Drug Administration (FDA) approval for general marketing for the 
treatment of hypercholesterolaemia and cardiovascular prevention under a number of manufacturer names. 
Although no particular manufacturer will be chosen for this study, the sourced study medication will be 
consistent across sites where practical. The study medication selected will be the atorvastatin 40mg (Lorstat) 
which is scored, and allows down-titration to 20mg should a participant develop symptoms.  The study 
medication will be packaged, labelled and dispensed directly to particpants by  the Syntro Health pharmacy in 
Australia.  A comparable atorvastatin 40mg is being sourced in Chile, and will be dispensed from the pharmacy 
of the Clínica Alemana de Santiago and Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, 
Santiago, Chile. 
 
14.2 Labelling 
Country-specific labelling requirements will be followed. Labels will include: (a) name of the sponsor; (b) 
pharmaceutical dosage form, route of administration, quantity of dosage units (and name/identifier of the 
product and strength/potency); (c) the batch and/or code number to identify the contents and packaging 
operation; (d) the trial participant identification number, where applicable; (e) directions for use; (f) “for 
clinical trial use only”; (g) the name of the investigator (if not included as a code in the trial reference code); 
(h) a trial reference code allowing identification of the trial site and investigator; (i) the storage conditions; (j) 
the period of use (use-by date, expiry date or re-test date as applicable), in month/year); (k) “keep out of reach 
of children”. 
 
14.3 Distribution & Resupply  
Syntro Health will manage distribution and resupply of study medication via courier either direct to participant 
in Australia. 
 
14.4 Storage 
The study medication will be stored at ambient temperature (<25°C) and protected from excessive light 
exposure in a secure area with limited access before distribution to participants.   
 
14.5 Drug Dispensing & Accountability 
All study medication dispensed to and returned from participants will be recorded on a dispensing and 
accountability log, maintained by the STRONGER study staff. Specific details on IMP management will be 
included in study-specific manuals and plans. 
 
14.6 Disposal & Destruction 

 
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All unused and/or expired study medication will be returned to the appropriate STRONGER site for destruction 
at a suitable facility following accountability, and confirmed and written authorisation from the study team at 
TGI.  A copy of the final signed confirmation of destruction will be provided to TGI by the facility for filing in 
the Trial Master File.  Destruction will be carried out in compliance with the regulatory requirements. 
 
15 Data Management & Quality Assurance 
All data entry will be completed via a secure web-based data management system called IBM Clinical 
Development. Data entry will be performed at the participating sites by authorised site staff who have 
completed training and been given appropriate role-based access to the system. Data logic and consistency 
checks will be programmed into the data entry forms so that data entry errors can be caught in real-time and 
queries auto-generated.  Authorised electronic signatures will be used to lock completed data entry forms 
once all data queries have been resolved within the system. Data entry and all subsequent changes or 
deletions will be captured in an accessible audit trail.  Coding of outcomes will be centrally performed either 
automatically via the IBM coding module or manually by the CCC. All coding will be reviewed and verified by 
the Medical Monitor. Reporting within the system will be used for regular data reviews and overall trial 
monitoring. Data will be stored and backed up on the IBM’s cloud servers in the United States. 
 
16 Monitoring & Auditing 
16.1 Monitoring 
Trial data will be monitored, using central risk-based monitoring principles, to detect any unusual patterns of 
data that would require further investigation. 
During the study, representatives of the CCC will monitor site performance and quality via remote methods 
including via videoconference to ensure that the study is conducted in accordance with the protocol, ICH-GCP 
guidelines and relevant ethical and regulatory requirements.  Relevant data and source documentation will be 
archived for a minimum of 15 years. 
 
16.2 Auditing 
The study may be audited by third parties and inspected by government regulatory authorities.  Paper CRFs, 
source documents and other study documentation must be accessible at all study sites at the time of auditing 
for inspection during and after the completion of the study. If an inspection is requested by a regulatory 
authority, the investigator must inform TGI immediately after this request has been made. 
 
17 Regulatory & Ethical Considerations 
17.1 Regulatory & Ethical Compliance 
This study protocol was designed, and shall be implemented and reported, in accordance with the ICH-GCP, 
NHMRC National Statement on Ethical Conduct in Human Research, and with the ethical principles laid down 
in the World Medical Associations Declaration of Helsinki. 
 

 
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The protocol and the proposed PISCF and any subsequent modifications will be reviewed and approved by an 
EC before any participants are enrolled.  Prior to study start, investigators are required to sign a protocol 
signature page confirming their agreement to conduct the study in accordance with these documents and all 
the instructions and procedures found in this protocol and to give access to all relevant data and records to 
TGI monitors, auditors, EC, and regulatory authorities as required.   
 
17.2 Protocol Amendments 
A protocol amendment is a written description of change(s) to, or formal clarification of a study protocol which 
may impact on the conduct of the clinical study, potential benefit of the clinical study, or may affect participant 
safety, including changes of study objectives, study design, participant population, sample size, study 
procedures, or significant administrative aspects.  An administrative change of a study protocol is a minor 
correction or clarification that has no significant impact on the way the study is to be conducted and no effect 
on participant safety (e.g. change of telephone number(s), logistical changes).  Protocol amendments must be 
approved by the SC and the EC.  In cases when the amendment is required in order to protect participant 
safety, the amendment can be implemented prior to EC approval.  Notwithstanding the need for formal 
approval of a protocol amendment, the investigator is expected to take any immediate action required for the 
safety of any participant included in this study, even if this action represents a deviation from the protocol.  In 
such cases, TGI should be notified of this action. 
 
17.3 Informed Consent 
Before the start of the study, a member of the study team will have the PISCF and any other materials that 
will be provided to the participants reviewed and approved by the EC.  This review and approval will be 
documented and stored with other study documents.   
Potential participants may only be included in the study after providing in-person written or online/remote 
verbal and written informed consent.  The responsible study team member must fully inform the participant 
of all relevant aspects of the trial.  The participant must be allowed ample time to ask details about the study, 
and to make a decision as to whether or not to participate.  The participant must personally or electronically 
sign the PISCF indicating their agreement to participate in the study.  An electronic copy of the signed PISCF 
will be provided to the participant. 
 
17.4 Confidentiality 
Every precaution will be taken to respect the privacy of participants in conduct of the study.  Only de-identified 
data will be entered in the study database to maintain participant confidentiality.  All information will be de-
identified in reporting data and results to protect the confidentiality of participants. 
 
17.5 Post-Study Care 
Following completion of the study, participants will be referred back to their primary care/treating physician 
for ongoing management.  Neuropsychological scores will be interpreted and provided to GP and participants 
in appropriate forms. 
 
 
 

 
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17.6 Reimbursement 
It is anticipated that most participants will be of working age and be required to attend clinics for assessments.  
The baseline and end of study visits will each last 3-4 hours, which may require time away from work or daily 
activities. Participants will therefore be reimbursed for their time (AUD$100) at the baseline and end of study 
visits, and any reasonable travel expenses for these and other study visits. 
 
18 Document Retention 
The study team will retain all study records required by TGI and by the applicable regulatory bodies in a secure 
and safe facility for a minimum period of 15 years.  
 
19 Publications Policy & Data Sharing 
Writing Committees, with oversight by the SC, will be formed from members of the various committees, 
statisticians, research fellows and investigators.  They will prepare all reports of the study to be published in 
the name of “STRONGER Investigators” with credit assigned to the collaborating investigators and other 
research staff.  Presentations of the study findings will be made at national and international meetings 
concerned with the management of cognitive assessments, mild cognitive impairment and dementia. 
 
Authors of publications must meet the following International Committee of Medical Journal Editors (ICMJE) 
guidelines for authorship. Authors must: 
a. Make substantial contributions to the conception and design of the study, acquisition of data, or analysis 
of data and interpretation of results. 
b. Draft the publication or, during draft review, provide contributions (data analysis, interpretation, or 
other important intellectual content) leading to significant revision of the manuscript with agreement 
by the other authors. 
c. Provide approval of the final draft version of the manuscript before it is submitted to the journal for 
publication. 
 
All contributors who do not meet the 3 criteria for authorship will be listed in an acknowledgments section 
within the publication, if allowed by the journal, per ICMJE guidelines for acknowledgement. 
 
At the completion of the study, requests for secondary analysis will be in accordance with a defined protocol 
from an experienced research group with an agreed analysis plan with TGI.  In addition, data will be shared 
with other investigators on the study, and investigators from other institutions around the world, according 
to a strict data sharing agreement. Data sharing will be available from 12 months after publication of the main 
results.  The PISCF will include information as to the purpose of this activity. Investigators are to make a formal 
request for data sharing through the Research Office of TGI, Australia and get approval from the SC. 
 
 
 

 
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20 Appendices 
20.1 Appendix 1 – SPHERE Questionnaire 
 
 

 
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20.2 Appendix 2 – SDMT 
Please look at these boxes at the top of the page. You can see that each box in the upper row has a 
little mark in it. Now look at the boxes in the row just underneath the marks. Each of the boxes under the 
marks has a number. Each of the marks in the top row is different, and under each mark in the bottom row is 
a different number. 
Now look at the next line of boxes (point) just under the top two rows. Notice that the boxes on top 
have marks, but the boxes underneath are empty. You are to fill each empty box with the number that should 
go there according to the way they are paired in the key at the top of the page and tell me what the number 
is. For example, if you look at the first mark, and then look at the key, you will see that the number 1 goes in 
the first box. So, you call out the number 1 for the first box. Now, what number should you put in the second 
box? Just call it out to me (number 5) That’s right. So, you would say “5” to me. What number goes in the third 
box? (number 2). Two, right. That’s the idea. You are to fill each of the empty boxes with the numbers that 
should go in them according to the key and call out the numbers to me. Now for practice, tell me the numbers 
and fill in the rest of the boxes until you come to the double line. When you come to the double line, stop. 
No when I say “go” call out the numbers just like you have been doing until I say “STOP”. I will write 
the numbers down for you. When you come to the end of the first line, go quickly to the next line without 
stopping, and so on. If you make a mistake, tell me what you think the correct answer is. Do not skip any boxes 
and work as quickly as you can. Ready? Go. Allow 90secs. 
 
 

 
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20.3 Appendix 3 – RAVLT-D 
 

 
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20.4 Appendix 4 – OTMT A 
 
 

 
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20.5 Appendix 5 – OTMT B 
 
 

 
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20.6 Appendix 6 – D-KEF-CWIT 
 

 
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20.7 Appendix 7 – SF  
 

 
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20.8 Appendix 8 – PHQ-9 
 
 
 
 

 
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20.9 Appendix 9 – PSQI 
 
 
 

 
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20.10 Appendix 10 – GAD-7 
 
 
 

 
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20.11 Appendix 11 – EQ-5D-5L 
 
 
 
 

 
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20.12 Appendix 12 – Blind MoCA 
 

 
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20.13 Appendix 13 – Sleep Diary 
 

 
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20.14 Appendix 14 – NPS SAMS 
 
 

 
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21 References 
1. 
Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and 
treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324:782-793 
2. 
Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and pathogenesis of sars-cov-2. BMJ. 
2020;371:m3862 
3. 
Del Rio C, Collins LF, Malani P. Long-term health consequences of COVID-19. JAMA. 2020 
4. 
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from 
hospital: a cohort study. Lancet. 2021;397:220-232 
5. 
Taquet M, Geddes JR, Musain M, Luciano S, Harrison PJ. 6-molnth neurological and psychiatric outcomes in 236379 
survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry 2021 
(published online April 6, 2021). 
6. 
Darley DR, Dore GJ, Cysique L, Wilhelm KA, Andresen D, Tonga K, et al. Persistent symptoms up to four months after 
community and hospital-managed SARS-CoV-2. MJA 214:279-80. 
7. 
Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and neurologic 
manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA Neurol. 2020;77:1018-
1027 
8. 
Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute COVID-19. JAMA. 
2020;324:603-605 
9. 
Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ. 
2020;370:m3026 
10. Zhou H, Lu S, Chen J, Wei N, Wang D, Lyu H, et al. The landscape of cognitive function in recovered COVID-19 
patients. J Psychiatr Res. 2020;129:98-102 
11. Iadecola C, Anrather J, Kamel H. Effects of covid-19 on the nervous system. Cell. 2020;183:16-27 e11 
12. Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric 
presentations associated with severe coronavirus infections: a systematic review and meta-analysis with 
comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020;7:611-627 
13. Kremer S, Lersy F, de Seze J, Ferre JC, Maamar A, Carsin-Nicol B, et al. Brain mri findings in severe COVID-19: a 
retrospective observational study. Radiology. 2020;297:E242-E251 
14. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among 
survivors of severe sepsis. JAMA. 2010;304:1787-1794 
15. Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, et al. Evidence-based prevention of alzheimer's disease: 
Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. 
J Neurol Neurosurg Psychiatry. 2020;91:1201-1209 
16. Duering M, Finsterwalder S, Baykara E, Tuladhar AM, Gesierich B, Konieczny MJ, et al. Free water determines 
diffusion alterations and clinical status in cerebral small vessel disease. Alzheimers Dement. 2018;14:764-774 
17. Gullett JM, O'Shea A, Lamb DG, Porges EC, O'Shea DM, Pasternak O, et al. The association of white matter free 
water with cognition in older adults. Neuroimage. 2020;219:117040 
18. Dumont M, Roy M, Jodoin PM, Morency FC, Houde JC, Xie Z, et al. Free water in white matter differentiates MCI 
and AD from control subjects. Front Aging Neurosci. 2019;11:270 
19. Maillard P, Fletcher E, Singh B, Martinez O, Johnson DK, Olichney JM, et al. Cerebral white matter free water: a 
sensitive biomarker of cognition and function. Neurology. 2019;92:e2221-e2231 
20. Wang Y, Wang Q, Haldar JP, Yeh FC, Xie M, Sun P, et al. Quantification of increased cellularity during inflammatory 
demyelination. Brain. 2011;134:3590-3601 
21. Terblanche M, Almog Y, Rosenson RS, Smith TS, Hackam DG. Statins and sepsis: multiple modifications at multiple 
levels. Lancet Infect Dis. 2007;7:358-368 
22. Geifman N, Brinton RD, Kennedy RE, Schneider LS, Butte AJ. Evidence for benefit of statins to modify cognitive 
decline and risk in Alzheimer's disease. Alzheimers Res Ther. 2017;9:10 
23. Zhang X, Wen J, Zhang Z. Statins use and risk of dementia: a dose-response meta analysis. Medicine (Baltimore). 
2018;97:e11304 
24. McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 
2016:CD003160 
25. Samaras K, Makkar SR, Crawford JD, Kochan NA, Slavin MJ, Wen W, et al. Effects of statins on memory, cognition, 
and brain volume in the elderly. J Am Coll Cardiol. 2019;74:2554-2568 
26. Pandey RD, Gupta PP, Jha D, Kumar S. Role of statins in Alzheimer's disease: a retrospective meta-analysis for 
commonly investigated clinical parameters in RCTs. Int J Neurosci. 2013;123:521-525 
27. Joshi HN, Fakes MG, Serajuddin AT. Differentiation of 3‐hydroxy‐3‐methylglutaryl‐coenzyme a reductase inhibitors 
by their relative lipophilicity. Pharmacy and Pharmacology Communications. 1999;5:269-271 

 
STRONGER Protocol 
Version 2.0  
12 May 2021 
 
STRONGER Protocol v2.0, 12 May 2021 
 
Page 54 of 54 
28. Rahman SO, Hussain S, Alzahrani A, Akhtar M, Najmi AK. Effect of statins on amyloidosis in the rodent models of 
Alzheimer's disease: evidence from the preclinical meta-analysis. Brain Res. 2020;1749:147115 
29. Couvy-Duchesne B, Davenport TA, Martin NG, Wright MJ, Hickie IB. Validation and psychometric properties of the 
somatic and psychological health report (SPHERE) in a young australian-based population sample using non-
parametric item response theory. BMC Psychiatry. 2017;17:279 
30. Han AY, Mukdad L, Long JL, Lopez IA. Anosmia in COVID-19: mechanisms and significance. Chem Senses. 2020 
31. Bettcher BM, Libon DJ, Kaplan E, Swenson R, Penney DL. Digit symbol substitution test. 2018:1160-1165 
32. Kiely KM, Butterworth P, Watson N, Wooden M. The symbol digit modalities test: normative data from a large 
nationally representative sample of australians. Arch Clin Neuropsychol. 2014;29:767-775 
33. Koh CL, Lu WS, Chen HC, Hsueh IP, Hsieh JJ, Hsieh CL. Test-retest reliability and practice effect of the oral-format 
symbol digit modalities test in patients with stroke. Arch Clin Neuropsychol. 2011;26:356-363 
34. Hildebrand R, Chow H, Williams C, Nelson M, Wass P. Feasibility of neuropsychological testing of older adults via 
videoconference: implications for assessing the capacity for independent living. J Telemed Telecare. 2004;10:130-
134 
35. Geffen GM, Butterworth P, Geffen LB. Test-retest reliability of a new form of the auditory verbal learning test 
(AVLT). Arch Clin Neuropsychol. 1994;9:303-316 
36. Debette S, Seshadri S, Beiser A, Au R, Himali JJ, Palumbo C, et al. Midlife vascular risk factor exposure accelerates 
structural brain aging and cognitive decline. Neurology. 2011;77:461-468 
37. Brugulat-Serrat A, Salvado G, Sudre CH, Grau-Rivera O, Suarez-Calvet M, Falcon C, et al. Patterns of white matter 
hyperintensities associated with cognition in middle-aged cognitively healthy individuals. Brain Imaging Behav. 
2020;14:2012-2023 
38. Mrazik M, Millis S, Drane DL. The oral trail making test: effects of age and concurrent validity. Arch Clin 
Neuropsychol. 2010;25:236-243 
39. Delis DC. Delis-kaplan executive function system (D-KEFS) San Antonio. TX: The Psychological Corporation. 2001 
40. Milberg WP, Hebben N, Kaplan E, Grant I, Adams K. The Boston process approach to neuropsychological assessment. 
Neuropsychological assessment of neuropsychiatric and neuromedical disorders. 2009;3:42-65 
41. Munro Cullum C, Hynan LS, Grosch M, Parikh M, Weiner MF. Teleneuropsychology: evidence for video 
teleconference-based neuropsychological assessment. J Int Neuropsychol Soc. 2014;20:1028-1033 
42. Lowe B, Kroenke K, Herzog W, Grafe K. Measuring depression outcome with a brief self-report instrument: 
sensitivity to change of the patient health questionnaire (PHQ-9). J Affect Disord. 2004;81:61-66 
43. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: The GAD-7. 
Arch Intern Med. 2006;166:1092-1097 
44. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep quality index: a new instrument 
for psychiatric practice and research. Psychiatry Res. 1989;28:193-213 
45. Goldman MD, LaRocca NG, Rudick RA, Hudson LD, Chin PS, Francis GS, et al. Evaluation of Multiple Sclerosis 
disability outcome measures using pooled clinical trial data. Neurology. 2019;93:e1921-e1931