68Ga-FAPI PET/CT to Detect Ongoing Fibroblast Activity in Post-acute COVID-19 With Respiratory Impairment After Hospital Discharge
Conditions: Post-Acute COVID-19, Post-Acute COVID-19 Infection, Post-Acute COVID-19 Syndrome, Pulmonary Fibrosis
Sponsor: University Medical Center Groningen

NL80095.042.22  
 
 
 
 
 
FAPI COVID-CLIMATE Study 
 
 
 
   
 
 
 
 
 
 
 
68Ga-FAPI PET/CT to detect ongoing fibroblast 
activity in post-acute COVID-19 with respiratory 
impairment after hospital discharge: “The FAPI 
COVID-CLIMATE Study” 
 
 
 
 
 
 
 

NL80095.042.22  
 
 
 
 
 
FAPI COVID-CLIMATE Study 
 
 
 
PROTOCOL TITLE: 68Ga-FAPI PET/CT to detect ongoing fibroblast activity in post-acute 
COVID-19 with respiratory impairment after hospital discharge: “The FAPI COVID-CLIMATE 
Study” 
 
Protocol ID 
202100802 
Short title 
The FAPI COVID-CLIMATE Study 
EudraCT number  
2021-006797-24 
Version 
4.0 
Date 
02/06/2023 
Coordinating investigator/project 
leader  
 
Prof. dr. Riemer HJA Slart, Medical Imaging Centre, 
Department of Nuclear Medicine & Molecular 
Imaging, UMCG, NL 
r.h.j.a.slart@umcg.nl  
Ph: 0031-50-3611835 
 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
Dr. Janesh Pillay,   
Department of Critical Care, UMCG, NL  
j.pillay@umcg.nl   
 
 
Dr. Marieke L. Duiverman, Department of Pulmonary 
Diseases/Home Mechanical Ventilation, UMCG, NL 
m.l.duiverman@umcg.nl 
 
Dr. Douwe F. Postma, Department of Internal 
Medicine & Infectious Diseases, UMCG, NL  
d.f.postma@umcg.nl 
 
Drs. Mark Londema, Department of Critical Care, 
UMCG, NL 
m.londema@umcg.nl 
 
Drs. Bram van Leer,  
Department of Medical Imaging, 
Department of Critical Care, UMCG, NL 
b.van.leer@umcg.nl 
 
Prof. Dr. Andor Glaudemans, Medical Imaging 
Centre, Department of Nuclear Medicine & Molecular 
Imaging, UMCG, NL 
a.w.j.m.glaudemans@umcg.nl 
 

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FAPI COVID-CLIMATE Study 
 
 
 
Prof. dr. Philip Elsinga, Medical Imaging Centre, 
Department of Nuclear Medicine & Molecular 
Imaging, UMCG, NL 
p.elsinga@umcg.nl  
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
MIC, UMCG 
Subsidising party 
UMCG/ZonMw 
Independent expert  
Dr. Walter Noordzij, MIC, UMCG 
 
 
 
 
Laboratory sites  
MIC, UMCG 
 
 
Pharmacy  
MIC, department of Nuclear Medicine & Molecular 
Imaging 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof.dr. Rudi AJO Dierckx, Head of MIC 
 
 
 
 
 
22 March 2022 
Principal Investigator: 
Prof.dr. Riemer HJA Slart, staff MIC 
 
 
 
 
 
22 March 2022 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
1.1 
Background to pulmonary fibrosis in post-COVID-19 syndrome ............................10 
1.2 
Study Aim .............................................................................................................11 
1.3 
Research Hypothesis ............................................................................................11 
1.4 
Rationale for Study ...............................................................................................11 
2. 
OBJECTIVES ................................................................................................................12 
Primary objectives ............................................................................................................12 
3. 
STUDY DESIGN ...........................................................................................................13 
4. 
STUDY POPULATION ..................................................................................................14 
4.1 
Population (base) ..................................................................................................14 
4.2 
Inclusion criteria ....................................................................................................14 
4.3 
Exclusion criteria ...................................................................................................14 
4.4 
Sample size calculation .........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................14 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................15 
6.1 
Name and description of investigational product(s) ...............................................15 
6.2 
Summary of findings from non-clinical studies.......................................................15 
6.3 
Summary of findings from clinical studies ..............................................................15 
6.4 
Summary of known and potential risks and benefits ..............................................15 
6.5 
Description and justification of route of administration and dosage .......................15 
6.6 
Dosages, dosage modifications and method of administration ..............................15 
6.7 
Preparation and labelling of Investigational Medicinal Product ..............................15 
6.8 
Drug accountability ...............................................................................................15 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................16 
8. 
METHODS ....................................................................................................................17 
8.1 
Study parameters/endpoints .................................................................................17 
8.2 Randomisation, blinding and treatment allocation .......................................................17 
8.3 
Study procedures ..................................................................................................17 
8.4 
Withdrawal of individual subjects...........................................................................20 
8.5 
Replacement of individual subjects after withdrawal .............................................20 
8.6 
Follow-up of subjects withdrawn from treatment ....................................................20 
8.7 
Premature termination of the study .......................................................................20 
9. 
SAFETY REPORTING ..................................................................................................21 
9.1 
Temporary halt for reasons of subject safety .........................................................21 
9.2 
AEs, SAEs and SUSARs ......................................................................................21 
9.2.1 
Adverse events (AEs) .......................................................................................21 
9.2.2 
Serious adverse events (SAEs) .........................................................................21 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ...........................22 
9.3 
Annual safety report ..............................................................................................23 
9.4 
Follow-up of adverse events .................................................................................23 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] .................................23 

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10. 
STATISTICAL ANALYSIS .........................................................................................24 
10.1 
Primary study parameter(s) ...................................................................................24 
10.2 
Secondary study parameter(s) ..............................................................................24 
10.3 
Other study parameters ........................................................................................24 
10.4 
Interim analysis (if applicable) ...............................................................................24 
11. 
ETHICAL CONSIDERATIONS ..................................................................................25 
11.1 
Regulation statement ............................................................................................25 
11.2 
Recruitment and consent ......................................................................................25 
11.3 Objection by minors or incapacitated subjects (if applicable).....................................25 
11.4 Benefits and risks assessment, group relatedness ....................................................25 
11.5 
Compensation for injury ........................................................................................25 
11.6 
Incentives ..............................................................................................................25 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ........................26 
12.1 
Handling and storage of data and documents .......................................................26 
12.2 
Monitoring and Quality Assurance.........................................................................26 
12.3 
Amendments .........................................................................................................26 
12.4 
Annual progress report ..........................................................................................26 
12.5 
Temporary halt and (prematurely) end of study report ...........................................27 
12.6 
Public disclosure and publication policy ................................................................27 
13. 
STRUCTURED RISK ANALYSIS ..............................................................................28 
13.1 
Potential issues of concern ...................................................................................28 
13.2 
Synthesis ..............................................................................................................29 
14. 
REFERENCES .........................................................................................................30 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
6-MWT 
ABR 
6 Minute Walking Test 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-
formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
 
DLCO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
Diffusing capacity of the Lungs for Carbon Monoxide 
DSMB 
ECM 
Data Safety Monitoring Board 
Extracellular Matrix 
EU 
European Union 
EudraCT 
FAP 
FAPI           
European drug regulatory affairs Clinical Trials  
Fibroblast Activation Protein 
Fibroblast Activation Protein Inhibitors 
GCP 
GMP 
Good Clinical Practice 
Good Manufacturing Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
HRCT 
IB 
High-Resolution Computed Tomography 
Investigator’s Brochure 
IC 
ILA 
Informed Consent 
Interstitial Lung Abnormalities 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC 
 
MBq 
PASC 
PET/CT  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
Megabecquerels 
Post-Acute Sequelae of SARS-CoV-2 Infection 
Positron emission tomography/computerized tomography 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 

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Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
SUV 
TLF 
Suspected Unexpected Serious Adverse Reaction 
Standardized Uptake Value 
Total Lesion Fibrosis 
UAVG 
 
VC 
Dutch Act on Implementation of the General Data Protection Regulation; 
in Dutch: Uitvoeringswet AVG 
Vital Capacity 
WMO 
 
wlFAPI-
MAV 
wlTL-
FAPI 
wlSUV 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
Whole Lung FAPI-Metabolic Active Volume 
 
Whole Lung Total Lesion-FAPI 
 
Whole Lung Standardised Uptake Value 
 
 
 

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SUMMARY 
 
 
Rationale: The pathogenesis of post-acute COVID-19 with respiratory complaints remains 
unknown. We aim to explore the pulmonary pattern and fibrosis activity in patients with post-
acute COVID-19 with respiratory complaints using 68Ga-FAPI Positron Emission 
Tomography-Computed Tomography (PET/CT) imaging.  
Objective: To relate pulmonary fibroblast activity, measured by FAPI-PET/CT at least 3 
months after hospital discharge, to interstitial lung abnormalities on HRCT at the same time 
point in post-acute COVID-19 patients with respiratory complaints.  
Study design: This is a ZonMw funded single center prospective observational cohort study 
of post-acute COVID-19 patients with respiratory complaints. 
Study population: We will recruit 20 adult patients with post-acute COVID-19 and 
respiratory complaints that will undergo 68Ga-FAPI PET/CT imaging to establish pulmonary 
fibrosis activity.   
Main study parameters/endpoints: To assess the degree of Fibroblast Activation Protein 
expression on 68Ga-FAPI PET/CT at least 3 months after hospital discharge and to relate this 
to interstitial lung abnormalities on HRCT at the same time point.      
 
 
 

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1. INTRODUCTION AND RATIONALE 
 
1.1 Background to pulmonary fibrosis in post-COVID-19 syndrome  
 The ongoing pandemic caused by the novel coronavirus (SARS-COV-2), which causes the 
disease known as COVID-19, is leading to another epidemic of post-acute patients with 
persistent health impairments. The majority of COVID-19 patients survive the infection and 
acute illness, however, the long-term health effects are largely unknown. A substantial 
proportion of patients experience long-term symptoms, ranging from pure respiratory 
symptoms to disabling fatigue and mental issues (1,2), referred to as long COVID-19 or post-
acute sequelae of COVID-19 (PASC). It has been shown that the majority of COVID-19 
survivors have some persistent interstitial lung abnormalities (ILA) on HRCT, most extensive 
in post-intensive care unit patients and patients with longer duration of hospitalization (3,4). 
However, both the evolution of these ILA and their nature are unknown, since they can 
reflect ongoing inflammation, residual areas of organizing pneumonia, or early fibrosis. This  
may result in persistent pulmonary complaints, with or without an abnormal lung function test, 
with up to 76% of the patients still having normal diffuse capacity (5). Although chest 
computed tomography (CT) has been shown to be a useful tool in identifying lung 
abnormalities in patients with PASC, it does not provide information about the pathogenesis 
and possible targets for intervention. Advanced molecular imaging to assess ongoing 
fibroblast activity has the potential to provide a pathophysiological model and, possibly, 
personalized targeted pharmacological interventions. The recently developed 68Ga-FAPI PET 
tracer has this potential.  
Fibroblast activation protein (FAP) alpha is a type II transmembrane protease with dipeptidyl 
peptidase and endopeptidase activity which is induced in fibroblasts upon activation and is 
negligible or absent in resting fibroblasts or other cell types (6). The recently developed 
radiolabeled quinoline-based positron emission tomography (PET) tracers binding to FAP, 
like 68Ga-FAPI, demonstrate tracer uptake in various tumor entities (7). Expression of FAP as 
detected by 68Ga-FAPI PET also correlates with fibrotic activity and disease progression in 
the lungs of patients with systemic sclerosis-associated interstitial lung disease (8).  
68Ga-FAPI PET can therefore aid in the understanding of the pathophysiology of PASC with 
persistent pulmonary complaints. With 68Ga-FAPI PET we aim to quantify the fibroblastic 
activity in relation to the percentage of interstitial lung abnormalities on high resolution 
computed tomography (HRCT), lung function testing including diffusing capacity of the lungs 
for carbon monoxide (DLCO) and vital capacity (VC), fibrotic and inflammatory blood 
markers, systemic and upper respiratory tract cellular phenotypes as determined by single 
cell RNA sequencing, 6-minute walking test (6-MWT) and self-reported daily impairments 
measured by EQ-5D questionnaire of patients with PASC at >3 months after hospital 

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discharge and, in case of persisting symptoms, at 8-10 months after 68Ga-FAPI PET/CT 
scan.   
 
1.2 Study Aim 
With 68Ga-FAPI PET we aim to quantify the fibroblastic activity in relation to the interstitial 
lung abnormalities on high resolution computed tomography (HRCT), lung function including 
DLCO and VC, fibrotic and inflammatory blood markers, systemic and upper respiratory tract 
cellular phenotypes determined by single cell RNA sequencing, 6-MWT and self-reported 
daily impairments measured by EQ-5D questionnaire in post-acute COVID-19 patients. 
   
1.3 Research Hypothesis 
We hypothesize that increased fibroblast activity can be found on PET and interstitial lung 
abnormalities on HRCT in post-acute COVID19 patients with pulmonary complaints, with a 
match and/or mismatching pattern between both imaging modalities. 
 
1.4 Rationale for Study 
The quantification of pulmonary fibrosis activity using 68Ga-FAPI PET has the ability to 
advance our understanding of the pathological processes that occur in post-acute COVID-19 
patients with persistent pulmonary complaints. It is unknown whether the persistent 
respiratory impairments and fibrotic lesions on HRCT are the result of ongoing fibroblast 
activity. The findings from this study will provide us with much needed pathophysiological 
insight in post-acute COVID-19 and result in identification of patients that may benefit in the 
future from anti-fibrotic medication to enhance pulmonary recovery.  
 

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2. OBJECTIVES 
 
Primary objectives 
To relate pulmonary fibroblast activity, measured by FAPI-PET/CT at least 3 months after 
hospital discharge, to interstitial lung abnormalities on HRCT at the same time point (T0) in 
post-acute COVID-19 patients with respiratory complaints.  
 
Secondary objectives 
To relate pulmonary fibroblast activity, measured by FAPI-PET/CT, to specific fibrosis and 
inflammatory blood markers, upper respiratory and systemic cell phenotypes, 6-MWT, lung 
function including DLCO and VC, and self-reported daily impairments measured by the EQ-
5D questionnaire at the same time point (T1) and to HRCT findings, EQ-5D and 6-MWT, in 
case of persistent respiratory complaints 8-10 months after timepoint T0.    
 

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3. STUDY DESIGN 
 
This is a prospective observational cohort study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Flow chart of study procedures. 
 
 
 
 
 
 
 
Nuclear medicine department, at least 3 months after hospital 
discharge (timepoint T0): 
 
Insertion iv line + blood drawing  
Lung function test 
Nasal swab 
FAPI-PET/CT + HRCT  
6-MWT  
Participant to return EQ-5D questionnaire 
Identification of participants fulfilling the inclusion criteria at (post-
COVID) pulmonary outpatient department (including referrals from 
other clinics) by attending pulmonologist. Handing over of patient 
information (PIF) and consent form. 
8-10 months after timepoint T0: 
Phonecall from investigator to subject 
In patients undergoing repeat HRCT (ordered by attending pulmonologist, as part 
of regular care) for persisting respiratory complaints: Repeat 6-MWT and EQ-5D 
questionnaire  
2 weeks after pulmonary outpatient department visit: 
If consented: investigator to contact participant.  
Arrange FAPI-PET CT within 4 weeks 
Send EQ-5D questionnaire by (e-)mail 

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4. STUDY POPULATION 
 
4.1 Population (base)   
We will recruit 20 hospital-discharged adult patients with post-acute COVID-19 and 
respiratory complaints.  
 
  
4.2 Inclusion criteria 
• 
Male patients >18 years and female patients >20 years discharged from hospital 
after PCR-confirmed COVID-19 infection. 
• 
Previous ICU or ward admission with high flow nasal oxygen (HFNO) or mechanical 
ventilation. 
• 
Persistent respiratory complaints (shortness of breath) at least 3 months after 
hospital discharge.  
 
4.3 Exclusion criteria 
 
Subjects should not enter the study if any of the following criteria are fulfilled: 
• 
Inability or unwilling to give informed consent. 
• 
History of claustrophobia or feeling of inability to tolerate supine position for the 
PET/CT scans. 
• 
Severe or significant comorbidity, defined as COPD GOLD stage II or higher, 
known interstitial lung disease and/or an ASA score (11) of IV and higher. 
• 
Women who are pregnant or breastfeeding. 
  
4.4 Sample size calculation 
This is an explorative study and a power analysis cannot be applied to calculate the number 
of included patients. The total number will be 20 patients, as performed usually in these kinds 
of feasibility studies (12).  
 
5. TREATMENT OF SUBJECTS 
 
Not applicable. 

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6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational product(s) 
68Ga–fibroblast activation protein inhibitor ([68Ga]FAPI-46) is a quinoline-based 
radiopharmaceutical used for the in vivo detection of the fibroblast activation protein using 
positron emission tomography (PET). Chemical name is Gallium;(R)-2,2’,2’’-(10-(2-(4-(3-((4-
(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-
yl)(methyl)amino)propyl)piperazin-1-yl)-2-oxoethyl)1,4,7,10,tetraazacyclododecane-1,4,7-
triyl)triacetate. [68Ga]FAPI-46 is produced as a sterile, intravenously injectable solution of the 
radiopharmaceutical, containing  10% ethanol in 0.9% phosphate buffered sodium chloride 
(PBS) solution (v/v) 
6.2 Summary of findings from non-clinical studies 
Please see the Investigational Medicinal Product Dossier (IMPD).  
6.3 Summary of findings from clinical studies 
See section 13.1.  
6.4 Summary of known and potential risks and benefits 
See Section 13.1.  
6.5 Description and justification of route of administration and dosage 
68Ga-FAPI has been administered to humans and demonstrated its ability to detect areas of 
fibrosis activity within different cancers at acceptable radiation doses (1.6 mSv) (13). No 
other available route of administration.  
6.6 Dosages, dosage modifications and method of administration 
Intravenous injection of 200 megabecquerels (MBq) 68Ga-FAPI.  
6.7 Preparation and labelling of Investigational Medicinal Product 
68Ga-FAPI will be manufactured locally in a GMP licensed facility adjacent to the PET 
scanners. Quality Control will be performed on a sample of the final product before releasing 
68Ga-FAPI for use against pre-established specifications including radiochemical and 
chemical purity, residual solvents, endotoxin content and pH. Sterility will also be confirmed 
post release. 
6.8 Drug accountability 
Not applicable. 
 

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7. NON-INVESTIGATIONAL PRODUCT 
 
Not applicable. 

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8. METHODS 
 
8.1 Study endpoints 
 
8.1.1 Main study endpoint 
To assess the degree of Fibroblast Activation Protein expression on 68Ga-FAPI PET/CT at 
least 3 months after hospital discharge (timepoint T0) and to relate this to interstitial lung 
abnormalities on HRCT at the same time point.   
 
 
8.1.2 Secondary study endpoints 
1. To relate the degree of Fibroblast Activation Protein expression at least 3 months after 
hospital discharge to DLCO and VC, ECM and inflammatory blood markers, systemic and 
upper respiratory tract cellular phenotypes,  6MWT and EQ-5D at the same time point. 
2. To relate the degree of Fibroblast Activation Protein expression at least 3 months after 
hospital discharge to interstitial lung abnormalities on HRCT, 6MWT and EQ5D 8-10 months 
after timepoint T0 in patients with persisting respiratory complaints. 
 
8.2 Randomisation, blinding and treatment allocation 
Not applicable. 
 
8.3 Study procedures 
 
8.3.1 PET Radiotracer 68Ga-FAPI production 
68Ga-FAPI will be manufactured locally in a GMP licensed facility adjacent to the PET 
scanners. Quality Control will be performed on a sample of the final product before releasing 
68Ga-FAPI for use against pre-established specifications including radiochemical and 
chemical purity, residual solvents, endotoxin content and pH. Sterility will also be confirmed 
post release. 
 
 
8.3.2 PET/CT imaging 
 
To assess pulmonary fibrosis activity, we will perform 68Ga-FAPI biodistribution studies in 20 
post-COVID-19 patients using established protocols. After insertion of a periperheral 
intravenous catheter, each subject will undergo a PET and low dose CT (PET/CT) 
scan (Vision or QUADRA Biograph mCT, Siemens Medical Systems, Erlangen, Germany), 
from head to proximal lower limb 60 minutes following intravenous injection of 200 MBq 68Ga-

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FAPI. An HRCT scan will be performed immediately afterwards, on the same scanner. Total 
scanning time will be 15 minutes.  
If HRCT, as ordered by attending pulmonologist as part of regular care, is repeated 11-13 
months after hospital discharge for persisting pulmonary complaints, this data will be used for 
analysis. 
PET analysis: 
68Ga-FAPI uptake as a measure of fibrosis activity in the lung will be evaluated by visual 
assessment of the active pulmonary 68Ga-FAPI lesions . Increased 68Ga-FAPI uptake will be 
compared with the muscle background uptake and defined as being positive when higher, 
and verified by follow-up with HRCT. For quantitative analysis, a specialized software 
platform from Hermes Hybrid 3D (Hermes Medical Solutions AB, Stockholm, Sweden) will be 
used. The mean and maximum standardized uptake value (SUV) and the metabolic active 
volume (MAV) normalized to body weight will be manually computed for the active pulmonary 
lesions and healthy tissues by drawing a 3-dimensional volume of interest. Multiplication of 
SUVmean and MAV results in total lesion FAPI (TL-FAPI). Whole-lung FAPI-MAV (wlFAPI-
MAV) can then be calculated by summation of MAV over all lung areas. Whole lung mean 
SUV (wlSUVmean) will be calculated as the mean of the SUV values of all five pulmonary 
lobes. These parameters will allow us to calculate whole lung TL-FAPI (wlTL-FAPI) by 
multiplying wlFAPI-MAV with SUVmean.  
SUVmax ratio for the pulmonary hotspot will be defined as the quotient of the SUVmax of this 
lesion and the normal muscular tissue, and target-to-background ratio (TBR) for active 
pulmonary lesions will be calculated according to the formula: TBR = tSUVmax/mSUVmean, 
where tSUVmax is the maximum SUV of lung lesion, and mSUVmean is the mean SUV of 
muscle.  
HRCT analysis:  
In the absence of a validated scoring system to evaluate HRCT scans for the presence of 
fibrosis in PASC, we will use a validated scoring system developed by Desai and Goh for 
evaluation of interstitial lung abnormalities on HRCT in patients with systemic sclerosis 
associated interstitial lung disease, idiopathic pulmonary fibrosis and idiopathic non-specific 
interstitial pneumonia (14,15). HRCT scans will be reviewed at five levels. At each level, four 
features of fibrosis will be quantified: the extent of interstitial lung disease, the relative 
proportions of interstitial lung disease made up of a reticular pattern and ground-glass 
opacification, the amount of emphysema, and the coarseness of fibrosis. Finally, an overall 
grade of interstitial lung disease depending on the relative extent of a reticular pattern will be 
given. 
 
 
8.3.3 Questionnaire 

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For assessment of self-reported daily impairments, all subjects will be asked to complete the 
EQ-5D questionnaire. Completion of the EQ-5D takes 5 to 10 minutes. The EQ-5D is a 
generic classification system used to characterize current health states of individuals, for 
which “of the shelf” utilities from members of the general public are available in the literature. 
The EQ-5D consists of 5 domains (mobility; self-care; usual activity; pain/discomfort; 
anxiety/depression) and a Visual Analogue Scale (EQ-VAS). Subjects are asked to indicate 
their level of health by checking one of three levels of functioning for each domain. For the 
VAS, subjects draw a line from a box to the point on the thermometer like-scale 
corresponding to their health state, 0-100 (100 is best health state). 
Outcome of the test is a unitless number between 0 and 1 that be calculated from an online 
calculator at the website of the developer of the test (euroqol.org), with 1 being the best 
possible outcome and 0 the worst.  
Subjects will return the EQ-5D personally or via mail. The investigator will check whether all 
questionnaires are fully completed and will correct, if necessary, in consultation with the 
subject.  
If HRCT, as ordered by attending pulmonologist as part of regular care for persisting 
pulmonary complaints, is repeated 8-10 months after timepoint T0, 6 minute walking test will 
be performed again. 
 
 
8.3.4 Blood sample collection 
At the time of FAPI PET/CT, 30ml of blood for measurement of circulating Extracellular 
Matrix (ECM) markers and inflammatory parameters (C-reactive protein, leucocyte count, 
lymphocyte count, erythrocyte sedimentation rate) will be drawn from the intravenous 
catheter. ECM markers consist of several biomarkers that have been shown to predict lung 
function decline and mortality in pulmonary fibrosis (16). Serum samples will be labeled with 
a unique code which is made up of FAPI-COVID, the subject’s study number and date of 
drawing, stored at -80°C and sent for further analysis after collection of all samples. The 
samples will be accessible during the study period to the investigators. The encryption key is 
accessible to the coordinating investigator only.  
 
 
8.3.5 Nasal epithelium collection 
 
Nasal epithelium collection will be performed as follows. Subjects are asked for their 
favourable nostril to perform the procedure. Subjects are then asked to blow their nose and 
attempt to remove any mucous from the nose. 1 mL of Lidocaine (10mg/mL) is collected in a 
1mL or 2 mL syringe. Subjects are asked to make the sound of the letter K repeatedly while 

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0.5mL of lidocaine is injected into the nostril (aiming toward the inferior turbinate) to numb 
the area to be brushed. The subjects are asked to lean forward and any remaining Lidocaine 
is collected onto a tissue. The steps are repeated with another 0.5mL of lidocaine. After a 
few minutes, using the speculum to open the nostril, the lateral area underneath the inferior 
turbinate is the brushed for 3 seconds and the brush is placed in 2 mL screw-cap Eppendorf 
tube containing 1.5 mL of RNAProtect Cell solution. The brush is then cut into the tube using 
a wire cutter cleaned with RNAse Zap and alcohol. 
 
 
8.3.6 Physical exercise 
All subjects will perform a 6-minute walking test at the same visit of the FAPI PET/CT. The 
test will be taken according to guidelines (17). Heartrate and peripheral oxygenation will be 
measured before and after the test. Outcome of the test is total walking distance in meters. 
The whole test takes approximately 10 minutes.  
If HRCT, as ordered by attending pulmonologist as part of regular care, is repeated 8-10 
months after timepoint T0 for persisting pulmonary complaints, 6 minute walking test will be 
performed again. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
8.5 Replacement of individual subjects after withdrawal 
Replacement for subjects after withdrawal from the study if the patients withdraws after 
inclusion.  
 
8.6 Follow-up of subjects withdrawn from treatment 
Patients that withdraw from the study will not be followed up.  
 
8.7 Premature termination of the study 
Not applicable. 
 
 
 
 
 

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9. SAFETY REPORTING 
 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or 
safety. The sponsor will notify the accredited METC without undue delay of a temporary halt 
including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects are 
kept informed. Unexpected incidental findings on the 68Ga-FAPI PET/CT will be noted and 
reported to the head practitioner of the patient who inform the patient as well. 
 
9.2  AEs, SAEs and SUSARs 
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the investigational product and trial procedure. All 
adverse events reported spontaneously by the subject or observed by the investigator or his 
staff will be recorded. 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events, except for the following SAEs:   
 

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The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
− SUSARs that have arisen in the clinical trial that was assessed by the METC; 
− SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once every half year to the METC. This line-listing provides an overview of all SUSARs from 
the study medicine, accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or ToetsingOnline 
is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other Member 
States, according to the requirements of the Member States.  
 

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The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life-threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the report.  
 
9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, and 
competent authorities of the concerned Member States. 
This safety report consists of: 
− a list of all suspected (unexpected or expected) serious adverse reactions, along 
with an aggregated summary table of all reported serious adverse reactions, 
ordered by organ system, per study; 
− a report concerning the safety of the subjects, consisting of a complete safety 
analysis and an evaluation of the balance between the efficacy and the 
harmfulness of the medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported until the end of the study within the Netherlands, as defined in the 
protocol. 
 
9.5 Data Safety Monitoring Board (DSMB) 
Considering the low risk associated with this study, a DSMB will not be instituted.  

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10. STATISTICAL ANALYSIS 
 
Normally distributed quantitative variables will be presented with the mean, standard 
deviation and 95 % confidence interval. Non-normally distributed data will be presented with 
median and interquartile range. Outcomes of primary and secondary study parameters will 
be exploratory outcomes.  
 
10.1 Primary study parameter(s) 
Descriptive statistics will be used to analyze the degree of Fibroblast Activation Protein 
expression on 68Ga-FAPI PET/CT, expressed as wlTL-FAPI and wlFAPI-MAV. Correlations 
between FAPI-PET/CT findings and HRCT findings will be assessed using Pearson’s 
correlation coefficient or Spearman’s rank-order correlation. A p-value of <0.05 will be 
considered significant.  
 
10.2 Secondary study parameter(s)  
The correlation between FAPI PET/CT findings and lung function (DLCO and VC), 6-MWT, 
EQ5D and HRCT fibrosis findings will be assessed using Pearson’s correlation coefficient or 
Spearman’s rank-order correlation. Statistical significance between consecutive tests will be 
assessed using analysis of variance, paired t-test or Wilcoxon signed-rank test, as 
appropriate.  A p-value of <0.05 will be considered significant. 
 
10.3 Other study parameters 
Not applicable. 
 
10.4 Interim analysis (if applicable) 
Not applicable. 
 
 
 
 
 
 
 
 
 

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11. ETHICAL CONSIDERATIONS 
 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th 
WMA General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the 
Medical Research Involving Human Subjects Act (WMO).  
 
11.2 Recruitment and consent 
Patients will be recruited at the post-COVID outpatient clinic in the UMCG, including referrals 
from pulmonologists in the north of the Netherlands. A participant information file (PIF) and 
consent form will be handed over to possible inclusions by the attending pulmonologist. The 
patient will return the consent form by mail to the principal investigator if the patient decides 
to participate.  
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
 
11.4 Benefits and risks assessment, group relatedness 
The findings from this study will provide us pivotal biomechanistic insight in post-acute 
COVID-19. It will also result in identification of patients that may benefit in the future from 
anti-fibrotic medication to enhance pulmonary recovery. The risk of developing cancer as a 
consequence of the exposure to radiation in this study is very low. 
 
11.5 Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7 of 
the WMO. 
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives 
Participants will receive traveling costs in compensation and a gift card of 75 euro for their 
participation in the study.   

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
12.1 Handling and storage of data and documents 
All Investigators and study site staff involved with this study must comply with the 
requirements of the EU General Data Protection Regulation and the Dutch Act on 
Implementation of the General Data Protection Regulation with regard to the collection, 
storage, processing and disclosure of personal information and will uphold these Act’s core 
principles. Access to collated participant data will be restricted to individuals from the 
research team treating the participants, representatives of the sponsor(s) and 
representatives of regulatory authorities. 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
Published results will not contain any personal data that could allow identification of 
individual participants. RedCap will be used for data storage and analysis. 
 
12.2 Monitoring and Quality Assurance  
This study will be monitored yearly by a monitor from the UMCG monitoring pool (Johan 
Wiegers). 
 
12.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to affect to 
a significant degree: 
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 

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numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the 
study within a period of 90 days. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC and the Competent Authority. 
 
12.6 Public disclosure and publication policy 
Ownership of the data arising from this study resides with the study team. The study results 
will be submitted unreservedly for publication in a peer-reviewed journal or other scientific 
platform. Both positive and negative results will be disclosed. Published results will not 
contain any personal data that could allow identification of individual participants. 

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13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
There are some potential hazards of the investigations that we will perform as part of the 
trial. The main issues relate to exposure to ionising radiation and arterial line insertion. 
 
a. Level of knowledge about mechanism of action 
Ionising radiation can cause cancer which manifests itself after many years or decades. The 
estimated associated risk of developing fatal cancer is proportional to dose and also to the 
participant’s age at the time of exposure. The risk for younger people is higher than for older 
people and the risk for females is higher than for males of the same age. According to report 
26 of the Netherlands Commission on Radiation Dosimetry, radiation exposure for this study 
must be in category IIb at most. Since total radiation exposure in this study is 5 mSv, males 
must be at least 10 years old and females must be at least 20 years old to fall into category 
IIb (18). 
A recent study scanned 25 patients following injection of between 198 and 299 MBq 68Ga-
FAPI-4 (19). With consideration to minimising dose, all participants in this study will receive a 
maximum of 200 MBq per IV administration of 68Ga-FAPI-4 with a total dose of 1.6 mSv. All 
participants will receive an additional dose from the (low dose) CT-component of the scanner 
(an additional 0.7 mSv), including a baseline HRCT (2.7 mSv) so in total each PET/CT 
including HRCT will be associated with 5mSv of radiation exposure (see Supplement 
Radiation dose calculation). The follow-up chest HRCTs will be clinically performed. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar 
biological mechanism 
[68Ga]FAPI-46 has been applied in several human studies in patients with various types of 
cancer (12,13,19–21) and pulmonary fibrosis (8). No adverse events have been reported in 
these studies.  
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human 
cell material? 
Not for this study as we are looking into pulmonary fibrosis timeline in humans.  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Not applicable. 
 
e. Analysis of potential effect 
Please see: Synthesis.  

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f. Pharmacokinetic considerations 
Not applicable. 
 
g. Study population 
We will recruit 20 adult patients with post-acute COVID-19 and respiratory complaints that 
will undergo 68Ga-FAPI PET/HRCT imaging to establish pulmonary fibrosis activity. This 
group will be divided in two subgroups:   
Group 1: pulmonary complaints and abnormal lung function test. 
Group 2: pulmonary complaints and normal lung function test. 
The Total Research Protocol Dose (TRPD) per patient is 5 mSv.  
 
h. Interaction with other products 
Patients should not be included in other studies including ionizing radiation while being part 
of our study. No other pharmacodynamic interactions expected.  
 
i. Predictability of effect 
Not applicable. 
 
j. Can effects be managed? 
Potential risk is minimal at current radiation doses. Patients will be advised to avoid further 
ionizing radiation.   
 
13.2 Synthesis 
The absolute lifetime risk of developing cancer as a consequence of taking part in this study 
for the participant at highest risk, i.e. a 20-year-old female, is 0.04% (22). For comparison, 
the natural lifetime cancer incidence in the general population is about 50%. Taking part in 
this study increases the participant’s chance of this happening to them from 50% to 50.04%. 
The average annual background radiation dose arising from natural sources of ionising 
radiation in the environment in the Netherlands is 1.7 mSv to 2.5 mSv (23). Participants in 
our study will receive the equivalent of about 2 to 2.5 times annual background radiation from 
natural sources.  
 
 
 

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