Evaluation of the Feasibility and Reproducibility of 2 Point-of-Care Tests for SARS-Co-V-2 Antibodies (INSIGHT 017)
Conditions: COVID-19, SARS CoV 2 Infection
Sponsor: University of Minnesota



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Table of Contents 
1 
Protocol Summary ...............................................................................................................1 
2 
Introduction ..........................................................................................................................3 
 
Study Rationale ............................................................................................................3 
 
Background...................................................................................................................4 
 
Point-of-Care Platforms.................................................................................................5 
2.3.1 
LumiraDX SARS-CoV-2 antibody test ....................................................................5 
2.3.2 
RightSign COVID-19 IgG/IgM rapid test .................................................................7 
3 
Methodology ........................................................................................................................8 
 
Study Design ................................................................................................................8 
 
Study Objectives ...........................................................................................................9 
3.2.1 
Field test ................................................................................................................9 
3.2.2 
Central laboratory ................................................................................................10 
 
Sample Size and Statistical Considerations ................................................................10 
3.3.1 
Local versus central POC test result ....................................................................10 
3.3.2 
Local and central POC test result versus GenScript cPass assay result ..............11 
3.3.3 
Case-control comparison .....................................................................................11 
 
Participant Selection for the Field Test ........................................................................11 
3.4.1 
Inclusion criteria ...................................................................................................11 
3.4.2 
Exclusion criteria ..................................................................................................12 
 
Data and Blood Collection Plan ...................................................................................13 
4 
Data Analysis .....................................................................................................................13 
 
Field Evaluation of Platforms: Ease of Use, Time for Test Result ................................13 
 
Local versus Central POC Test Result Comparison ....................................................13 
 
Local and Central POC Test Result versus GenScript cPass Assay ...........................14 
 
Association of POC Test Results with TICO Outcomes: A Nested Case-Control Study 
of Completed TICO Trials ......................................................................................................14 
 
Analysis of the Quantitative Results from the LumiraDX Assay ...................................15 
5 
Protection of Human Subjects and Other Ethical Considerations .......................................15 
 
Anticipated Risks and Benefits ....................................................................................15 
 
Participating Clinical Sites and Local Review of Protocol and Informed Consent ........15 
 
Ethical Conduct of the Study .......................................................................................15 
 
Informed Consent of Study Participants ......................................................................16 
 
Confidentiality of Study Participants ............................................................................16 
 
Regulatory Oversight ..................................................................................................16 

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6 
Storage and Use of Specimens ..........................................................................................16 
7 
Supporting Documentation .................................................................................................17 
APPENDIX A: Sample Informed Consent Form .....................................................................18 
APPENDIX B: List of Acronyms .............................................................................................27 
APPENDIX C: INSIGHT 017 Protocol Team..........................................................................29 
APPENDIX D: References .....................................................................................................30 
 
 
 
List of Tables  
Table 1: Further information about the 2 POC assays to be investigated under this protocol. .....4 
Table 2: Sensitivity of the LumiraDX assay for various numbers of days from a positive test. .....6 
Table 3: Sensitivity of the RightSign IgM assay for various numbers of days from a positive test.
 ...................................................................................................................................................7 
Table 4: Sensitivity of the RightSign IgG assay for various numbers of days from a positive test.
 ...................................................................................................................................................7 
Table 5: The power of McNemar’s chi-square test for testing the agreement of 2 assays as it 
depends on the odds ratio and the smaller of the 2 probabilities for test discordance. This 
assumes the sample size is 375................................................................................................11 
 
 
List of Figures 
Figure 1: A depiction of the operation of the LumiraDX testing platform. Note that for this 
protocol only the specimen identifier will be captured by the instrument, not personal identifiers.
 ...................................................................................................................................................6 
Figure 2: A depiction of the operation of the RIghtSign testing platform. ....................................8 
 
 
 
 
 
 

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1 Protocol Summary 
DESIGN 
EPOC is designed to examine the feasibility of conducting point-of-care 
(POC) tests for SARS-CoV-2 antibodies and compare the reproducibility of 
these tests to tests run at a central laboratory on specimens obtained from 
the same study participants at the same time. This will involve recruiting 375 
individuals at 20-30 US and international sites who have tested positive for 
SARS-CoV-2 and consenting them to up to 4 fingersticks, the collection of 9 
mL of venous blood and responding to a set of standardized questions. All 
these activities will take place during a single study visit. The whole blood 
from the fingersticks will be used to test for SARS-CoV-2 antibodies using 2 
POC tests, both of which have a CE mark, emergency use authorization 
(EUA) from the US Food and Drug Administration (FDA) and are Clinical 
Laboratory Improvement Amendments of 1988 (CLIA) waived. Participants 
and their providers will be instructed that the results of these tests are not to 
be used for patient management and the results of the tests will not be 
shared with participants or their providers. The 9 mL of blood will be 
processed locally and shipped to a central repository in the US where it will 
be labeled with a specimen code that can only be matched to the 
participant’s other data using a participant identifier at the Statistical and 
Data Coordinating Center at the University of Minnesota (UMN). UMN will 
only have the specimen code and the participant identifier: the matching of 
the participant identifier to a participant can only be done at the sites. 
In addition to this cross-sectional study (also referred to as the field test 
below), a nested case-control study utilizing specimens already collected 
from participants in the Therapeutics for Inpatients with COVID-19 (TICO) 
trial will be conducted. Participants in the TICO trial have already consented 
to the use of their specimens for future research on COVID-19. The POC 
tests will be conducted on these specimens and compared to results that 
have already been generated using an assay at a central laboratory called 
the GenScript cPass assay (referred to here as the GenScript assay). 
The 2 POC assays that will be investigated under this protocol are the 
LumiraDx SARS-CoV-2 Antibody Test and the RightSign COVID-19 IgG/IgM 
Rapid Test. Both platforms will be used on all specimens. It is not the goal of 
this study to impact the indications for either test. 
The primary objective of the field test is to test for an association between 
the outcome of the locally obtained POC test and the centrally obtained 
result from the GenScript assay on a blood sample obtained at the same 
time as the sample for the POC tests.  
The primary objective of the nested case-control study is to test for an 
association between the POC test result on stored baseline specimens and 
the primary efficacy outcome in TICO on a subset of specimens from TICO 
participants for whom the GenScript assay result has already been 
determined. Since conducting POC assays on large numbers of stored 
specimens is time consuming (since each assay takes 10-20 minutes and 

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each individual specimen must be analysed), a case-control design will be 
utilized. The case definition is death or time to sustained recovery that 
exceeds 28 days. To maximize the difference between cases and controls, 
controls are defined as those with a time to sustained recovery of no more 
than 16 days. With these definitions there are 68 cases and 77 controls for a 
total sample size of 145. Of these participants, 104 experienced a sustained 
recovery (the primary outcome in TICO) and 20 died. 
DURATION 
Participants in the cross-sectional study will be completed with the study 
within 24 hours of consent. Actual participation will just involve the consent 
process, 2 POC tests, and completion of a case report form (CRF) and a 
blood draw, thus we expect participation to last no more than a few hours. 
SAMPLE 
SIZE 
Sample size for the cross-sectional study is targeted at 375. With this 
sample size the study will have 83% power for detecting a difference in the 
probability of a positive test between 2 assays when the odds ratio for the 2 
assays is 2.6 and the smaller of the 2 probabilities of test discordance is 3%.  
The sample size for the nested case-control study is 145. Analysis of the 
case-control population using the GenScript assay detected a sub-hazard 
ratio of 1.91. With a sub-hazard ratio of 1.91, 104 events provide 90% power 
for rejecting the null hypothesis that the sub-hazard ratio is 1 and this 
number of events provides 80% power for a sub-hazard ratio of 1.75. 
POPULATION 
The population for the field test was selected to match that of those 
participating in the TICO trials from which the case-control specimens were 
selected. This population consisted of adults hospitalized for COVID-19 with 
symptoms being present no more than 12 days. Participants needed to have 
a positive test result within 3 days or a positive test more than 3 days prior to 
randomization and progressive disease suggestive of ongoing SARS-CoV-2 
infection. Participants must not have received neutralizing monoclonal 
antibodies (nMabs), SARS-CoV-2 hyperimmune intravenous 
immunoglobulin (hIVIG), or convalescent plasma. For this protocol 
participants must not have received these compounds within 6 months prior 
to collection of the blood samples for this protocol. Participants with severe 
disease (as defined by a list of conditions and interventions) are also 
excluded to be consistent with the TICO trials from which specimens will be 
used.  
 
 
 
 

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2 Introduction 
 
Study Rationale 
A platform trial of therapeutics for patients hospitalized for COVID-19 entitled “A Multicenter, 
Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational 
Therapeutics for Hospitalized Patients with COVID-19”, referred to as Therapeutics for 
Inpatients with COVID-19 (TICO), has undertaken the investigation of 6 treatments thus far. 
TICO trials of bamlanivimab, sotrovimab (also known as VIR-7831), and BRII-196/198, a meta-
analysis that included these trials, a trial of hIVIG, and the RECOVERY trial have identified the 
potential for baseline antibody levels to impact safety and efficacy outcomes with administration 
of nMab therapy1,2,3,4,5,6. The TICO trial of bamlanivimab found a statistically significant 
interaction for the primary efficacy outcome, and the TICO trial of BRII-196/198 was consistent 
with such an interaction. These studies have found that while there may be a benefit for patients 
who have not yet mounted an antibody response, patients with endogenous antibody probably 
do not benefit from this treatment, and this may result in misuse of resources and expose 
patients to unnecessary toxicity, increased costs, and treatment delays. Moreover, in addition to 
affecting response to therapy, results from the TICO trials also demonstrate that baseline 
antibody levels were predictive of safety and efficacy outcomes in the placebo group: those with 
endogenous antibody had better outcomes.  
In the TICO trials, antibody levels were assessed using a surrogate neutralizing antibody assay 
that detects the ability of antibodies to block the interaction of the receptor binding domain 
(RBD) of the spike protein with the host ACE-2 receptor (the GenScript cPass assay, referred to 
as the GenScript assay here). While these results point to promising approaches to the 
provision of care, these results are of limited clinical value as the use of this assay for patient 
management is extremely challenging due to time and laboratory requirements. This is due to 
the requirement that the assay be run in batches at a central laboratory, and this delays the 
determination of the presence of endogenous antibody. Given the urgency of treatment early in 
the course of disease, this delay could impact patient outcomes.  
There are a large number of POC antibody tests with an EUA from the FDA available for 
detection of antibodies to SARS-CoV-2, thereby presenting an opportunity to rapidly determine 
if a patient has endogenous antibodies, which can then be used for patient management. Under 
the current EUAs, these tests only produce a qualitative interpretation of serostatus. This limits 
their ability to be used for participant management as the cut-offs are generally selected to 
optimize specificity. Optimization of specificity is sensible for an assay designed for large scale 
screening, where false positives are the primary concern. In contrast, if there is a safety concern 
associated with administration of nMabs to those who are seropositive, false negatives are the 
primary concern. Hence, there is interest in studying POC antibody tests that produce a rapid 
quantitative result so that the operating characteristics of different cut-offs can be investigated. 
This would inform using other cut-offs for timely patient management. 
There are 2 aspects of a POC testing platform of interest when designing a trial that may use 
such a test for patient management: 1) performance of the POC test in a hospital setting where 
patients would be consented and screened for enrolment; and 2) the ability of the results from 
the POC test to reproduce the association of baseline antibody levels with clinical outcomes that 
has been found with the GenScript assay. While the former will be examined prospectively at 
clinical sites that enroll patients, the latter will use stored specimens from completed TICO trials 
for expeditious evaluation of the association of POC test results with major TICO outcomes in 
the context of treatment with nMabs (e.g., a 90-day composite safety outcome and time to 
sustained recovery, the primary endpoint of TICO trials). Ideally, one would want to determine if 

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there is an interaction between the result of a POC antibody test and outcomes of interest in 
TICO, as was found using the GenScript assay, but this would require analysing a larger 
number of stored specimens than is practical to have acceptable power. As a compromise, here 
we focus on detecting an association between baseline antibody status using the POC test 
results and safety and efficacy outcomes of interest in TICO among those in the placebo group 
from completed TICO trials. The hypothesis to be tested here is that those with endogenous 
antibody as determined by the POC assay will have better outcomes as was observed using the 
GenScript assay. 
This protocol will examine 2 POC platforms: the LumiraDX and the RightSign platforms. Both 
platforms have a US FDA EUA and a CE mark for a CLIA-waiver when used on fingerstick 
whole blood. The LumiraDX platform provides a qualitative result in 10-20 minutes and can also 
provide a quantitative assessment, but this cannot be provided at the POC at this time. (A 
quantitative POC test is currently under development by the manufacturer). The RightSign 
platform is exclusively qualitative with a 10-20-minute turnaround time. Table 1 provides further 
information and links to more detailed information about each assay. Both assays are certified 
under the CLIA, 42 U.S.C. §263a, that meet requirements to perform medium complexity tests. 
Nothing is known at this time about the performance of either assay on emerging variants of 
concern. 
Date EUA 
Issued or 
Last 
Updated 
Entity 
Diagnostic 
(Most Recent 
Letter of 
Authorization) 
and Date EUA 
Issued 
Attributes3 
Authorizatio
n 
Documents2 
Antigen in 
the assay 
used to 
detect 
antibodies  
Readout 
08/02/2021 
LumiraDx 
UK Ltd. 
LumiraDx 
SARS-CoV-2 
Ab Test 
08/02/2021 
Total Antibody 
(Ab), 
Fluorescence 
Immunoassay, 
Fingerstick 
Whole Blood 
HCP, Recipie
nts, IFU 
RBD and S-
protein 
mixture 
A dedicated 
fluorescence detector 
reads total Ab 
(immunoglobulin G 
[IgG], immunoglobulin 
M [IgM] and 
immunoglobulin A 
[IgA]); qualitative 
12/21/2020 
Hangzhou 
Biotest 
Biotech 
Co., Ltd. 
RightSign 
COVID-19 
IgG/IgM Rapid 
Test Cassette 
06/04/2020 
IgM and IgG 
Lateral Flow, 
Fingerstick 
Whole Blood 
HCP, Recipie
nts, IFU  
RBD 
One IgG band and one 
IgM band 
Table 1: Further information about the 2 POC assays to be investigated under this protocol. 
 
Background 
TICO is a platform trial designed to efficiently identify treatments for adults who have been 
hospitalized with COVID-19. A manuscript providing details on the protocol has been published7 
so here a brief description of the trial is provided. As a platform trial, multiple agents can be 
investigated simultaneously which allows for efficiencies due to a shared placebo group. Each 
investigational agent is studied in a randomized placebo-controlled trial with an early futility 
assessment based on two 7-category ordinal outcomes assessed at day 5 of follow-up to 
assess efficacy and a composite of grade 3 and 4 adverse events (AEs), serious adverse 
events (SAEs), clinical organ failure or serious infection or death through day 5 to assess safety. 
The primary efficacy outcome is time to sustained recovery, which is the first time after 

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randomization at which someone returns to their pre-hospitalization residence and stays there 
for 14 days prior to day 90. All-cause mortality through 90 days of follow-up is an important 
secondary outcome.  
Thus far, 6 agents have entered the platform trial with the first 4 being nMabs or combinations of 
nMabs. These agents are as follows: 
1. Bamlanivimab. 
2. Sotrovimab (also referred to as VIR-7831). 
3. BRII-196/198. 
4. AZD7442. 
5. MP0420. 
6. PF-07304814. 
The study has been completed and papers have been written describing the outcomes for the 
first 3 compounds, while the results for the remainder are still blinded. These 3 trials were 
stopped for futility at the time of the early futility assessment. Baseline antibody results are 
available for the first 3 compounds using the GenScript assay. 
Analyses of the qualitative GenScript results from participants in the placebo arm of the first 3 
trials (n=320) found that being seropositive was associated with superior efficacy and safety 
outcomes. Competing risk regression was used to test for an association between the baseline 
qualitative result from the GenScript assay and time to sustained recovery. The result was 
statistically significant with a sub-hazard ratio of 1.45 and a 95% confidence interval (CI) of 
(1.17, 1.81). The estimated hazard ratio for death (positive/negative) was 0.17 with a 95% CI of 
(0.05, 0.57), hence also statistically significant6. 
While the semi-quantitative GenScript results do not have any authorization for use in patient 
management, there is evidence that the use of different thresholds for dichotomizing this semi-
quantitative result leads to different estimates of the magnitude of the association between the 
antibody test and time to sustained recovery. By using a lower threshold for antibody levels and 
thereby reducing the specificity and increasing the sensitivity for being seropositive, one detects 
a stronger association. The threshold used for the qualitative result finds that 46% of the 320 
participants in the placebo arm are seropositive. If the threshold is lowered so that 58% of the 
participants are seropositive, we find that the sub-hazard ratio increases from 1.45 to over 1.6.   
 
Point-of-Care Platforms 
2.3.1 
LumiraDX SARS-CoV-2 antibody test 
Assay summary: The LumiraDx SARS-CoV-2 Antibody Test is a single use fluorescence 
immunoassay device designed to detect the presence of SARS-CoV-2 total antibody in human 
serum, plasma (dipotassium EDTA), venous whole blood (dipotassium EDTA), and fingerstick 
whole blood. The test is run on a microfluidic test strip which is inserted into a device that will 
display the qualitative results within 11 minutes of specimen application. Table 2 displays the 
sensitivity as a function of the number of days since a positive reverse transcription polymerase 
chain reaction (RT-PCR) test: averaging over the time since the first known positive test, the 
sensitivity is 97%. Using 240 specimens known to be negative, all specimens were found to be 
negative, giving an estimated specificity of 100% with a 95% CI of 99%-100%8. There are two 
targets: the Spike RBD and the Spike 1 (S1) and pan Ig antibodies directed against these 
targets are detected. A qualitative result is displayed on the device and a semi-quantitative 
measure of the fluorescence can be accessed as research use only. The device is portable and 
can be moved on a cart between uses. 

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Time from positive 
RT-PCR test to blood 
collection (days) 
Number of samples 
Number and percent 
positive 
95% CI 
0-7  
17 
15 (88.2) 
64%-99% 
8-14 
6 
6 (100) 
54%-100% 
15 or more 
49 
49 (100) 
93%-100% 
Total 
72 
70 (97.2) 
90%-100% 
Table 2: Sensitivity of the LumiraDX assay for various numbers of days from a positive test. 
 
Figure 1: A depiction of the operation of the LumiraDX testing platform. Note that for this 
protocol only the specimen identifier will be captured by the instrument, not personal identifiers. 
Principle of the assay: The test works using microfluidics. Serum, plasma, venous whole 
blood, or fingerstick whole blood are applied to the sample application area of the test strip and 
inserted in the instrument. Each test strip contains 4 channels: 2 channels for the RBD, 1 
channel for S1, and 1 channel for controls. Fluid moves the specimen up into the cartridge 
where it is mixed with reagents including magnetic particles coated with the RBD, S1, or control 
depending on the channel. Antibodies in the serum, plasma, or whole blood specific for RBD or 
S1 bind to the magnetic beads. A secondary pan-human Ig antibody conjugated to fluorescence 
then binds to the antibodies. The magnetic particles are captured in a magnetic field, and any 
unbound antibodies are removed using air. The fluorescent signal is then measured.  

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The analysis is based on the amount of fluorescence the instrument detects within the 
measurement area of the test strip. The qualitative results are displayed on the Instrument 
touchscreen in approximately 11 minutes from the addition of sample as “Positive +” or 
“Negative -”. The semi-quantitative measure of the fluorescence can be accessed as research 
use only.  
2.3.2 
RightSign COVID-19 IgG/IgM rapid test 
Assay summary: The RightSign COVID-19 IgG/IgM Rapid Test Cassette is a lateral flow 
immunochromatographic assay for the detection of SARS-CoV-2 antibodies in venous whole 
blood, serum, or plasma. The test is run on a disposable lateral flow device (test cassette). The 
test targets IgG or IgM antibodies specific for the Spike RBD. The readout of the assay is 
qualitative: positive for IgG and/or IgM or negative within 10-20 minutes of specimen application. 
Tables 3 and 4 summarize the sensitivity as a function of the number of days since the first 
positive polymerase chain reaction (PCR) test. Averaging over the number of days since first 
known positive test the sensitivity of the IgM assay is 93%, while the sensitivity of the IgG assay 
is 94%. Specificity was estimated using 210 specimens known to be negative and the result was 
negative for IgM 206 times and negative for IgG 209 times. This gives an estimated specificity of 
98% with a 95% CI of (95%, 99%) for IgM, and an estimated specificity of 100% with a 95% CI 
of (97%, 100%) for IgG9. For analyses that simply treat the RightSign assay as positive or 
negative, the RightSign test will be considered positive if the test is positive for IgM or IgG. 
Time from positive 
PCR test to blood 
collection (days) 
Number of samples 
Number and percent 
positive 
95% CI 
0-7  
9 
6 (67) 
30%-93% 
8-14 
83 
77 (93) 
85%-97% 
15 or more 
158 
150 (95) 
90%-98% 
Total 
250 
233 (93) 
89%-96% 
Table 3: Sensitivity of the RightSign IgM assay for various numbers of days from a positive test. 
Time from positive 
PCR test to blood 
collection (days) 
Number of samples 
Number and percent 
positive 
95% CI 
0-7  
9 
6 (67) 
30%-93% 
8-14 
83 
76 (92) 
83%-97% 
15 or more 
158 
152 (96) 
92%-99% 
Total 
250 
234 (94) 
90%-96% 
Table 4: Sensitivity of the RightSign IgG assay for various numbers of days from a positive test. 
Principle of the assay: This test uses anti-human IgM antibody (test line IgM), anti-human IgG 
(test line IgG) and goat anti-mouse IgG (control line C) immobilized on a nitrocellulose strip. The 
conjugate pad contains recombinant SARS-CoV-2 antigen (based on the Spike protein RBD 
domain) conjugated with colloid gold. During testing, the specimen binds with SARS-CoV-2 
antigen-conjugated gold colloid coated particles in the test cassette. When a specimen followed 
by assay buffer is added to the sample well, IgM and/or IgG antibodies if present, will bind to 
COVID-19 conjugates making an antigen-antibody complex. This complex migrates through the 
nitrocellulose membrane by capillary action. When the complex meets the line of the 
corresponding immobilized antibody (anti-human IgM &/or anti-human IgG), the complex is 
trapped forming a colored line which confirms a reactive test result. Absence of a colored line in 
the test region indicates a non-reactive test result. To serve as a procedural control, a colored 

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line should always appear in the control line region, indicating that the proper volume of 
specimen has been added and membrane wicking has occurred. 
 
Figure 2: A depiction of the operation of the RIghtSign testing platform. 
3 Methodology 
 
Study Design 
There are several related questions that this protocol is designed to answer, and these are 
reflected in 2 different components of the design. There will be a cross-sectional study designed 
to evaluate how the POC test works in practice and how the results are related to the GenScript 
assay measured on a plasma sample collected at the same time as the fingerstick blood 
samples for the two POC tests to be evaluated. This will involve recruiting and consenting 
individuals presenting to the clinical sites with a positive test for SARS-CoV-2. Consenting 
participants will have a fingerstick for each POC test conducted. If a test fails, 1 additional 
fingerstick may be conducted for each POC test (so, up to 4 fingersticks may occur). In addition, 
a 9mL blood specimen will be collected. Participants and care providers will not be informed of 
test outcomes. After the fingersticks, blood collection, and responses to a set of standardized 
questions from a CRF, the participant will have completed involvement with the study. The 
blood specimen will allow for both a comparison with the GenScript assay and the assessment 
of the impact of processing, freezing, and shipping on the POC test results. There will also be a 
nested case-control study to understand how POC tests carried out on stored plasma 
specimens from completed TICO trials are related to outcomes measured in the TICO protocol. 
Consent from TICO participants has already been obtained for the use of their stored 
specimens, so the case-control study will not involve additional consent or the recruitment and 
follow-up of patients.  

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For the field test, POC platforms will be distributed to 20-30 sites in the US and internationally 
for completion of the two POC tests on 15 participants at each site. In addition to conducting the 
POC test on site as per the instruments’ instructions (using blood from a fingerstick), a blood 
specimen will be obtained for processing, freezing, and shipping to a central lab for central 
testing using the GenScript assay and repeat POC testing using plasma. If a POC test is 
indeterminate the test will be repeated 1 time and the outcome of the indeterminate test and the 
second test will be recorded. If the second test is also indeterminate that will be recorded but 
the test will not be conducted again on that participant. This procedure applies to POC testing at 
the sites and at the central laboratory. 
A nested case-control study will also be conducted to allow for testing of the association 
between antibody levels at baseline, as assessed by the POC tests and safety and efficacy 
outcomes among participants randomized to the placebo group in the bamlanivimab, 
sotrovimab, and BRII-196/198 trials of TICO. The case definition is death or time to sustained 
recovery that exceeds 28 days. To maximize the difference between cases and controls, 
controls are defined as those with a time to sustained recovery of no more than 16 days. With 
these definitions there are 68 cases and 77 controls for a total sample size of 145. Among  
these participants, 104 experienced a sustained recovery and 20 died. 
Conduct of this nested case-control study will require use of the POC assay on stored 
specimens. One cannot conduct such tests in a batched fashion which makes this analysis time 
consuming. This testing will be facilitated by procuring multiple POC platforms at a central 
location. The use of multiple platforms will allow for multiple tests to be conducted in parallel 
which is more efficient since each specimen must be run one at a time, and each takes 10-20 
minutes.  
 
Study Objectives   
3.2.1 
Field test 
The overall objective of the field test is to determine if a POC test can be used to identify 
individuals who lack endogenous antibodies. The primary objective is to test for an association 
between the outcome of the locally obtained POC test and the centrally obtained result from the 
GenScript assay on a blood sample obtained at the same time as the sample for the POC test. 
There are also a number of secondary objectives that will investigate the feasibility of this 
approach, and others that will help interpret the outcome of the primary objective. These are as 
follows: 
1. Determine the frequency with which the POC test fails to give an unambiguous result. 
2. Determine the time required to obtain a POC result. 
3. Determine the magnitude of the association between the locally obtained POC test result 
by the 20-30 sites and the same POC assay on the same specimens determined 
centrally after processing, freezing, storing, and shipping. 
4. Determine the magnitude of the association between the POC test result and the 
GenScript assay on the same specimens both determined centrally. 
Secondary objective 3 will provide information on the impact of processing (centrifugation for 
plasma), freezing, storing, and shipping on the test results using the same assay while 
secondary objective 4 will provide a head-to-head comparison of the assays using the same 
specimen subjected to the same handling procedures. Specimen handling and the specific 
assay used both likely contribute to differences we may observe between the local POC test 
and the results from the GenScript assay.  

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3.2.2 
Central laboratory 
The overall objective of central testing of stored specimens is to understand the impact of 
baseline serology, as assessed by the POC tests, on outcomes of relevance for the TICO trial. 
The primary objective is to test for an association between the POC test result on stored 
baseline specimens and the primary efficacy outcome in TICO on a subset of specimens from 
TICO participants for whom the GenScript assay has result has already been determined. 
Secondary objectives are as follows: 
1. Test for an association between each POC test result on stored baseline specimens and 
efficacy/safety outcomes in TICO in a case-control design. 
2. Compare the POC test results to the GenScript results and other antibody test results 
such as those from Bio-Rad and Quanterix that have already been obtained for these 
stored specimens. 
3. Select a threshold for the quantitative LumiraDX result to optimize the association 
between the dichotomized assay result and safety and efficacy outcomes using the 
stored specimens. 
4. Compare the 2 POC platforms to each other and the GenScript result using locally (at 
each site) and centrally determined POC results. 
5. Examine associations between these antibody assays and antigen assays which have 
already been obtained for the stored specimens.  
6. Determine the effect of vaccination and other participant characteristics on the antibody 
test results. 
 
Sample Size and Statistical Considerations 
3.3.1 
Local versus central POC test result 
The power for comparisons of results from paired qualitative tests on specimens was assessed 
using Schlesselman’s formula for the power of McNemar’s chi-square test10. This requires 
specification of the odds ratio and the probability of 1 test being positive when the other is 
negative (denoted p01 in the table). Table 1 shows the power as it depends on these 2 
parameters with a sample size of 375. By taking the odds ratio to be greater than 1 we are 
assuming that p01 is the smaller of the 2 probabilities of 1 test being positive while the other is 
negative. For example, p01=0.01 and an odds ratio of 2.2 implies that the 2 probabilities that one 
test is positive while the other is negative are 0.01 and 0.022, and the probability that the 2 tests 
agree is 96.8%. As can be seen in Table 5, with a sample size of 375 the power of the test is 
low in this scenario (0.24), but this is fairly strong agreement across the assays. As can be seen 
from the same table, the test will have over 80% power if p01=0.03 and the odds ratio is at least 
2.6. This corresponds to the discordance probabilities of 0.03 and 0.078 and the corresponding 
probability that the 2 tests agree is 89.2%. With this configuration of probabilities for test 
agreement the standard error for the difference in the probability that the 2 tests are positive is 
0.023. There is currently no data available for this comparison.  
Odds ratio 
p01=0.01 
p01=0.03 
p01=0.05 
2.0 
0.19 
0.49 
0.72 
2.1 
0.21 
0.56 
0.79 
2.2 
0.24 
0.62 
0.85 
2.3 
0.27 
0.68 
0.89 
2.4 
0.30 
0.74 
0.93 
2.5 
0.33 
0.79 
0.95 
2.6 
0.36 
0.83 
0.97 

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Table 5: The power of McNemar’s chi-square test for testing the agreement of 2 assays as it 
depends on the odds ratio and the smaller of the 2 probabilities for test discordance. This 
assumes the sample size is 375. 
3.3.2 
Local and central POC test result versus GenScript cPass assay result 
Sample size considerations for these comparisons are similar to those from the previous 
section, but we do have data from 302 participants on the relationship between the central POC 
test using the RightSign platform and the GenScript assay using stored specimens for both 
assays. The association depends on which isotype is measured with the RightSign assay: there 
is evidence that the odds ratio is different from 1 for IgM (odds ratio 7.5, p<0.001) but not for 
IgG (odds ratio 1.1, p=0.82). These preliminary data indicate that 375 samples obtained as part 
of the field test will provide more than adequate power for detecting a difference for the 
GenScript assay and RightSign IgM assay and very low power for detecting a difference 
between the GenScript assay and the RightSign IgG assay due to the high degree of 
association between the latter pair of assays. 
3.3.3 
Case-control comparison 
An analysis of the qualitative GenScript result with the 145 patients that will be used for the 
nested case-control study found a significant difference (p=0.002) in the time to sustained 
recovery, with a sub-hazard ratio of 1.91 (95% CI: 1.35, 2.7) for baseline serostatus, indicating 
that seropositive patients had a quicker time to sustained recovery. (This used the Fine-Gray 
approach to modelling competing risks). The quantitative result from this assay also 
demonstrated a statistically significant association with time to sustained recovery and 
adjustment for study level effects did not impact the associations meaningfully. An analysis of 
case control status also detected an odds ratio that was significantly different from 1 (p=0.015) 
with an odds ratio of 2.34 (95% CI: 1.18, 4.65). 
With a sub-hazard ratio of 1.91, 104 events provide 90% power for rejecting the null hypothesis 
that the sub-hazard ratio is 1, and this number of events provides 80% power for a sub-hazard 
ratio of 1.75. An analysis of case control status has lower power and would require an odds ratio 
of 2.72 to have 80% power for detecting an association between baseline antibody levels and 
case control status with this sample size (larger than what was observed for the GenScript 
assay). 
 
Participant Selection for the Field Test 
Interested sites will be selected based on their ability to recruit patients that meet the eligibility 
criteria for TICO. Planned enrollment into TICO is not necessary for participation in the field test. 
All participants will need to consent to participate in the field test component of the protocol, 
including those co-enrolled in TICO. The inclusion and exclusion criteria for the field test are as 
follows: 
3.4.1 
Inclusion criteria 
1. Age ≥ 18 years. 
2. Informed consent by the patient or the patient’s legally authorized representative 
(LAR) for up to 4 fingersticks for POC testing and a blood draw for stored blood 
samples. 
3. SARS-CoV-2 infection, documented by a nucleic acid test (NAT) or equivalent 
testing within 3 days prior to consent OR documented by NAT or equivalent testing 
more than 3 days prior to consent AND progressive disease suggestive of ongoing 
SARS-CoV-2 infection per the responsible investigator. (For non-NAT tests, only 

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those deemed with equivalent specificity to NAT by the protocol team will be allowed. 
A central list of allowed non-NAT tests is maintained for TICO and that list will also 
be used for this protocol.) 
4. Duration of symptoms attributable to COVID-19 ≤ 12 days per the responsible 
investigator. 
5. Requiring admission for inpatient hospital acute medical care for clinical 
manifestations of COVID-19, per the responsible investigator, and NOT for purely 
public health or quarantine purposes. 
3.4.2 
Exclusion criteria  
1. Prior receipt of SARS-CoV-2 hIVIG, convalescent plasma from a person who 
recovered from COVID-19, or SARS-CoV-2 nMAb within 6 months of the blood 
draws for testing as part of this protocol. 
2. Disease severity beyond that of stratum 1 in the TICO trial.  
This includes the following conditions:  
    a. stroke  
    b. meningitis  
    c. encephalitis  
    d. myelitis  
    e. myocardial infarction  
    f. myocarditis  
    g. pericarditis  
    h. symptomatic congestive heart failure (CHF; New York Heart Association  
 
[NYHA] class III-IV)  
    i. arterial or deep venous thrombosis or pulmonary embolism 
Or current requirement for any of the following:  
    a. high-flow supplemental oxygen 
    b. non-invasive ventilation  
    c. invasive mechanical ventilation  
    d. extracorporeal membrane oxygenation  
    e. mechanical circulatory support  
    f. vasopressor therapy  
    g. commencement of renal replacement therapy at this admission (i.e., not    
         patients on chronic renal replacement therapy). 
3. In the opinion of the responsible investigator, any condition for which, participation 
would not be in the best interest of the participant or that could limit protocol 
specified assessments. 
A blood specimen for storage is required for participation in the study. 
These eligibility requirements are nearly identical to those used in the TICO trial from which 
specimens will be used for the case-control study. One major difference is that TICO 
participants must agree to not participate in other COVID-19 treatment trials until after Day 5 
(this is clearly not relevant for this protocol). The exclusion criteria here are more restrictive than 
those in the TICO trial. This is so participants in this protocol are comparable to those who 
enrolled in the TICO trials from whom specimens will be used for the case-control study. Those 
trials had more restrictive exclusion criteria than listed in the TICO protocol at the request of the 
FDA and match the exclusion criteria listed here. This will facilitate interpretation of analyses 
that use specimens from the field test and from the previously conducted trials. Eligibility criteria 
were also selected to be similar to those in the TICO trial to ensure these results are relevant for 

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future trials in hospitalized patients conducted by INSIGHT and aligned networks for which 
eligibility criteria are likely to be similar to TICO. 
Participant characteristics will be monitored during data collection and adjustments to the 
characteristics of those recruited for participation may be made. 
 
Data and Blood Collection Plan 
After providing written informed consent, a CRF will be completed for each participant and blood 
will be collected by up to 4 fingersticks and by a venous blood draw of 9 mL (in an EDTA 
collection tube for aliquoting plasma after centrifugation into 4 2 mL cryovials, each with about 1 
mL of plasma). The blood from the fingersticks will be used to conduct the POC tests and the 
plasma cryovials will be stored locally in a -70°/-80° freezer until they can be shipped to the 
central biorepository. The CRF will capture the outcome of the POC tests, the length of time 
from the start of the assay to recording the test outcome, and selected data collected on the 
TICO Screening and Baseline and Randomization forms. This will include  
1. Participation in other INSIGHT studies.  
2. Demographics. 
3. Date of onset of COVID-19 symptoms. 
4. Severity of COVID-19. 
5. Oxygen requirements.  
6. History of chronic comorbidities. 
7. SARS-CoV-2 vaccination information.  
8. Targeted concomitant medications.  
9. Height and weight.  
Two fingerstick samples of blood will be obtained, one for each POC test. The plasma samples 
collected will be used for determination of antibody and antigen levels, and central laboratory 
determination of the two POC tests. 
All study procedures will be performed by study personnel. Training materials and the consent 
document will clearly state that the results of the POC tests are not to be used for patient 
management and so should not be shared with the patient or care giver. All study procedures 
must be performed within 24 hours of completing the written informed consent. 
Information will be collected from site staff about ease of use of each platform. 
4 Data Analysis 
 
Field Evaluation of Platforms: Ease of Use, Time for Test Result 
The number and proportion of failed tests and tests not obtained within 20 minutes will be 
determined overall and for each site. The median and interquartile range of the time from the 
start of the assay to recording of the test outcome on the CRF will be determined overall and for 
each site. 
 
Local versus Central POC Test Result Comparison 
The primary analysis will test if the odds ratio for the association is 1 using McNemar’s chi-
square test with a significance level of 0.05. Samples for which either test result is missing will 
be excluded from this analysis. This test will be supplemented by a 95% CI for the difference in 
the probability of testing positive. Site level effects will be estimated by using generalized 
estimating equations for Bernoulli outcomes using a logistic link with pairs of results modelled as 

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being correlated (the test outcome is the binary outcome). This model will include fixed effects 
for the test type (i.e., local or central) and site. Sites may be grouped based on geography or 
ICC membership to improve the precision of site level estimates and the interaction between 
site and test type will be investigated. Subgroups based on age, existence of an 
immunocompromising condition and vaccination status will be investigated (provided enough 
individuals with an immunocompromising condition enroll). These subgroup analyses will test for 
an interaction between group membership and test type. This analysis will be used for both 
POC tests, and there will not be an adjustment for the conduct of the 2 sets of analyses. 
In addition to the primary analysis, associations between test results and participant 
characteristics will be investigated. These characteristics include age, sex, existence of an 
immunocompromising condition and vaccination status. 
 
Local and Central POC Test Result versus GenScript cPass 
Assay  
The GenScript assay will also be conducted on the specimens at the central laboratory. The 
locally and centrally determined POC results will be compared to the GenScript result using 
McNemar’s chi-square test and will be supplemented by 95% CIs for the difference in the 
probability of testing positive. Investigation of site effects and test performance in subgroups will 
be pursued as described in Section 4.2. 
 
Association of POC Test Results with TICO Outcomes: A Nested 
Case-Control Study of Completed TICO Trials 
TICO specimens selected for the case-control study will be shipped from the repository at 
Advanced Biomedical Labs LLC to the central laboratory for analysis. The Fine-Grey approach 
to competing risk regression will be used to test for an association between the POC test result 
and time to sustained recovery while controlling for the parent sub-study effect. A significance 
level of 0.05 will be used to test the null hypothesis that the regression coefficient associated 
with the presence of antibodies at baseline is zero. The association between baseline POC test 
results and time to death will be investigated using Cox models stratified by parent sub-study. 
The association between baseline POC test results and the primary safety composite at days 5, 
28 and 90 will be investigated using logistic regression models that control for parent sub-study.  
Finally, data will be pooled from the field test and the stored specimens for all qualitative assays 
conducted to test for differences. This would include the local POC, central POC, and GenScript 
results from the field test, the GenScript result for the stored specimens and the POC results for 
the stored specimens. This analysis will use generalized estimating equations for binary 
outcomes with effects for the type of assay (3 values), if the assay was conducted locally or 
centrally, and in which protocol/sub-study the participant enrolled. The association due to the 
specimen coming from the same person will be accounted for by including this information as a 
clustering effect in the model. Tests for differences in the assays will be based on the Wald test 
for the regression coefficients for the assays. No multiplicity adjustment will be made for these 
tests. 
Associations between qualitative antibody and continuous antigen assays will be examined 
using 2 by 2 tables by dichotomizing the antigen assay results at the median level for a given 
trial, and Fisher’s exact test will be used to test for an association. Logistic regression models 
will be used to compute adjusted odds ratios where adjustment will be made for parent study 
and site (where sites may be grouped as described above).  

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Analysis of the Quantitative Results from the LumiraDX Assay 
All comparisons that were conducted using the qualitative result from the LumiraDX assay will 
be repeated using the quantitative result using the appropriate modification of the analysis to 
accommodate a continuous variable. Comparisons to the RightSign and qualitative GenScript 
results will use the Wilcoxon rank sum test with the 2 groups being determined by the outcomes 
of the RightSign or GenScript test (i.e., the ranks of the LumiraDX results for positive and 
negative results for the other assays will be compared). Adjusted analyses will be pursued using 
linear regression after transformation (e.g., logarithmic), if appropriate. Comparisons of the 
locally and centrally conducted LumiraDX assay will be conducted using linear regression with 
adjustments made by the inclusion of relevant covariates. The quantitative result will also be 
used in the competing risk regression models as a continuous covariate and as a set of 
indicator variables that represent the quartiles of the distribution of this assay (to avoid the 
linearity assumption). 
Other approaches to dichotomizing the quantitative LumiraDX results will be investigated and 
assessed. Potential values to use for dichotomizing the results will be based on deciles of the 
distribution and for each potential threshold the sub-hazard ratio for the impact of baseline 
serostatus on time to sustained recovery will be computed. An alternative cut-off may be 
selected if there are substantial differences in the hazard ratios. 
5 Protection of Human Subjects and Other Ethical 
Considerations 
 
Anticipated Risks and Benefits 
There is no direct benefit to participants in this study. Risks are no more than minimal, 
consisting of a single small-volume venous blood draw and potential loss of confidentiality.  
Normal hospital procedures are considered an adequate safeguard for any potential risk of 
drawing blood. Safeguards to protect participants’ identity are described in Section 5.5 below.  
 
Participating Clinical Sites and Local Review of Protocol and 
Informed Consent 
This study will be conducted by major medical centers participating in INSIGHT and partnering 
networks, including especially NHLBI networks. It is anticipated that potential participants will be 
recruited by the site investigators (and/or their delegates, as appropriate) and/or that positive 
SARS-CoV-2 laboratory testing will be used to enquire about potential enrollment. Information 
about this study will be disseminated to health care workers at enrolling sites. 
Prior to the initiation of the study at each clinical research site, the protocol, informed consent 
form and any participant information materials will be submitted to and approved by a 
central/national institutional review board (IRB)/ethics committee (EC) and/or the site’s local 
IRB/EC as required. Likewise, any future amendments to the study protocol will be submitted 
and approved by the same IRB(s) or EC(s). After IRB/EC approval, sites must register for this 
study before screening potential participants and must register for any protocol amendments. 
Protocol registration procedures are described in the protocol instruction manual (PIM). 
 
Ethical Conduct of the Study 
The study will be conducted according to the Declaration of Helsinki in its current version; the 
requirements of Good Clinical Practice (GCP) as defined in Guidelines, European Union 

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(EU) Clinical Trials Directive (2001/20/EC), and EU GCP Directive (2005/28/EC); 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use Guidelines; Human Subject Protection and Data Protection Acts; the US Office 
for Human Research Protections (OHRP); or with the local law and regulation, whichever 
affords greater protection of human subjects. 
 
Informed Consent of Study Participants 
Informed consent must be obtained (see sample in Appendix A) prior to conducting any 
study-related procedures. For patients who are incapacitated, informed consent may be 
obtained from a LAR. Capacity will be assessed according to local standards and policies. 
Local standards and policies will also determine who is legally authorized to consent for an 
individual who is incapacitated. Should the individual regain capacity during the study, their 
direct consent should be obtained at the earliest opportunity. 
Electronic consent may be used when a validated and secure electronic system is in place to 
do so, if in compliance with national legislation and approved by the local IRB/EC. Other 
methods of obtaining documentation of consent may be used when site staff are unable to be 
in direct contact with a potential participant or a LAR due to infection-control restrictions. No 
matter how the participant’s consent is obtained and documented, it is expected that consent 
will be preceded by research staff providing an explanation of the research and an 
opportunity for the participant (or their LAR) to have questions answered. Sites should follow 
all available local or national guidance on suitable methods for obtaining documentation of 
participant (or their LAR) consent. 
 
Confidentiality of Study Participants 
The confidentiality of all study participants will be protected in accordance with GCP 
guidelines and national regulations, including the US Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) and the EU General Data Protection Regulation (GDPR, 
EU 2016/679).  
 
Regulatory Oversight 
As previously stated, all sites will conduct the trial in accordance with the requirements of 
GCP as codified in their local law and regulation, under the oversight of their institution and 
competent regulatory authority. 
As part of fulfilling GCP requirements for adequate trial monitoring, multiple modalities will be 
employed.  
6 Storage and Use of Specimens 
The plasma obtained from participants will be sent to a central biorepository in the US. In 
addition to the antibody and antigen tests described in this protocol, these specimens will be 
available for further study of SARS-CoV-2 and COVID-19. Any future use of these specimens 
will be reviewed and approved by a scientific steering committee overseeing research 
conducted by this collaboration. Results of these tests will not be shared with participants or 
their clinicians. Aggregated results of such tests will be presented. No individual results will be 
linked to a study participant. 
 

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7 Supporting Documentation 
Detailed study procedures are described in the PIM which is available on the INSIGHT website. 
The laboratory manual provides detailed descriptions of procedures for specimen collection, 
storage, and shipping to the central biorepository. 
 
 

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APPENDIX A: Sample Informed Consent Form 
 
CONSENT FOR PARTICIPATING IN AN NIH-FUNDED RESEARCH STUDY  
SITE INVESTIGATOR: ________________________________ PHONE: __________  
 
Evaluation of the Feasibility and Reproducibility of 2 Point-of-Care Tests for  
SARS-Co-V-2 Antibodies (INSIGHT 017) 
 
Short Title:  INSIGHT 017: Evaluation of Point-of-Care (EPOC)  
Sponsored by:  The University of Minnesota  
Funded by:  National Institute for Allergy and Infectious Diseases, US National Institutes 
of Health 
 
A Multicenter Study of the International Network for Strategic Initiatives in Global 
HIV Trials (INSIGHT)  
 
 
 
This is a research study to find out if new rapid tests for COVID-19 are easy to use for 
people with COVID-19 who are in the hospital.  We are asking you to participate 
because you are in the hospital with symptoms of COVID-19 and have tested positive 
on a standard test.  It is your choice whether to be in this study or not.  
 
We are doing this study in many countries around the world.  We hope to have about 
300-400 people with COVID-19 be in this study.   
 
[The following text box is required for sites in the US, in accordance with the 2018 
Common Rule.] 
OHRP Requirements to be read by the sites: (remove this text box from your site-specific consent) 
 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY 
THE LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC 
APPROVAL OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL 
COORDINATING CENTER.  SPONSOR-APPROVED CHANGES IN THE PROTOCOL MUST BE 
APPROVED BY THE LOCAL IRB/EC BEFORE USE UNLESS INTENDED FOR THE ELIMINATION 
OF APPARENT IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE SHARED WITH 
EXISTING SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR TO 
INVOLVEMENT, OR AS THE LOCAL IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 

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What is being studied? 
The COVID-19 tests that are being used in the hospital are tests that have to be done in 
special laboratories by trained technicians.  It can be hours or days before you get the 
result.  Recent studies suggest that some COVID-19 treatments may work differently 
depending on whether you already have antibodies to COVID-19 in your blood.  It would 
be helpful to have a COVID-19 antibody test that could give results quickly so your 
doctor has more information on what treatments might be most effective for you. 
 
There are new tests available that can tell us about your antibodies in a few minutes.  
They do not have to be done in a lab.  So far they have only been studied in people who 
are not in the hospital.  We are doing this study to see if it is easy for these tests to be 
used right at your bedside in the hospital.  This is called a “point-of-care” (POC) test. 
 
We are looking at 2 different POC tests.  One is called LumiraDX and the other is called 
RightSign. 
 
What do you have to do in the study? 
If you agree to be in this study, we will ask you about what other medical conditions you 
have, what symptoms you are having, and what medicines you have gotten to treat your 
KEY INFORMATION  
• You can join the study if you are in the hospital with COVID-19 and have 
already tested COVID-19 positive on a standard test within the last 3 
days, or if the test was more than 3 days ago and you have gotten sicker 
from COVID-19. 
• If you agree to be in the study, you will have two finger sticks to draw 
blood.  This will be tested on two different point-of-care (rapid) tests.   
• You will also have a small amount of blood drawn from your arm to be 
tested in a central laboratory. 
• Once you have done this, you are done with the study. 
• There are minor risks to having blood drawn from your arm, but this risk 
is not different from blood draws that are already being done for your 
regular care. 
• There are no direct benefits to you from being in this study.  You will help 
us learn more about how these rapid tests work in people in the hospital 
with COVID-19. 
• This study does not include any treatments apart from your usual care.  
You and your doctor will decide how to treat your COVID-19. 
• You do not have to be in this study.  You can stop being in the study at 
any time.  This will not change your medical care or other benefits. 

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COVID-19.  We will ask if you have been vaccinated against COVID-19.  Your study 
team may be able to get this information from your medical record.   
 
We will stick your finger with a small sharp tool called a lancet to get a little bit of blood 
to use for the rapid tests.  We will do this twice, once each for the 2 different tests. If a 
test fails then we will stick your finger 1 more time, so you could have up to 4 finger 
sticks.  We will not tell you the results of these tests. This is because we do not know 
how to use these test results to choose treatments for you.  That would be investigated 
in future studies.  The results of these tests will not be used to guide your care. 
 
We will take about 9 milliliters (a little less than 2 teaspoons) of blood from a vein in your 
arm using a needle.  We will send these samples to a central laboratory in the United 
States.  More information is below. 
 
Once you have done these things, you are done with this study.   
 
This study does not provide any treatment for COVID-19.  You do not have to be in this 
study if you do not want to be.  If you agree to be in the study, you can stop at any time.  
Your decision about whether to be in this study or to stop the study will not change your 
usual medical care or any benefits to which you are otherwise entitled.   
 
The study will pay for the tests that are part of this study. 
 
[The next paragraph is for US sites only.  Sites in other countries should delete the next 
paragraph and replace it with the language appropriate for your location.] 
You, your insurance company, or some other third-party payer must pay for any 
medicines or other tests for your COVID-19 and for your hospital costs. 
 
What are the risks and benefits of being in this study? 
The only risks to you to be in this research study are the risk of having blood taken and 
the possibility that someone could find out you are in the study.  These risks are small 
and are the same as risks you already have from your hospital care.  Having blood 
taken may be a little painful. You may have a bruise where the needle goes in.  In rare 
cases, people have fainted or gotten an infection after having blood taken.   
 
You will not get any direct benefit from being in this study, but it may help others in the 
future if we can get a better understanding of how new tests for COVID-19 work.   
 
What do we do with the samples at the central laboratory? 
The study will test the blood samples to compare the results of the 2 POC tests to each 
other and to a standard antibody test.  You and your doctor will not get the results of 
these tests.   
 

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Any blood samples that are left over after these tests will be stored at the central 
laboratory for as long as we are able to keep them.  We hope to use these in the future 
to answer other questions about COVID-19, the virus that causes it, and how people 
respond to the virus.  You and your doctor will not get any results from these tests.  
You can withdraw your consent for us to keep these samples at any time.  Let your 
study team know if you do not want the study to keep your samples anymore.  We will 
make every effort to destroy all of your samples that are still at the central laboratory. 
We will not test your genes (DNA).  We will not sell your samples and they will not be 
used for research aimed at making money (commercial research).  The laboratory 
where the samples are stored will not have any information that could identify you. 
 
How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it.  Your information (data) and samples will not be identified by 
name, or in any other way, in anything published about this study.  You will be identified 
only by a code.  We will not release information from your records without your written 
permission. 
 
[The following paragraph is for sites outside the US only] 
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it.  We may have to release your personal information if 
required by law.  
 
[The following is for all sites] 
These people may see your medical and research information:  
 
• the [insert the name of the site] ethics committee (institutional review board, IRB); 
• the sponsor, the University of Minnesota (UMN), the group paying for the 
research (United States [US] National Institutes of Health [NIH]), other study 
staff, and people they designate as helping with the study; 
• US and other participating countries’ health and regulatory agencies. 
 
All of these people are committed to protect your privacy.   
 
As the research staff at [insert the name of the site], we must make sure that people not 
involved with this study cannot see your research and medical information.  We will 
keep your information in a safe place and will handle your personal information very 
carefully.   
 
Your study data are sent electronically to the UMN in the US through a secure 
application.  By signing this consent, you agree to having your data sent to UMN.  No 
information that could directly identify you is sent to UMN.  In this information, you are 

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identified only by a code number, your year of birth, and a 3-letter code that you or the 
study staff choose.  This is called “pseudonymized data”.   The UMN limits access to the 
data through security measures, and no data breach or unauthorized access has ever 
occurred in this system.  After the study is over, the data will be stored securely for as 
long as the law requires. 
 
We will share your study data with the US NIH (which is paying for this study), and with 
regulators that oversee the study.  We are required by law to do this.  UMN may share 
your data and blood sample with other people who study COVID-19.  UMN will remove 
the code number, year of birth, and 3-letter code from your data before sharing.  This is 
called “anonymizing the data” and makes it impossible for anyone to link the data back 
to you.  We will not ask you for additional consent for this sharing.  UMN will only share 
data for research projects that are approved by INSIGHT. 
 
For one of the new tests we are studying, the LumiraDX test, the test results will be sent 
through the internet to LumiraDX’s computers.  They are sent in a secure way and the 
information is encrypted (coded so no one can read it unless they have a special key).  
LumiraDX will then send this data to the UMN in a secure way.  LumiraDX uses this test 
in many countries around the world and must follow the privacy laws of those countries, 
including the countries where this study is being done.   
 
The test results sent to LumiraDX include the time, date, and hospital where the test 
was done.  The only information that LumiraDX will have that could be linked to you 
personally is a number on the kit used to take your blood.  This is a different code 
number than what is on the data that your site sends to UMN.  These two numbers can 
be linked together at UMN and at your site, but only the site knows who you are.  These 
numbers will not be part of any data that is shared as described above. 
 
This study has a Certificate of Confidentiality from the US Federal government.  This 
means that UMN cannot share any data it has about you with national, state, or local 
civil, criminal, administrative, legislative, or other authorities unless you specifically allow 
us to share it.  
 
[Note for US sites: Because each institution typically has requirements for specific 
HIPAA language in the consent or in a separate document, none is provided in this 
template.  Follow your institutions’ requirements for informing potential participants of 
their rights under HIPAA.] 
 
[The following section (up to “What if you are hurt as part of this research?”) is for 
countries subject to the GDPR or similar legislation requiring this information.  It should 
only be included in consents for sites subject to such legislation.  It will vary from place 
to place whether it must be in this consent document, a separate consent document, or 
an information sheet that does not require signature.  The amount of information 

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provided may be reduced as long as it still meets requirements of the particular country 
(e.g., not all countries/ECs require an enumeration of all of a data subject’s rights).] 
 
What are your rights regarding your data? 
UMN is a public research university, and this study is funded primarily by the US 
Federal government.  The State of Minnesota and the US Federal government require 
UMN to follow regulations and policies that are meant to protect your privacy.  UMN is 
also required to comply with the General Data Protection Regulation (GDPR), because 
it processes data obtained from European residents.  
 
There is no specific independent supervisory authority overseeing the processing of 
data in the US.  Any complaint you might have about the use of your data would be 
made to your national data protection authority. 
 
The GDPR gives you additional rights which we would like to inform you about below. 
 
Right to Information 
You have the right to know what data about you is being processed.  You can also get a 
free copy of this data. 
 
Right to Correction 
You have the right to correct any information about you which is incorrect or had 
become incorrect. 
 
Right to Erasure/Anonymization 
The sponsor is required under both EU and US law to retain data from research studies 
such as this one for many years.  However, you have the right to request that your 
personal data be completely anonymized.  This is done by destroying the information at 
your study center that links your identity to the pseudonymized data held by UMN.  This 
means that no one would ever be able to link the data held by UMN to you personally.  
 
Right to Restriction of processing 
Under certain conditions, you have the right to demand processing restrictions, i.e., the 
data may then only be stored, not processed.  You must apply for this.  Please contact 
your study doctor or the data protection officer of the study center if you want to do so.  
This right may be limited if the restriction would affect the reliability of the study results. 
 
Right to Data portability  
You have the right to receive the personal data that you have provided to the study 
center.  This will allow you to request that this information be transmitted either to you 
or, where technically possible, to another agency designated by you. 
 
Right to Contradiction 

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You have the right to object at any time to any specific decision or action taken to 
process your personal data.  This right is limited for data that have already been 
processed and may be limited if your objection would affect the reliability of the study 
results. 
 
Right to Withdrawal of this consent 
You may withdraw your consent at any time with effect for future data collection.  This 
withdrawal may be in an informal or verbal communication to your study doctor.  If you 
withdraw your consent this will not affect the lawfulness of the data processing that has 
been or will be done with data collected until you withdraw consent.  Data already 
collected will be anonymized. 
 
If you would like to use one of these rights, please first contact the person responsible 
for the data collection at your study center: 
Person responsible for data collection at the study center: 
Name: 
 
Address:  
Phone: 
 
Email 
 
 
For concerns about data processing and compliance with data protection requirements 
you can also contact the data protection officer responsible for the study center: 
Data protection officer responsible for the study center: 
Name: 
 
Address:  
Phone: 
 
Email 
 
 
In addition, you have the right to lodge a complaint with the competent authority if you 
believe that the processing of personal data concerning you is contrary to the GDPR: 
Data protection authority responsible for the study center: 
Name: 
 
Address:  
Phone: 
 
Email 
 
 
What if you are hurt as part of this research? 
If you are hurt because of being in this study, [insert the name of the hospital/clinic] will 
treat your injury right away.  You or your insurance will have to pay for this treatment.  
The study cannot pay you or pay for any care for study-related injuries or for your 
illness. 
 

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[If the above is not true for your site, i.e., if trial insurance covers such cost, please 
replace the above with appropriate language.] 
 
What if you have questions? 
If you have questions about this study, or about the storage or use of your data, or if you 
are hurt by being in the study, you can contact (site PI and contact information).  If you 
have questions about your rights as a research participant, you can contact (name and 
contact information). 
 
 

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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE INSIGHT 017 STUDY 
(EPOC)  
 
I have read the consent or have had it explained to me.  I am satisfied that I understand 
the information.  By signing this consent, I am stating that I want to join this study.  I 
understand that I do not waive any of my legal rights as a study participant by signing 
this consent.  I understand that I will receive a copy of the signed and dated consent. 
 
 
 
 
 
 
 
 
________________________________________________________ 
Name of staff member conducting consent process (typed or printed) 
 
____________________________________________________ 
______________ 
Staff member’s signature 
Date 
 
________________________________________________________ 
*Witness’s name (typed or printed) 
 
____________________________________________________ 
______________ 
Witness’s signature 
Date 
*A witness to the participant’s signature is strongly encouraged.  
 
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record.  A copy of the signed and dated consent must be 
given to the participant.  A copy should be placed in the participant’s medical 
record, if applicable.  
 
 
 
_________________________ 
______________________________  
__________ 
Participant’s name  
           Participant’s signature 
                      Date 

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APPENDIX B: List of Acronyms 
Ab 
antibody 
ACE-2 
angiotensin converting enzyme-2 
AE 
adverse event 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments of 1988 
CRF 
case report form 
EC 
ethics committee 
EDTA 
ethylenediamine tetraacetic acid 
EU 
European Union 
EUA 
emergency use authorization 
FDA 
US Food and Drug Administration 
GCP 
good clinical practice 
GDPR 
General Data Protection Regulation 
hIVIG 
hyperimmune intravenous immunoglobulin 
ICC 
International Coordinating Center 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IRB 
institutional review board 
LAR 
legally authorized representative 
NAT 
nucleic acid test 
nMab 
neutralizing monoclonal antibody 
OHRP 
US Office for Human Research Protections 
PCR 
polymerase chain reaction 
PIM 
protocol instruction manual 
POC 
point-of-care 
RBD 
receptor binding domain 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 

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TICO 
Therapeutics for Inpatients with COVID-19 
UMN 
University of Minnesota 
US 
United States of America 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C: INSIGHT 017 Protocol Team 
A protocol team will be established to oversee implementation of this protocol. This team will 
include: 
• 
Protocol co-chairs. 
• 
NIAID, Division of Clinical Research representatives. 
• 
INSIGHT University of Minnesota representatives. 
• 
INSIGHT International Coordinating Center representatives. 
• 
PETAL representatives. 
• 
CTSN representatives. 
• 
US Department of Veterans Affairs representatives. 
• 
Collaborating laboratory representatives. 
• 
Site investigators. 
• 
Study biostatisticians. 
• 
Community representative. 
A core team consisting of representatives from these groups and the INSIGHT Principal 
Investigator will meet regularly to review study progress and address issues that may arise. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: References 
1 ACTIV-3/TICO Study Group, Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, 
et al. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med. 
2020. doi: 10.1056/NEJMoa2033130. 
 
2 RECOVERY Collaborative Group, Horby PW, Mafham M, et al. Casirivimab and imdevimab in 
patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-
label, platform trial [Internet]. Infectious Diseases (except HIV/AIDS); 2021 [cited 2021 Jul 4]. 
Available from: http://medrxiv.org/lookup/doi/10.1101/2021.06.15.21258542. 
 
3 ACTIV-3/TICO Bamlanivimab Study Group, Lundgren JD, Grund B, et al. Clinical and 
Virological Response to a Neutralizing Monoclonal Antibody for Hospitalized Patients with 
COVID-19 [Internet]. Infectious Diseases (except HIV/AIDS); 2021. Available from: 
http://medrxiv.org/lookup/doi/10.1101/2021.07.19.21260559. 
 
4 ACTIV-3/TICO Bamlanivimab Study Group.  Clinical and Virological Response to a 
Neutralizing Monoclonal Antibody for Hospitlaized Patients with COVID-19 (in press Annals 
Intern Med). 
 
5 ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group.  Neutralizing 
Monoclonal Antibody Therapies VIR-7831 and BRII-196/198 for Adults Hospitalized with 
COVID-19: A Randomized Controlled Trial (in press Lancet ID). 
 
6 Babiker A. SARS-Cov-2 Serostatus and Antigen Levels: Prognostic Value and Impact on 
Clinical Effect of Passive Immunotherapy. ACTIV Passive immunit Biomarker Workshop, 
September 2021.  
 
7 Murray DD, Babiker AG, Baker JV, et al. Design and implementation of an international, multi-
arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: 
Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3). Clin Trials 2021 doi: 
10.1177/17407745211049829.  
 
8 https://www.fda.gov/media/151252/download. Accessed 07 December 2021. 
 
9 https://www.fda.gov/media/138660/download. Accessed 07 December 2021. 
 
10 Schlesselman JJ, Case Control Studies. Oxford University Press, New York, 1982.