Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 234
Healthy volunteers: no

Brief summary:
At present there is no approved drug treatment for Covid-19. In this study we plan to investigate if an experimental drug called IMU-838 (vidofludimus calcium) can improve your symptoms, prevent worsening that would initiate further treatments such as ventilation, and can lower your virus number if given in addition to your doctor's choice of standard therapy. We will also test if IMU-838 has any side effects and measure the level of IMU 838 in your blood.

Experimental drug means that it is not yet authorized for marketing in your country. To date approximately 600 individuals have received IMU-838 (or a drug similar to IMU-838 that contains the same active substance as IMU-838) in research studies.

Detailed description:
The trial consists of a Phase 2 proof-of-concept phase (Part 1) with the option to extend enrollment (without interruption) to Phase 3 (Expansion Phase, Part 2).

This trial is a multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to evaluate the safety and efficacy of IMU-838 as addition to investigator's choice of SoC treatment in patients with COVID-19. Eligible patients will be centrally randomized 1:1 to twice-daily (BID) oral 22.5 mg IMU-838 (45 mg/day + SoC) or placebo (+ SoC). Randomization will be stratified by age (\< or \>=65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and Chloroquine, all other antivirals).

Adaptive sequential trial design and overall trial design

The trial uses an adaptive sequential design. An IDMC will review unblinded data and provide the Sponsor with recommendations regarding modifications of sample size and trial conduct.

A 1st interim analysis (IA1) will be performed after approximately 200 patients have completed the trial (either as scheduled or prematurely), while enrollment continues. If no activity of IMU 838 is observed by the IDMC in this IA, further patient enrollment will be stopped, and a final analysis of Part 1 will be performed (FA1). It is expected that the final analysis of Part 1 will include approximately 230 patients. If the IA1 results indicate activity of IMU-838 in COVID-19, the trial may be extended to Part 2 with a revised sample size derived by the IDMC based on IA1 results and with possible other trial adjustments. If the trial is extended into Part 2, a 2nd IA (IA2) is planned after approximately two-thirds of patients (based on the overall global sample size \[Part 1 and Part 2 combined\]) have been enrolled to potentially adjust sample size and other trial features if needed. The final analysis of the trial (FA2) will then be done after all patients have completed Part 2.

In addition, an early interim safety analysis will be performed and evaluated by the IDMC after 30 patients have been enrolled to assess unblinded safety data. Further safety analyses can be initiated at any time by the IDMC or Sponsor when new safety signals are identified within this or other trials of IMU-838.

Screening

Patients can be screened for a maximum of 2 days (from Day -2 to Day 0) and eligible patients will be randomized on Day 0 and treated with IMP + SoC for 14 days. It is encouraged to screen potential participants immediately at the day of hospitalization (including informed consent, assessment of inclusion/exclusion criteria, screening laboratory tests all done locally, assessment of clinical and blood gas criteria) and randomize patients on the same day (Day 0). To assess eligibility criteria, existing local laboratory values obtained within 48 hours of randomization can also be used, except for testing of positive status of SARS-CoV-2 infection where a 4-day window is allowed.

IMP administration should start as quickly as possible after randomization and first IMP intended to be given in the evening of the screening day (Day 0).

Blinded Treatment period (Day 0 to Day 13) and Day 14 (end-of-treatment)

The first dose of IMP (2 tablets) should always be given on Day 0 (allowed range for first dose: 12:00 noon on Day 0 to 02:00 a.m.). All further IMP doses are 1 tablet each in the morning and evening. Information about the status and patient care are continuously obtained and documented once or twice daily.

After the last IMP dose in the evening of Day 13, the end-of-treatment assessments will be done on Day 14. Blood sampling for IMU-838 trough values must be performed in the morning around the time the morning dose was usually taken by the respective patient. Patients may then continue to receive SoC without any further restrictions on concomitant medications as during the 14-day BT period .

Day 28 Visit (EoS)

The patient should return for the final trial visit on Day 28 (EoS). If IMP is prematurely discontinued for any reason, the EoS visit should always be conducted on Day 28 and no earlier EoS should be performed. If patients withdraw from IMP prematurely, they should be encouraged to allow the EoS visit as part of the follow-up. If the patient dies during the trial, the investigator should indicate that this visit was not performed. However, even if no EoS visit was performed, information about patient status should be reported on the EoS page in the case report form. If the patient refuses any EoS visit or the patient is lost to follow-up, it is permissive in this trial that the investigator contacts the patient, the family of the patient or the referring physician by phone or email to obtain status of life information, or is able to search in registers or publicly available information for such status of life information.

Arms:
arm 1: twice-daily (BID) oral 22.5 mg IMU-838 (45 mg/day + SoC) arm 2: twice-daily (BID) oral placebo (+ SoC)

Interventions: intervention 1: IMU-838 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets will be taken BID with a glass of water (if possible); one tablet each in the morning (15 to 50 min before a meal if applicable), and in the evening (2 hours after any meal if applicable).

If the patient is intubated for ventilation, IMP is to be given via a gastric tube. The tablet has no coating and a homogeneous content and can be crushed into smaller pieces (if necessary) for dosing via gastric tube. intervention 2: Matching placebo, twice-daily administration BID as described for the test product, identical number of tablets as given for IMU-838

Protocol document:
Prot_SAP_000.pdf: 
 
 
CLINICAL TRIAL PROTOCOL 
 
A Prospective, Multi-Center, Randomized, Placebo-
Controlled, Double-Blinded Study to Evaluate the Efficacy, 
Safety and Tolerability of IMU-838 as Addition to 
Investigator’s Choice of Standard of Care Therapy, in 
Patients with Coronavirus Disease 19 
 
(CALVID-1) 
 
IND: 
149,167 
EudraCT No: 
2020-001264-28 
Protocol no.: 
P2-IMU-838-COV 
Sponsor: 
Immunic AG 
Lochhamer Schlag 21 
82166 Graefelfing, Germany 
Coordinating investigator: 
Prof. Neera Ahuja, Stanford University School 
of Medicine 
Protocol version and date: 
Final 3.0, 04-Sep-2020 
Previous protocol versions and date: 
Final 2.1 (USA), 29-May-2020 (valid only in US) 
 
Final 2.1 (BG), 20-May-2020 (valid only in BG) 
 
Final 2.1 (DE), 05-May-2020 (valid only in DE) 
 
Final 2.0, 30-Apr-2020 
 
Final 1.0, 21-Apr-2020 
This clinical trial protocol must be kept strictly confidential. Disclosure of the contents (in whole 
or part) to third parties is permissible only with written consent of Immunic AG. 


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REVISION CHRONOLOGY  
• Original version: Version 1.0, dated 21-Apr-2020 
• Version 2.0, dated 30-Apr-2020 
The following changes were included in Version 2.0 compared with Version 1.0: 
o 
Section 1 and Section 9.3 (Exclusion Criterion 11), Section 11.2.1, and Section 11.2.2: 
Included that Chloroquine and Hydroxychloroquine are prohibited for all centers in all 
countries unless already taken for indicated use before entering the trial (in Version 1.0 
it was only prohibited for all centers in Germany and allowed with special 
recommendations in other countries) 
o 
Section 1, Section 9.3 (Exclusion Criterion 11), and Section 11.2.2: 
− 
Included that use of other DHODH inhibitors, including teriflunomide or 
leflunomide is prohibited 
− 
Orafenib was replaced by sorafenib (spelling mistake) 
o 
Section 1 and Section 7: 
Under Secondary endpoints 
Clinical patient status on the 9-category WHO ordinal scale1 on Days 6, 14, and 28  
Changed to 
Change in daily clinical patient status on the WHO 9-category ordinal scale1  
o 
Appendix 1: 
Urine uric acid deleted in Lab Kit A as this was added there in error instead of blood 
serum-based uric acid 
Clarified that estimated glomerular filtration rate (eGFR) will be calculated according 
to the Schwartz bedside equation for children and adolescents and not according to 
the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation that 
will be used for adults. Respective references were added. 
o 
Editorial changes. 
• Version 3.0, dated 04-Sep-2020 
 The following changes were included in Version 3.0 compared with Version 2.0, 
2.1(DE), 2.1 (BG), and 2.1 (USA) as indicated 
Protocol P2-IMU-838.COV was primarily amended to specify that Part 1 and Part 2 of 
the trial will now be handled and analyzed completely independent of each other. The 
primary objective of Part 1 is to show proof-of-activity. If activity of IMU-838 can be 


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demonstrated during the main analysis of Part 1 (MA1), Part 2 will be initiated. Sample 
size estimations for Part 2 will be done based on the MA1 results. Further, endpoints and 
other trial features will be re-evaluated and adjusted if deemed necessary. 
Changes based on this modification of trial design and further changes are outlined below. 
Country-specific changes are indicated in italics. 
If changes are indicated old replaced text is struck through and newly added text written 
in bold. 
 
Sections affected Change 
Applicable for Version 
 
 
2.0 
2.1 
(DE) 
2.1 
(BG) 
2.1 
(USA)
Title Page and 
Section 2 
Address of Sponsor changed 
 
 
 
 
 
Revision 
Chronology 
Under ‘changes included in Protocol Version 2.0 
compared with Version 1.0’, explained why urine uric 
acid was deleted from Lab Kit A (see above Appendix 1) 
 
 
 
 
1 (below 
Table 1), 4 
Deleted that in case of inconsistencies between text in the 
protocol and the schedule of assessments, the schedule of 
assessment (Table 1) will predominate’. 
 
 
 
 
1, Table 1, 8.1, 
12.6 
Included safety follow up to be performed after D28/EOS 
examination until Day 60. Sections updated accordingly 
and new Section 12.6 ‚Safety follow up‘ added.  
 
 
 
(+Sec. 
12.1) 
 
1 
• The SFU added to trial periods 
 
 
 
 
 
• Statistical methods shortened and adjusted to describe 
modifications as outlined below for Section 16.3.2 
 
 
 
 
1, Table 1, 8.1, 
11.1.3, 11.1.5, 
12.3, 12.5 (only 
valid in BG) 
Following a request from the Bulgarian Drug Agency, 
patients randomized into the trial in Bulgaria must be kept 
hospitalized for the entire 14-day treatment period (Day 0 to 
Day 14). Sections updated accordingly 
 
 
 
 
1, 6 
Participating countries updated, number of centers 
updated 
 
 
 
 
1, 7 
Under secondary efficacy endpoints the specification that 
some endpoints maybe evaluated for a subset of only 
surviving patients deleted as this will be specified in the 
SAP 
 
 
 
 
 
Under pharmacokinetic endpoints: indicated that morning 
plasma trough values of IMU-838 will be measured at 
Days 0, 1 through 6, 14, and 28 (instead of Days 0, 1, 2, 3, 
6, 14 and 28) to be consistent with Table 1 
 
 
 
 
 
‘Proportion of patients surviving without respiratory 
failure’ added as key secondary endpoint and respective 
objective 
 
 
 
 


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Sections affected Change 
Applicable for Version 
 
 
2.0 
2.1 
(DE) 
2.1 
(BG) 
2.1 
(USA)
1, 7 (continued) 
Following secondary endpoint changed as indicated: 
‘Cumulative dose of vasoactive therapies (daily until Day 
14) and days with vasoactive therapies (daily until Day 
14)’ 
 
 
 
 
 
Following secondary endpoint corrected as indicated: 
‘Proportion of patients with clinical improvement, defined 
as the time from first dose of IMP to an improvement of at 
least 2 points on the WHO 9-category ordinal scale….’’,  
 
 
 
 
 
For the secondary endpoint ‘Proportion of patients with 
auxiliary therapy, indicated that the need of auxiliary 
oxygen therapy is sufficient for this endpoint and clarified 
that this proportion will be assessed not on but until Days 
6, 14, and 28 
 
 
 
 
 
For the secondary endpoint ‘Rate of IC admission’ 
clarified that this proportion will be assessed not on but 
until Days 6, 14, and 28 
 
 
 
 
1, 8.1 
Clarified that early safety analysis will be performed after 
30 patients have completed Day 28. For US centers only, 
enrollment will be paused in the US at this time until after 
the IDMC has reviewed trial safety stopping criteria for 
the trial. 
 
 
 
 
 
Safety follow-up added 
 
 
 
 
 
For consistency reasons ‘early interims safety analysis’ 
replaced by ‘early safety analysis’ 
 
 
 
 
1, 8.1, 9.1, 16.1, 
16.3.1, 16.4  
Sections updated to reflect the following as applicable: 
• Specified that Part 1 and Part 2 will be handled as 
independent parts and respective changes in analysis, 
sample size and trial conduct described 
 
 
 
 
 
 
 
 
 
• Alpha level for Part 2 changed from 0.05 to 0.025 
(1-sided); information rate from 20% (α<0.0001) to 
50% (α=0.0026) 
 
 
 
 
 
• Sample size calculation adjusted 
 
 
 
 
1, 9.2 (Inclusion 
Criterion 1) 
Included that the potential extension of the trial to include 
children after the MA1 will only be implemented after the 
approval of a respective protocol amendment 
 
 
 
 
1, 9.3 
The following exclusion criteria were added 
• Patients with clinically relevant conditions leading to 
hyperuricemia (Exclusion Criterion 12)  
 
 
 
 
 


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Sections affected Change 
Applicable for Version 
 
 
2.0 
2.1 
(DE) 
2.1 
(BG) 
2.1 
(USA)
1, 9.3 
(continued) 
The following exclusion criteria were added 
• Patients with known Gilbert syndrome (unless their 
indirect [unconjugated] bilirubin level is confirmed to 
be <1.2 x ULN, i.e. <1.1 mg/dL) (Exclusion 
Criterion 16) 
 
 
 
 
 
 
 
 
• Patients with known acute or clinically relevant 
chronic renal failure, patients currently on dialysis, as 
well as patients with an estimated glomerular filtration 
rate value <30 mL/min/1.73 m² body surface area 
according to the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation for 
adults (or the Schwartz bedside equation for children 
and adolescents, if applicable) (Exclusion Criterion 
17) 
 
 
 
 
 
1, 9.3 
Previous Exclusion Criterion 14 now Exclusion Criterion 
15 was modified to include in addition to patients with 
Child Pugh C liver impairment also patients with Child 
Pugh B liver impairment 
 
 
 
 
1, 23  
Start and end of trial updated 
 
 
 
 
Table 1 
Status hospitalization/status ICU, SARS-CoV-2 viral load, 
SARS-CoV-2 status, and Serology: SARS-CoV-2 
antibodies added for USV(SFU) 
 
 
 
(+Sec. 
12.1) 
 
 
SARS-CoV-2 viral load and SARS-CoV-2 status 
assessments changed from a daily to a 2-daily assessment  
 
 
 
(+Sec. 
12.1) 
 
 
Indicated that use of RRT and ECMO at SFU must not be 
noted if performed as telephone visit 
 
 
 
 
 
Indicated that score assessment (9-point WHO scale), 
documentation of ECMO use, RRT use, vasopressor dose, 
and O2 supplementation must be performed also on 
Day 28 (needed for respective endpoints) (only Table 1) 
 
 
 
 
Table 1, Section 
15.3 
Clarified that height and weight are only to be measured at 
D0, pre-dose 
 
 
 
(+Sec. 
12.1) 
 
Table 1, 
Appendix 1 
Clarified which samples must be sent to the central safety 
laboratory and which to the central virology laboratory 
 
 
 
 
Table 1, 
Appendix 2,  
A list of required local laboratory tests was included; 
Appendix 2 newly added, previous Appendix 2 now 
Appendix 3 
 
 
 
(+Sec. 
12.1) 
 


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Sections affected Change 
Applicable for Version 
 
 
2.0 
2.1 
(DE) 
2.1 
(BG) 
2.1 
(USA)
Table 1, 14.3, 
Appendix 1 
Included that nasopharyngeal swab and spontaneous 
sputum samples must be stored at at least -20°C (-4°F) on 
site, and shipped to the laboratory on dry ice within 7 days 
(instead of storing at ambient temperature and shipment 
on day of sampling) 
 
 
 
 
 
Clarified that the qualitative SARS-CoV-2 status 
assessment will be based on the viral load test. 
 
 
 
 
Table 1, 14.3, 
Appendix 1 
(continued) 
Further clarified that qualitative SARS-CoV-2 status 
assessment may be evaluated as absence or presence of 
virus in the quantitative SARS-CoV-2 RT-PCR 
assessments 
 
 
 
(+Sec. 
12.1) 
 
Table 1, 13.3 
Specified that any new viral or non-viral infection as well 
as site of infection and source of culture will be 
documented if assessed during routine clinical practice. 
 
 
 
(+Sec. 
12.1) 
 
Table 1, 
14.3,19.3 
Sections updated to reflect the following as applicable: 
Additional blood collection to evaluate immune cells and 
immune reactions in future research studies added (at 
Days 0, 6, 14, and 28), only valid for centers in the USA 
and optional for patients consenting to these additional 
blood collections. 
 
 
 
(+Sec. 
12.1) 
 
Table 1, 14.1, 
14.2, 14.3, 
15.2.2, 
Appendix 1 
Clarified to store laboratory samples at at least -20°C 
(-4°F) 
 
 
 
 
Figure 1 
SFU added 
 
 
 
 
2, 6 
Central virology laboratory added 
 
 
Only 
US 
lab 
Only 
EU 
lab 
10.1 
The following was added: 
For the MA1 the IDMC and Sponsor will be unblinded, 
the blind will, however, be kept for patients and 
investigators until FA1. 
 
 
 
 
11.2.2 
Specified that CYP2C8 metabolized drugs, potent 
CYP2C8 inhibitors and strong and moderate CYP2C8 
inducers should be used with caution 
 
 
 
 
12 
Schedule of assessment (Table 3) included; new 
subheading i.e., 12.1 Schedule of assessment included; 
heading numbering of remaining section headings 
adjusted 
 
 
 
 
14 
Indicated that samples must be prepared according to the 
respective laboratory manuals 
 
 
 
 


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Sections affected Change 
Applicable for Version 
 
 
2.0 
2.1 
(DE) 
2.1 
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2.1 
(USA)
15.1.3 
AE reporting indicated as follows to be consistent with 
Table 3: All AEs occurring between the time written 
informed consent was obtained and 14 days after the 
patient’s last IMP intake until the end of the safety 
follow-up period (safety observation period) or until 
EoS, whatever occurs later, must be recorded.  
All AEs that occur during the safety observation period… 
 
 
 
 
15.1.6 
Was modified to indicate that also COVID-19 related 
symptoms with clinically unusual worsening during the 
trial must now be reported as AEs as follows:  
Typical COVID-19-related symptoms present at 
Baseline (examples such as fever, dyspnea, viral 
pneumonia, or hypoxia) and continuing during the 
trial without clinically unusual worsening* are 
considered anticipated clinical events of the underlying 
condition and will not be collected as AEs, and disease- 
 
 
 
 
 
 
 
 
related symptoms such as temperature, blood oxygen 
saturation, respiratory rate and presence of viral 
pneumonia and bacterial superinfections are collected 
separately as efficacy measures. In addition, disease 
characteristics and severity will be regularly captured 
within the scope of the clinical status assessment and 
complete physical examinations will be recorded multiple 
times. Death, or hospitalization, and use of ventilation, 
ECMO, or dialysis due to COVID-19 or its complications 
(which all are recorded as clinical endpoints for this 
trial) are is not considered an AEs (see Section 15.1.2) 
and should not be considered medically significant 
events by itself for the assessment of SAEs. are recorded 
as clinical endpoints for this trial. 
Any clinically unusual worsening* of COVID-19-related 
disease symptoms present at trial inclusion and any 
clinically relevant changes in clinical laboratory 
parameters, vital signs or other findings during 
physical examination which are considered unusual 
for COVID-19 disease and where a relationship to 
drug treatment cannot be excluded should only be 
recorded as an AEs if their course is abnormally severe, 
significant or unexpected. 
* “Unusual worsening” means that, in terms of type or 
severity of symptoms, time frame or symptom 
fluctuations, the course of the disease progression is 
different from that in most patients with the same 
general conditions (disease status, age, health status, 
concurrent diseases). 
 
 
 
 


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Sections affected Change 
Applicable for Version 
 
 
2.0 
2.1 
(DE) 
2.1 
(BG) 
2.1 
(USA)
15.1.6 
(continued) 
Typical COVID-19-related symptoms present at Baseline 
(examples such as fever, dyspnea, viral pneumonia, or 
hypoxia) and continuing during the trial without clinically 
unusual relevant worsening* are considered anticipated 
clinical events of the underlying condition and will not be 
collected as AEs. In addition, disease characteristics and 
severity will be regularly captured within the scope of the 
clinical status assessment. Death, or hospitalization and 
use of ventilation, ECMO, or dialysis due to COVID-19 
or its complications (which all are recorded as clinical 
endpoints for this trial) are is not considered an AEs (see 
Section 15.1.2) and should not be considered medically 
significant events by itself for the assessment of SAEs. 
are recorded as clinical endpoints for this trial. 
Any clinically relevant unusual worsening* of COVID-
19-related disease symptoms present at trial inclusion, and 
any clinically relevant changes in clinical laboratory 
parameters, vital signs or other findings during physical 
examination which are considered unusual for COVID-
19 disease and where a relationship to drug treatment 
cannot be excluded should be recorded as an AEs. 
*“Unusual worsening” means that, in terms of type or 
severity of symptoms, time frame or symptom 
fluctuations, the course of the disease progression is 
different from that in most patients with the same 
general conditions (disease status, age, health status, 
concurrent diseases). 
 
 
 
 
15.2 
Section renamed to ‘Safety laboratory investigations’ 
 
 
 
 
 
Clarified that clinically significantly abnormal values 
must be reported as AE, if not already clinically 
significantly abnormal at Baseline or if there are known 
circumstances unrelated to a disease or the medication 
(such as patient activities or sample handling) that are 
a likely explanation for the abnormal value 
 
 
 
 
 
Clarified that clinical safety laboratory tests are to be 
performed at the indicated times 
 
 
 
 
16.3.2 
Section updated to reflect the following: 
• Included that patients who are lost to follow-up or 
discontinue the trial on or before Day 13 (last 
treatment day) due to any reason other than death, and 
who discontinue with a last observed WHO clinical 
status no lower than that at Screening are considered 
treatment failures for the primary endpoint. 
 
 
 
 
 
 
 
 


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16.3.2 
(continued) 
Section updated to reflect the following:  
• New sensitivity analysis for the primary endpoint 
specified for patients who discontinued before EoS, 
using the available information on INV until EoS. 
 
 
 
 
 
 
 
 
 
• Analysis of the new key secondary endpoint 
‘proportion of patients surviving without respiratory 
failure’ added; sensitivity analysis specified 
 
 
 
 
 
• Center as covariate excluded in the logistic regression 
analyses (Part 2)  
 
 
 
 
 
• Rules for imputation of missing ICU data specified 
 
 
 
 
 
• Corrected that patients who discontinued the trial 
before Day 28 due to any other reason than death will 
be considered as deaths survived, unless survival 
status can be obtained through other means 
 
 
 
 
 
• Sensitivity analysis for all-cause mortality specified  
 
 
 
 
 
• Analyses applicable for Part 1 and Part 2 described 
separately; clarified that Part 1 will only be done 
exploratory, while Part 2will include confirmatory 
tests 
 
 
 
 
16.4 
Completely rewritten and adjusted to the new trial design; 
new heading, procedures and criteria for Part 1 to Part 2 
transition described 
 
 
 
 
17.1 
For the purpose of patient discontinuation for safety text 
changed as follows: 
Any SAE of Grade 3 or 4, that in the opinion of the 
investigator, (1) is likely related to IMP and (2) when in 
the investigator’s opinion the benefits do not outweigh the 
risk for continuing in the trial 
 
 
 
 
18 
The following changes to IDMC meetings and enrollment 
stop were made: 
• 
… 
• 
Meeting for MAIA1 
• 
… 
 
 
 
 
 
‘If at any interim analysis the IA2 the IMU-838 therapy 
arm proves to be statistically significantly more 
beneficial..’ 
 
 
 
 
19.3 
Included that patients from whom additional blood 
samples will be collected to immune cell subtyping for 
further research studies will have to provide their consent 
to that optional additional procedure in the ICF (only 
applicable for the US) 
 
 
 
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20 
Section 20.1 Trial safety stopping criteria newly introduced, 
numbering of subsequent sections adapted 
 
 
 
 
 
 
 
 
Clarified that the trial will be stopped during the early and 
potential additional any interim safety analyses analysis when 
the stopping criteria are fulfilled: … 
 
 
 
 
 
 
 
 
 
Section 20.2 (previous Section 20.1) renamed in ‘Other criteria 
for halting or terminating the trial’ 
 
 
 
 
 
 
 
22.6 
Specified that the results of Part 1 and Part 2 of the trial 
will be each summarized in a clinical trial report 
according to the ICH E3 
 
 
 
 
 
Clarified that conclusions of early safety analysis, MA1 
IA1 and IA2 will be submitted as appropriate. 
 
 
 
 
1, 2, 6, 7, 9.2 
(Inclusion 
Criteria 2 + 4), 
19.1, 19.3, 22.6 
Information applicable for centers in the USA included 
 
 
 
 
Table 1, 8.1, 
11.1.3, 11.1.5, 
12.1, 12.3 
Procedures to be performed in case of hospital discharge 
before Day 14 included (not applicable in BG) 
 
 
 
 
 
Editorial changes 
 
 
 
 
 
 
 


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1 
Summary and flow chart 
Trial code  
P2-IMU-838-COV 
Title of the trial  
A Prospective, Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Study to Evaluate 
the Efficacy, Safety and Tolerability of IMU-838 as Addition to Investigator’s Choice of Standard 
of Care Therapy, in Patients with Coronavirus Disease 19  
Short title  
CALVID-1 
Principal investigators and trial centers  
Planned: about 10 to 45 centers in the European Union, Bosnia and Herzegovina, Moldova, North 
Macedonia, Russia, Ukraine, and USA (and as back up countries: Croatia and Serbia)  
Coordinating investigator: Prof. Neera Ahuja, Stanford University, School of Medicine 
Clinical phase: Phase 2 (Part 1), Phase 3 (optional Part 2)  
Phase 2 (Proof-of-Activity Phase, Part 1): 
Estimated start (first patient in): 
May 2020 (actual 12-Jun-2020) 
Estimated recruitment period: 
4 months 
Estimated end of trial (last patient out): 
Nov 2020 
Optional Phase 3 (Part 2): 
Depending on the outcome of the main analysis of Part 1 (MA1), this optional trial expansion will 
be started which will then be considered a Phase 3 trial. 
Trial periods  
The trial consists of screening, a 14-day blinded treatment (BT) period, a 14-day follow-up (FU) 
period, and a 32-day safety FU (SFU).  
Trial objectives and endpoints 
Objective 
Endpoint 
Primary 
 
• To evaluate the efficacy of IMU-838 plus 
investigator’s choice of standard of care 
therapy (SoC) vs placebo plus SoC in the 
treatment of coronavirus disease 2019 
(COVID-19) based on the need for invasive 
ventilation (INV) up to 28 days 
• Proportion of patients without any need* for 
INV until end-of-study (EoS) 
 


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Trial objectives and endpoints (continued) 
Key secondary 
 
• To evaluate the efficacy of IMU-838 
(+SoC) vs placebo (+SoC) in the treatment 
of COVID-19 based on survival without 
respiratory 
failure, 
the 
duration 
of 
hospitalization in intensive care unit (ICU) 
and all-cause mortality up to 28 days 
• Proportion of patients surviving without 
respiratory failure (defined as any need of 
ICU, 
INV, 
high-flow 
oxygen 
or 
extracorporeal 
membrane 
oxygenation 
[ECMO*] until EoS) 
• Duration of ICU treatment until EoS 
• 28-day all-cause mortality 
Secondary 
 
Efficacy 
• To evaluate the efficacy of IMU-838 
(+SoC) vs placebo (+SoC) in the treatment 
of COVID-19 based on a variety of further 
variables and time points (e.g., clinical 
status, renal impairment, oxygenation, 
hospitalization, 
concomitant 
vasoactive 
treatments, clinical recovery) 
 
 
• Time to clinical improvement, defined as 
the time from first dose of investigational 
medicinal 
product 
(IMP) 
to 
an 
improvement of at least 2 points on the 
WHO 9-category ordinal scale1, or live 
discharge from hospital without oxygen 
supplementation, whichever comes first 
• Duration of hospitalization (for US sites 
only: or treatment in special outpatient 
setting in lieu of hospitalization due to 
resource restraints) 
• Proportion of patients  
• free 
of 
renal-replacement 
therapy 
(RRT)* until EoS  
• free of ECMO* until EoS 
 
 
1 WHO. WHO R&D: Blueprint Novel Coronavirus COVID-19 Therapeutic Trial Synopsis [Online] 2020. 
Available from: https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Efficacy (continued) 
• Proportion of patients  
• free of INV until Days 6 and 14* 
• free of RRT until Days 6 and 14*  
• free of ECMO until Days 6 and 14* 
• with improvement of at least 2 points 
(from randomization) on the 9-category 
WHO ordinal scale1 on Days 6, 14, and 
28 
• with 
auxiliary 
oxygen 
therapy* 
(including all types of oxygen therapy) 
until Days 6, 14, and 28 
• with clinical recovery defined as 
• Axillary temperature ≤36.6 ℃, or oral 
temperature ≤37.2 ℃, or rectal or 
tympanic temperature ≤37.8 ℃; and 
• Respiratory frequency ≤24 times/min 
without oxygen inhalation; and 
• Oxygen saturation ≥98% without 
oxygen inhalation 
• With clinical improvement, defined as an 
improvement of at least 2 points on the 
WHO 9-category ordinal scale, or live 
discharge from hospital without oxygen 
supplementation, whichever comes first 
• Change in daily clinical patient status on the 
WHO 9-category ordinal scale1  
• Duration of INV 
• Duration of ECMO 
• Duration of RRT 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Efficacy (continued) 
• Duration of auxiliary oxygen therapy 
(including all types of oxygen therapy) 
• Duration of hospitalization for survivors 
• Rate of ICU* admission until Days 6, 14, 
and 28 
• Hospital-free days 
• Time from IMP treatment initiation to death  
• Time to first prescription of INV 
• Time to first prescription of RRT 
• Time to first prescription of ECMO 
• Time to first prescription of INV, RRT, and 
ECMO 
• Time to ICU admission 
• Cumulative dose of vasoactive therapies 
(daily until Day 14) and days with 
vasoactive therapies (until Day 14) 
• Time to clinical recovery 
Pharmacokinetics 
To evaluate trough plasma levels of IMU-838 
 
• Morning trough plasma levels of IMU-838 
on Days 0, 1 through 6, 14, and 28 
• Correlation of trough levels (quartiles) to 
selected clinical outcomes 
Safety 
To evaluate safety and tolerability of IMU-838  
 
• Adverse events (AEs) and serious AEs  
• Vital signs 
• Clinical 
laboratory 
parameters 
(blood 
chemistry, hematology, and urinalysis) 
• Electrocardiogram (ECG) parameters 
• Temperature 
 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Disease markers 
To explore blood levels of disease markers 
 
• D-dimer 
• Lactate dehydrogenase (LDH) 
• C-reactive protein  
• Troponin I  
• Procalcitonin  
• Correlation of disease markers to selected 
clinical outcomes 
 
The analysis for all endpoints includes absolute 
values and absolute change from Baseline over 
time; for LDH log transformed values will be 
used.  
Virologic markers, biomarkers, and serologic 
markers 
To explore viral titers, measures of viral 
virulence and inflammatory markers 
 
Virologic markers 
• Severe 
Acute 
Respiratory 
Syndrome 
Coronavirus Virus (SARS-CoV-2) mean 
viral load - log10 copies in spontaneous 
sputum and nasopharyngeal swab samples 
• Decrease of SARS-CoV-2 viral load 
• Time course of SARS-CoV-2 viral load 
• Qualitative 
virologic 
clearance 
in 
spontaneous sputum and nasopharyngeal 
swab samples (= 2 consecutive negative 
SARS-CoV-2 
reverse 
transcriptase 
polymerase chain reaction tests at least 24 
hours apart) 
• Rate of conversion to a negative SARS-
CoV-2 (qualitative) test on Days 6, 14 and 
28 
• Time to conversion to a negative SARS-
CoV-2 (qualitative) test 
 
 
 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Virologic markers, biomarkers, and serologic 
markers (continued) 
 
Biomarkers 
• Interleukin (IL)-17, IL-1ß, IL-6, interferon 
gamma (IFNγ), tumor necrosis factor alpha  
Serologic markers 
• Immunoglobulin (Ig)A and IgG antibodies 
against SARS-CoV-2 
• Time to appearance of IgA and/or IgG 
antibodies 
• Proportion of patients with IgA and/or 
IgG antibodies on Days 6, 14, and 28 
 
The analysis for all endpoints includes absolute 
values, relative and absolute change from 
Baseline over time, if applicable.  
* Patients who are assessed by the investigator to have a medical need of the respective treatment (i.e., INV, ECMO, RRT, ICU, 
hospitalization) but do not receive these treatments for other reasons will be counted for this endpoint.  
 
Methodology 
The trial consists of 2 independent parts: a Phase 2 proof-of-activity phase (Part 1) with the option 
to continue enrollment (without interruption) to a confirmatory Phase 3 part (Expansion Phase, 
Part 2). Part 2 will only be started after results from the main analysis of Part 1 (MA1) have been 
analyzed and results indicate activity of IMU-838 in COVID-19. 
Both parts follow a multicenter, double-blind, placebo-controlled, randomized, parallel-group 
design evaluating the safety and efficacy of IMU-838 as addition to investigator’s choice of SoC 
treatment in patients with COVID-19. Eligible patients will be centrally randomized 1:1 to twice-
daily (BID) oral 22.5 mg IMU-838 (45 mg/day + SoC) or placebo (+ SoC). Randomization will be 
stratified by age (< or ≥65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and 
Chloroquine, all other antivirals). 
Part 1 and Part 2 will be analyzed independently from each other. 
The unblinded main analysis of Part 1 (MA1) will be performed after approximately 200 patients 
have completed Day 28/EoS, either as scheduled or prematurely, while enrollment continues. 
Based on the MA1 results the trial may be expanded into Part 2, if activity of IMU-838 is observed, 
or stopped, if no activity of IMU-838 is observed. A further approximately 30 patients are expected 


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to be enrolled and treated in a double-blind manner until the results of the MA1 are available (when 
no activity of IMU-838 was found) or until the enrollment in Part 2 has commenced (if MA1 
indicated proof-of-activity). A final analysis of Part 1 (FA1) will be performed after completion of 
Part 1 using all enrolled patients, i.e. approximately 230 patients. 
In addition, an early safety analysis will be performed and evaluated by an Independent Data 
Monitoring Committee (IDMC) after 30 patients in Part 1 have completed Day 28 to assess 
unblinded safety data.  
For US centers only: Enrollment into the trial will be paused after these 30 patients have reached 
Day 28 until the IDMC has evaluated safety stopping criteria. If the trial safety stopping criteria 
are not fulfilled, the enrollment in the trial will be resumed and the IDMC will continue with a full 
review of the available safety data. 
Further safety analyses can be initiated at any time by the IDMC or Sponsor when new safety 
signals are identified within this or other trials of IMU-838.  
Apart from assessing the IMU-838 activity, the MA1 will also be used to establish the sample size, 
endpoint selection as well as possible other trial adjustments (e.g. changes for study conduct due 
to safety or changes in the study population) for Part 2. The IDMC will also review MA1 results 
and act in a consultative capacity to assist the Sponsor in sample size calculations, endpoint 
selection and other adjustments for Part 2. The final design of Part 2 will be submitted as protocol 
amendment to regulatory authorities, and enrollment in Part 2 will only start after approval of the 
amended Part 2 protocol. 
Part 2 of the trial, if performed, will use an adaptive sequential design with the IDMC reviewing 
unblinded data in an interim analysis during Part 2 (IA2) and providing the Sponsor with 
recommendations regarding modifications of sample size and trial conduct. The IA2 will be 
performed after approximately 50% of patients of the Part 2 sample size have been enrolled to 
adjust sample size and other trial features if needed. The final analysis of Part 2 (FA2) will be done 
after all patients have completed Part 2. 
Screening 
Patients can be screened for a maximum of 2 days (from Day -2 to Day 0) and eligible patients will 
be randomized on Day 0 and treated with IMP + SoC for 14 days. It is encouraged to screen 
potential participants immediately at the day of hospitalization (including informed consent, 
assessment of inclusion/exclusion criteria, screening laboratory tests all done locally, assessment 
of clinical and blood gas criteria) and randomize patients on the same day (Day 0). To assess 
eligibility criteria, existing local laboratory values obtained within 48 hours of randomization can 
also be used, except for testing of positive status of SARS-CoV-2 infection where a 4-day window 
is allowed.  


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IMP administration should start as quickly as possible after randomization and first IMP dose 
intended to be given in the evening of the screening day (Day 0). 
Blinded Treatment period (Day 0 to Day 13) and Day 14 (end-of-treatment) 
The first dose of IMP (2 tablets) should always be given on Day 0 (allowed range for first dose: 
12:00 noon on Day 0 to 02:00 a.m.). All further IMP doses are 1 tablet each in the morning and 
evening. For details of IMP administration see section Test product. Information about the status 
and patient care are continuously obtained and documented once or twice daily (see Table 1). 
Further examinations and tests, laboratory parameters, biomarkers, disease markers, and virologic 
parameters are to be assessed as outlined in Table 1.  
After the last IMP dose in the evening of Day 13, the end-of-treatment (EoT) assessments will be 
done on Day 14 (see Table 1). Blood sampling for IMU-838 trough values must be performed in 
the morning around the time the morning dose was usually taken by the respective patient. Patients 
may then continue to receive SoC without any further restrictions on concomitant medications as 
during the 14-day BT period (see Standard-of-care treatment and IMP-related exclusion criteria).  
For centers in Bulgaria: Patients must be hospitalized during the entire treatment period i.e., from 
Day 0 to Day 14. 
For centers in countries other than Bulgaria: In case of hospital discharge before Day 14, the 
following assessments should be done between hospital discharge and until Day 14 (patients should 
return for clinic visits at Day 6, if discharged before Day 6, and Day 14): 
• On the day of hospital discharge: 
o 
All trial-related assessments and procedures are completed as per Table 1 and finalized 
(evening assessments should be done, even when the patient is discharged during the 
day) 
o 
The date and time of hospital discharge need to be documented 
• Day 6 and Day 14: 
o 
The full lab assessments to be performed on Days 6 or 14, respectively (as indicated in 
Table 1) 
o 
Physical examination and ECG 
o 
Documentation of concomitant medications/procedures, AEs, temperature, vital signs, 
respiratory rate, type of oxygen supplementation, survival status, hospitalization status, 
assessment of WHO ordinal scale1 (only once daily assessment required) 
o 
Return of IMP by patients and drug accountability (Day 14 only) 
If the patent is discharged from the hospital before Day 14, the patient will receive the IMP and 
will take the remaining doses of IMP at home. 


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Day 28 Visit (EoS) 
The patient should return for the final trial visit on Day 28 (EoS). If IMP is prematurely 
discontinued for any reason, the EoS visit should always be conducted on Day 28 and no earlier 
EoS should be performed. If patients withdraw from IMP prematurely, they should be encouraged 
to allow the EoS visit as part of the follow-up. If the patient dies during the trial, the investigator 
should indicate that this visit was not performed. However, even if no EoS visit was performed, 
information about patient status should be reported on the EoS page in the case report form. If the 
patient refuses any EoS visit or the patient is lost to follow-up, it is permissive in this trial that the 
investigator contacts the patient, the family of the patient or the referring physician by phone or 
email to obtain status of life information, or is able to search in registers or publicly available 
information for such status of life information. 
Safety follow up  
Following the Day 28/EoS examination, the investigator will contact the patient regularly (at least 
once) by phone or email to obtain health data until Day 60. The patient should be asked to return 
for an on-site visit if the investigator deems this necessary for follow-up. 
Treatments 
Test product 
IMU-838 (vidofludimus calcium), a small molecule inhibitor of dihydroorotate dehydrogenase 
Formulation:  
Tablets with 22.5 mg IMU-838 
Administration:  
Tablets will be taken BID with a glass of water (if possible); one tablet each 
in the morning (15 to 50 min before a meal if applicable), and in the 
evening (2 hours after any meal if applicable).  
The 1st IMP dose on Day 0 should always be the “evening dose of Day 0”. 
To administer the 1st IMP dose as close as possible to time of 
randomization, the initial IMP dose (“evening dose of Day 0”, Note: for 
this initial dose 2 tablets are to be given at once) can be administered 
between 12:00 noon on Day 0 to 02:00 a.m. on Day 1. The 2nd IMP dose is 
then given in the morning of Day 1, and dosing continues twice daily until 
the evening dose of Day 13 (last IMP dose). Except for the initial IMP dose 
(2 tablets), all other IMP doses will consist of 1 tablet. The timing of 
morning and evening doses (except for initial evening dose on Day 0) 
should be at the same time of the day, if possible. 
If the patient is intubated for ventilation, IMP is to be given via a gastric 
tube. The tablet has no coating and a homogeneous content and can be 
crushed into smaller pieces (if necessary) for dosing via gastric tube. 


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Reference product 
Matching placebo, twice-daily administration as described for the test product, identical number of 
tablets as given for IMU-838 
Standard-of-care treatment 
Any treatments, medications and procedures that investigators would customarily use to treat 
COVID-19 in their clinical practice should be used as SoC treatment. The investigator’s choice of 
SoC can include supportive pharmaceutical treatments (including medications that are approved in 
other indications but that the investigator customarily uses in COVID-19 patients), medications 
with any approved antiviral indication, intravenous fluids, supplemental oxygen, noninvasive and 
invasive ventilation, antibiotic agents, vasopressor support, RRT, and ECMO. Investigational 
treatments not yet approved for commercial use in the respective country (for example obtained 
through an early access program) or parallel participation in different interventional trials are 
prohibited in this trial.  
In addition, Arbidol and Colchicine are prohibited for centers in all countries. Chloroquine and 
Hydroxychloroquine are also prohibited for all centers in all countries unless already taken for 
indicated use before entering the trial. 
Routine use of steroids is not recommended and should be reserved for patients with severe disease 
or with special circumstances. Concomitant use of steroids (e.g., required for existing pre-existing 
conditions) do not need to be discontinued when entering this trial, however, discontinuation 
should be considered. 
Number of patients (total and for each treatment) planned 
Part 1: MA1 approximately 200 patients; an additional 30 patients are expected (total of 
approximately 230 patients) until completion of Part 1  
Part 2:  determined based on the MA1, if applicable 
Inclusion criteria 
1. Male or female patients at least 18 years old (may only be extended to include children 
12 years or older after MA1 following approval of a protocol amendment) 
2. Admitted to the hospital or other medical in-patient treatment facility for treatment of 
COVID-19 
The hospitalization needs to be for medical reasons (treatment of COVID-19 disease) and 
cannot be for social reasons or due to housing insecurity. 
For US sites only: If the investigator would commonly hospitalize the patient but for 
healthcare resource reasons decides to treat the patient in a specially designed out-patient 
setting, then such patients are also allowed to enter the trial (please note that in this case 
the patient would be counted as clinical status category 3). The investigator then must assure 


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that the patient has at least a twice daily assessment by qualified trial personnel and all 
laboratory assessments can be adequately performed as per protocol. The Sponsor reserves 
the right to discontinue this option via administrative letter if such assurances cannot be met 
by any site. 
3. SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction test in 
a nasopharyngeal, oropharyngeal or respiratory sample at ≤4 days before randomization 
4. Moderate COVID-19 disease defined as fulfilling clinical status category 3 or 4 on the WHO 
9-point ordinal scale1: 
o 
Category 3: Hospitalized (see note above for US only), virus-positive, no oxygen 
therapy with the following condition: 
− 
The hospitalization needs to be for medical reasons (treatment of COVID-19 
disease) and cannot be for social reasons or due to housing insecurity 
o 
Category 4: Hospitalized, virus-positive, oxygen by mask or nasal prongs (excluding 
high-flow oxygen therapy) with the following conditions: 
− 
Peripheral capillary oxyhemoglobin saturation (SpO2) >92% at maximum of 6 liters 
oxygen flow per minute 
− 
Stable respiratory rate ≤30 breaths/min at maximum of 6 liters oxygen flow per 
minute 
5. Presence of at least 1 symptom characteristic for COVID-19 disease i.e., fever, cough or 
respiratory distress 
6. Willingness and ability to comply with the protocol  
7. Written informed consent given prior to any trial-related procedure 
8. For women of childbearing potential: Application of a highly effective method of birth 
control (failure rate less than 1% per year when used consistently and correctly) together 
with a barrier method between trial consent and 30 days after the last intake of the IMP. 
Highly effective forms of birth control are those with a failure rate less than 1% per year 
and include: 
o 
oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraceptives associated with inhibition of ovulation 
o 
oral, injectable, or implantable progestogen-only hormonal contraceptives associated 
with inhibition of ovulation 
o 
intrauterine device or intrauterine hormone-releasing system 
o 
bilateral tubal occlusion 


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o 
vasectomized partner (i.e., the patient’s male partner underwent effective surgical 
sterilization before the female patient entered the clinical trial and is the sole sexual 
partner of the female patient during the clinical trial) 
o 
sexual abstinence (acceptable only if it is the patient’s usual form of birth 
control/lifestyle choice; periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are no acceptable methods of contraception) 
Barrier methods of contraception include: 
o 
Condom  
o 
Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
gel/film/cream/suppository 
9. Male patients must agree not to father a child or to donate sperm starting at Screening, 
throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients 
must also  
o 
abstain from sexual intercourse with a female partner (acceptable only if it is the 
patient’s usual form of birth control/lifestyle choice), or 
o 
use adequate barrier contraception during treatment with the IMP and until at least 
30 days after the last intake of the IMP, and 
o 
if they have a female partner of childbearing potential, the partner should use a highly 
effective contraceptive method as outlined in inclusion criterion 8 
o 
if they have a pregnant partner, they must use condoms while taking the IMP to avoid 
exposure of the fetus to the IMP 
Exclusion criteria 
Underlying disease-related exclusion criteria 
1. Involvement in the trial is not in the patient’s best interest according to the investigator’s 
decision, including the presence of any condition that would, in the assessment of the 
investigator, not allow the protocol to be followed safely 
Note: The investigator should particularly consider exclusion of patients at increased risk 
for serious or fatal AEs in case of worsening of the pulmonary perfusion. This includes, but 
is not limited to, pre-existing pulmonary hypertension, severe chronic respiratory disease, 
severely increased risk for thromboembolic complications and moderate to severe left 
ventricular ejection fraction (LVEF) dysfunction. In addition, other known risk factors of 
highest risk of mortality in COVID-19 patients should be considered. 
2. Presence of respiratory failure, shock, and/or combined failure of other organs that requires 
ICU monitoring in the near foreseeable future 
3. Critical patients whose expected survival time <48-72 hours 


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4. Presence of the following laboratory values at screening: 
o 
White blood cell count (WBC) <1.0 x 109/L 
o 
Platelet count <100,000/mm³ (<100 x 109/L) 
o 
Total bilirubin>2 x upper limit of normal (ULN) 
o 
Alanine aminotransferase (ALT) or gamma glutamyl transferase (GGT) >5 x ULN 
5. Participation in any other interventional clinical trial  
6. Hospitalization primarily for reasons other than COVID-19 (including primarily for 
concomitant conditions during ongoing SARS-CoV-2 infection) 
7. Anticipated transport to a different hospital or institution, in particular when such transport 
is anticipated for pending ECMO or RRT treatment 
8. Clinical suspicion of a bacterial superinfection at Screening 
IMP-related exclusion criteria 
9. Patients who cannot take drugs orally 
10. Allergic or hypersensitive to the IMP or any of the ingredients 
11. Use of the following concomitant medications is prohibited from Screening to end of 
treatment with IMP in this trial (up to Day 14) if not indicated otherwise in this protocol: 
o 
Concurrent use of any mycophenolate mofetil or of methotrexate exceeding 17.5 mg 
weekly 
o 
Any medication known to significantly increase urinary elimination of uric acid, in 
particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid 
o 
Current treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, 
bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib 
o 
Any drug significantly restricting water diuresis, in particular vasopressin and 
vasopressin analogs 
o 
Use of rosuvastatin at daily doses higher than 10 mg 
o 
Arbidol and Colchicine  
o 
Any use of other DHODH inhibitors, including teriflunomide (Aubagio™) or 
leflunomide (Arava™) 
o 
Chloroquine and Hydroxychloroquine during the entire trial, unless taken for indicated 
use before entering the trial 
12. Patients with clinically relevant conditions leading to hyperuricemia 
13. Use of any investigational product within 8 weeks or 5x the respective half-life before the 
date of informed consent, whichever is longer, and throughout the duration of the trial 


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General exclusion criteria 
14. Patients who have a “do not intubate” or “do not resuscitate” order (unless the patient waives 
in writing this order and will allow intubation for the duration of the trial period) 
15. Patients with pre-existing end-stage liver disease (Child Pugh B and C score) 
16. Patients with known Gilbert syndrome (unless their indirect [unconjugated] bilirubin level 
is confirmed to be <1.2 x ULN, i.e. <1.1 mg/dL) 
17. Patients with known acute or clinically relevant chronic renal failure, patients currently on 
dialysis, as well as patients with an estimated glomerular filtration rate value 
<30 mL/min/1.73 m² body surface area according to the Chronic Kidney Disease 
Epidemiology Collaboration equation for adults (or the Schwartz bedside equation for 
children and adolescents, if applicable) 
18. History or presence of serious or acute heart disease such as uncontrolled cardiac 
dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled 
congestive heart failure (New York Heart Association [NYHA] class 3 or 4) 
Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. 
Patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is increased. 
19. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable 
to provide consent for the trial 
20. Pregnant or breastfeeding  
21. An employee of an investigator or Sponsor or an immediate relative of an investigator or 
Sponsor 
22. Patients institutionalized due to judicial order 
 
Statistical methods 
Part 1 
All endpoints will be analyzed descriptively. In addition, exploratory confidence intervals will be 
calculated for the primary and key secondary endpoints (and for other endpoints as appropriate) 
using an alpha of 0.1 (2-sided). No formal statistical tests will be conducted. The primary analysis 
will be based on the full analysis set (all randomized patients who received at least one dose of 
IMP as randomized). Secondary/sensitivity analyses may be performed using the per-protocol 
analysis set and the set of only surviving patients until EoS and will be further specified in the 
statistical analysis plan. 


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For the primary endpoint and the key-secondary endpoints based on patient proportions odds ratios 
with 2-sided 90% confidence intervals will be calculated adjusted for the stratification factors age 
and antiviral therapy. For duration of ICU a 2-sided 90% confidence interval for the median of 
differences between treatment groups (location shift) will be calculated. 
Patients who are lost to follow-up or discontinue the trial on or before Day 13 (last treatment day) 
due to any reason other than death and patients who discontinue with a last observed WHO clinical 
status no lower than that at Screening are considered treatment failures for the respective endpoints. 
For duration of ICU respective imputation methods will be implemented. 
The “need for INV” (considered positive for the primary endpoint) will include patients:  
1. placed on any INV method during the trial, 
2. who had an active “do not intubate” or “do not resuscitate” order established during the trial 
conduct or refused intubation for any reason but were assessed by the investigator to have a 
medical need for INV, 
3. who had a medical need for INV as assessed by the investigator but for reasons of medical 
resource exhaustion or due to triage decisions by the hospital had not received INV, or  
4. who died mainly due to respiratory failure but had a need for INV as assessed by the 
investigator or before such needed INV could have been started. 
 
Part 2 
The primary endpoint (as selected during MA1) and the key secondary endpoints that include 
proportion of patients (e.g. patients without respiratory failure, 28-day all-cause mortality) will be 
evaluated for superiority of IMU-838 vs placebo with an exact Cochran-Mantel-Haenszel test, 
adjusted for the stratification factors age and antiviral therapy. In addition, logistic regression 
analyses will be conducted including the covariates age, antiviral therapy, sex, and country. 
The distribution of any key secondary endpoints containing duration measurements (e.g. duration 
of ICU treatment) will be analyzed with the van Elteren test (stratified by age and antiviral therapy). 
In addition, time-to-event analyses using Kaplan Meier methodology and a stratified log rank test 
(stratification factors age and antiviral therapy) will also be performed.  
The primary and key secondary endpoints for Part 2 will be tested confirmatory, using a global 
alpha of 0.025 (1-sided). Results of other endpoints will be considered exploratory, even when 
statistical tests are performed.  
Confirmatory hypothesis testing of key secondary endpoints will be done only after the test of the 
primary efficacy endpoint was significant. Testing will be done strictly hierarchically in the given 
order to ensure the family wise error rate. Confirmatory hypothesis testing in the pre-defined order 
will stop once the first non-significant test result is obtained. 


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Further details will be given after MA1 assessment, if activity has been confirmed. 
Sample size calculation 
Part 1 
As no formal hypothesis testing will be conducted in Part 1, no formal sample size calculation is 
deemed necessary. In previous protocol versions, a pooling of p-values of Part 1 and Part 2 was 
planned and a sample size of N = 200 enrolled patients (100 per group) was calculated. It is 
assumed that with the previously planned sample size a robust estimation of all efficacy and safety 
parameters can be conducted. Thus, no adaptations in sample size for Part 1 are necessary. 
 
Previously, the following assumptions were made:  
3-stage group sequential test design with O’Brien and Fleming shaped boundaries 
Information rate for Part 1 analysis: 0.2 
O’Brien and Fleming alpha level for end of Phase 2 analysis: <0.0001  
Primary endpoint: Proportion of patients without any need for INV 
Randomization ratio: 
 
 
1:1 (45 mg/day IMU-838:placebo) 
Power:  
 
 
80% 
Global significance level:  
 
 
0.05, 1-sided 
Proportions of patients with need for INV  
for 45 mg/day IMU-838: 
 
 
32% 
for placebo: 
 
 
 
40% 
Number of patients (Part 1): 
 
 
188 
Considering a 6% drop-out rate, a total of 200 patients (100 per group) were to be enrolled. 
Part 2 
If the trial is expanded to Part 2, the sample size of Part 2 will be determined based on the results 
of MA1. 
The Part 2 (Phase 3, Expansion Phase) trial will be designed to keep a global 1-sided alpha level 
of 0.025 (one-sided). A 2-stage group sequential test adaptive design with O’Brien and Fleming 
shaped boundaries will be used. Stage 1 will be IA2 applying an overall information rate of 50% 
and using an alpha of 0.0026. The use of group sequential boundaries within the context of an 
adaptive design is enabled using the inverse normal method, combining the p-values of both stages 
with weights based on the sample sizes. Statistical analysis methods that control for the Type I 
error will be used. 
 


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Schedule of assessments and flow chart 
Figure 1: 
Trial flow chart 
 
 
BID = twice daily, D = day, EoS = end-of-study, EoT = end-of-treatment, exam = examination, SFU = safety follow-up. 
 
 
Screening  
exam 
D-1 
Screenin
Blinded treatment 14 days 
Follow-up 14 days 
R 
Placebo 
45 mg IMU-838 
EoS 
D0 
D14 
D28 
Investigators‘s choice of standard  therapy   
SFU 
Safety FU 32 days 
D60 


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Table 1: 
Schedule of assessments  
 
 
Assessments 
 Screening  
Blinded treatmentl 
EoT 
EoS 
USV 
 
 D-2 to D0g  
D0g 
D1 - D5 
D6 
D7 - D13 D14  
D28 
 SFUp 
 
Pre Post 
 
 
 
 
 
±1 d 
 
 
Informed consent 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Demographics, incl. high 
risk factorsf 
 
• 
 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Local screening labs 
performed or taken from 
existing labsk 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of positive 
SARS-CoV-2 status 
 
•m 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
• 
 
 
 
 
 
 
 
 
 
Medical history 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/procedures 
 
• 
 
 
• 
• (daily) 
• 
• (daily) 
• 
 
• 
 
• 
Physical examination 
 
• 
 
 
 
 
• 
 
• 
 
• 
 
 
Continuous monitoring 
with documentation of  
 
 
 
 
 
 
 
 
 
 
 
 
 
Status hospitalization/ 
status ICUc 
 
 
 
 
 
 
 
 
• 
 
• 
 
• 
Survival status  
 
 
 
 
 
 
 
 
• 
 
•n 
 
 
O2 supplementation 
(incl. type of ventil.) 
 
 
 
 
 
 
 
 
• 
 
• 
 
•p 
Temperature 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
Vital signsr 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
Respiratory rate 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
SpO2 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
Score assessment 
(9-point WHO scale)b 
 
• 
 
 
 
 
 
 
• 
 
• 
 
•p 
Vasopressor dose 
 
 
 
 
 
 
 
 
• 
 
• 
 
 
Radiol. confirmation in 
clinical practice of 
interst. lung diseasei 
 
 
 
 
 
 
 
 
• 
 
 
 
 
Document confirmation 
of any new infectionsj 
 
 
 
 
 
 
 
 
• 
 
 
 
 
Use of RRT 
 
 
 
 
 
 
 
 
• 
 
• 
 
• p 
Use of ECMO 
 
 
 
 
 
 
 
 
• 
 
• 
 
• p 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 


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Table 1: 
Schedule of assessments (continued) 
 
a 
Needs to be frozen at at least -20° C (-4° F) and sent to the central safety laboratory within 6 weeks. 
b 
Clinical status on a 9-category ordinal scale (as proposed by the WHO master protocol) 
c 
Including documentation of ICU admission and discharge times. 
d 
Existing local lab values obtained within 48 hours of randomization as well as locally obtained screening lab values can be 
used for assessment of eligibility. 
Assessments 
 
Screening 
 
Blinded treatmentl 
EoT 
EoS 
USV 
 
 D-2 to D0g 
 
D0g 
D1- D5 
D6 
D7 - D13 D14  
D28 
 SFUp 
 
Pre Post 
 
 
 
 
 
±1 d 
 
 
Lab assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Hematology 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Coagulationa 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Urinalysis 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Disease markersa 
 
 
 
• 
 
• (daily) 
• 
• (daily) 
• 
 
• 
 
 
Biomarkersa 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
IMU-838 trough 
levelsa 
 
 
 
• 
 
• (daily) 
• 
 
•o 
 
• 
 
 
SARS-CoV-2 viral 
load and SARS-CoV-2 
status (qualitative)e 
 
 
 
• 
 
• (Days 2 
& 4 only) 
• 
• (Days 8, 
10 & 12 
only) 
• 
 
• 
 
•p 
Serology: SARS-CoV-
2 antibodiesh 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Immune cell subtyping 
(US only)q 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Lab Kits used 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kit A 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Kit B 
 
 
 
 
 
• (daily) 
 
• (daily) 
 
 
 
 
 
Kit C 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Kit PK 
 
 
 
• 
 
• (daily) 
• 
 
•o 
 
• 
 
 
Kit D 
 
 
 
• 
 
• (daily) 
• 
• (daily) 
• 
 
• 
 
•p 
Kit E 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Immune cell 
subtyping (US only)q 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 
 
• 
 
 
 
 
 
 
 
 
• 
 
• 
ECG 
 
 
 
• 
• 
• (only 
Day 3) 
• 
 
• 
 
• 
 
 
IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of tablets 
 
 
 
- 
2 
 
 
 
 
 
 
 
 
Accountability 
 
 
 
 
 
 
 
 
• 
 
 
 
 
SoC treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 tablet each morning + evening 


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e 
At each time point only 1 nasopharyngeal swab and 1 sputum sample each will be taken. The viral load test will also be used 
as qualitative test (i.e. may be evaluated as absence or presence of virus in the quantitative SARS-CoV-2 assessments). 
Samples need to be frozen at at least -20° C (-4° F) and sent to the central virology laboratory within 7 days on dry ice. 
f 
Includes: Age≥65; cardiovascular disease (including hypertension), pre-existing pulmonary disease, diabetes, current 
treatment for malignancy or within the previous 3 years, immunosuppression (due to ongoing use of immunosuppressive 
drugs or existing disease leading to impaired immune status), body mass index. 
g 
Screening, randomization and first IMP administration can be performed the same day (Day 0). If screening is performed on 
Day 0, treatment will start with the evening dose. 
h 
Plasma sample for serology SARS-CoV-2 (IgG and IgA detection) should be frozen at at least -20° C (-4° F) and sent to the 
central safety laboratory within 6 weeks. 
i 
Confirmation of radiographic evidence of pulmonary infiltrates by chest X-ray or CT (only if done within the scope of routine 
clinical practice). 
j 
Confirmation of presence of any new viral or non-viral infection (this is not a protocol-required procedure, only documentation 
when done within the scope of routine clinical practice). Site of infection and source of culture will be recorded. 
k 
As performed during routine clinical practice in the center. Must include white blood cell count, platelet count, total bilirubin, 
alanine aminotransferase or gamma glutamyl transferase, serum creatinine, for women of childbearing potential: blood 
pregnancy test, and if the patient has known Gilbert syndrome: indirect [unconjugated] bilirubin.  
l 
For assessments, if patients will be discharged from the hospital before Day 14, see Blinded Treatment period (Day 0 to 
Day 13) and Day 14 (end-of-treatment). For centers in Bulgaria only: Patients must be hospitalized during the entire 
treatment period. 
m 
Within 4 days of randomization. 
n 
If no EoS visit was performed, information about patient status should be reported on the EoS page in the case report form. If 
the patient is lost to follow-up, the investigator must contact the patient, the patient’s family or the referring physician by 
phone or email to obtain survival status, or it must be possible to search in registers or publicly available information for these 
survival data. 
o 
 Blood sampling must be performed in the morning around the time the morning dose was usually taken by the respective 
patient. 
p 
Safety follow up assessments must be performed regularly (at least once) by phone or email between Day 28/EoS and Day 60 
and documented as an unscheduled visit in the eCRF. The patients should be asked to return for an on-site visit if the 
investigator deems this necessary for follow-up. The assessments not to be done if the visit is performed as a telephone or 
email contact in the scope of the safety follow up are marked as •p 
q 
Optional for centers in the USA only: 2 blood samples will be collected to evaluate immune cell subtypes and immune 
reactions for future research studies. This will be shipped directly to a US research site and not to the central laboratory. 
Shipment needs to be done at ambient temperature and immediately the same day after sampling. 
r 
Height and weight only to be measured at D0, pre-dose. 
 
AE = adverse event, CT = computed tomography, cont. = continued, D = day, ECG = electrocardiogram, ECMO = extracorporeal 
membrane oxygenation, EoS = end-of-study, EoT = end-of-treatment, ICU = intensive care unit, Ig = immunoglobulin, 
IMP = investigational medicinal product, incl. = including, interst. = interstitial, pre(post) = pre(post) IMP, RRT = renal-
replacement therapy, Radiol. = radiological, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, SFU = safety follow 
up, SoC = standard of care, SpO2 = peripheral capillary oxyhemoglobin saturation, ventil. = ventilation, USV = unscheduled visit, 
WHO = World Health Organization. 
 


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2 
Addresses and responsibilities 
Sponsor’s signatory 
Dr Andreas Muehler  
Chief Medical Officer, Immunic AG 
Lochhamer Schlag 21 
82166 Graefelfing, Germany  
Office:  
 +49 89 2500 794 64 
Mobile:  
+49 176 7873 8359 
Fax:  
+49 89 2500 794 66 
Email: 
andreas.muehler@imux.com 
 
Coordinating investigator 
Prof. Neera Ahuja  
Stanford University School of Medicine 
500 Pasteur Drive 
Stanford, CA 94305 
United States of America 
Phone: 
+1 650 497-7304 
Fax:  
+1 650 723-8596 
Email:  
nkahuja@stanford.edu 
 
Drug safety officer and 
pharmacovigilance services 
Dr med. Dipl. Inf. Susanne Kienzle-Horn 
SCRATCH Pharmacovigilance GmbH & Co. KG 
Schlossstrasse 25 
35510 Butzbach, Germany 
Phone:  
+49 6033 74535 50 
Fax:  
+49 6033 74535 59 
Email: 
safety-immunic@scratch-pv.com 
 
Central safety laboratory  
(including serologic markers and 
biomarkers) 
LKF - Laboratorium für Klinische Forschung GmbH 
Lise-Meitner-Strasse 25-29 
24223 Schwentinental, Germany 
Phone:  
+49 4307 8276 0 
Fax: 
+49 4307 8276 79 
Email: 
project@lkf-kiel.de 
 


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Central virology laboratory  
 
Europe: 
Covance Central Laboratory Services Sàrl 
Rue Moise-Marchines 7 
1217 Geneva Switzerland 
Phone:  
+41 58 8227000 
Fax: 
+41 58 8226999 
USA: 
Covance Central Laboratory Services LP  
8211 SciCor Drive 
Indianapolis, Indiana 46214, USA  
Phone:  
+1 317 273 5307 
 
Web site to order  
new lab kits: 
www.covance.com\kitordering 
 
 
 
A complete list of trial personnel will be available in the trial master file. 


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3 
Table of contents 
 
Page 
REVISION CHRONOLOGY ................................................................................................. 2 
1 
SUMMARY AND FLOW CHART ............................................................................. 11 
2 
ADDRESSES AND RESPONSIBILITIES ................................................................. 31 
3 
TABLE OF CONTENTS ............................................................................................. 33 
4 
ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 38 
5 
INTRODUCTION ........................................................................................................ 41 
5.1 
Background COVID-19 ............................................................................. 41 
5.2 
IMU-838 ...................................................................................................... 42 
5.2.1 
Background .................................................................................................. 42 
5.2.2 
Mode of action ............................................................................................. 42 
5.2.3 
Non-clinical studies ..................................................................................... 43 
5.2.4 
Clinical trials ................................................................................................ 44 
5.2.5 
Safety of IMU-838 ....................................................................................... 46 
5.3 
Rationale for the trial ................................................................................ 46 
6 
INVESTIGATORS, TRIAL ADMINISTRATIVE STRUCTURE, AND 
COMMITTEES ............................................................................................................ 48 
7 
TRIAL OBJECTIVES AND ENDPOINTS ............................................................... 49 
8 
TRIAL DESIGN AND DESIGN RATIONALE ........................................................ 54 
8.1 
Overall trial design .................................................................................... 54 
8.2 
Trial design rationale ................................................................................. 57 
8.3 
Risk-benefit assessment ............................................................................. 57 
9 
PATIENT SELECTION .............................................................................................. 60 
9.1 
Sample size .................................................................................................. 60 
9.2 
Inclusion criteria ........................................................................................ 60 
9.3 
Exclusion criteria ....................................................................................... 62 
10 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ............. 64 
10.1 
Blinding ....................................................................................................... 64 
10.2 
Emergency unblinding............................................................................... 64 
10.3 
Patient identification .................................................................................. 65 
10.4 
Randomization ........................................................................................... 65 


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11 
TREATMENTS ............................................................................................................ 65 
11.1 
Investigational medicinal product ............................................................ 65 
11.1.1 
IMU-838 ...................................................................................................... 65 
11.1.2 
Placebo ......................................................................................................... 65 
11.1.3 
Packaging, labeling and dispensing ............................................................. 66 
11.1.4 
Storage and stability ..................................................................................... 66 
11.1.5 
Treatment dose, dose selection, and administration .................................... 66 
11.1.6 
Drug accountability and patient compliance ................................................ 68 
11.2 
Prior and concomitant medications ......................................................... 68 
11.2.1 
Standard of care treatment and concomitant treatments .............................. 68 
11.2.2 
Prohibited and restricted medication ........................................................... 69 
12 
TRIAL SCHEDULE ..................................................................................................... 70 
12.1 
Schedule of assessment .............................................................................. 70 
12.2 
Screening (Day -2 to Day 0) and Day 0 .................................................... 73 
12.3 
Blinded treatment period (Day 0 to Day 13) and Day 14 (end-of-
treatment) ................................................................................................... 74 
12.4 
Unscheduled visit ....................................................................................... 75 
12.5 
End-of-study (EoS, Day 28) and premature termination ....................... 75 
12.6 
Safety follow-up .......................................................................................... 75 
13 
EFFICACY AND BASELINE ASSESSMENTS AND PROCEDURES ................. 75 
13.1 
Demographics and other baseline assessments ....................................... 75 
13.2 
Clinical disease severity assessment ......................................................... 76 
13.3 
Clinical and patient status assessments.................................................... 76 
13.4 
Assessment of respiratory rate and oxygen saturation .......................... 77 
14 
PHARMACOKINETICS, DISEASE MARKERS, AND BIOMARKERS ............. 77 
14.1 
Plasma trough levels of IMU-838 ............................................................. 77 
14.2 
Disease markers ......................................................................................... 78 
14.3 
Biomarkers ................................................................................................. 78 
15 
SAFETY ASSESSMENTS ........................................................................................... 79 
15.1 
Adverse events documentation and reporting ......................................... 79 
15.1.1 
Definitions.................................................................................................... 79 
15.1.1.1 
Adverse events......................................................................................................... 79 


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15.1.1.2 
Adverse drug reactions and unexpected adverse drug reactions ............................. 80 
15.1.1.3 
Serious adverse events ............................................................................................. 80 
15.1.1.4 
Suspected unexpected serious adverse reaction ...................................................... 81 
15.1.2 
Classification of adverse events ................................................................... 81 
15.1.3 
Documentation of adverse events ................................................................ 82 
15.1.4 
Documentation and reporting of immediately reportable adverse events ... 83 
15.1.5 
Follow-up of adverse events ........................................................................ 84 
15.1.6 
Handling of anticipated clinical events of COVID-19 ................................ 84 
15.1.7 
Further safety precautions ............................................................................ 85 
15.1.8 
Pregnancies .................................................................................................. 85 
15.2 
Safety laboratory investigations ............................................................... 86 
15.2.1 
Pregnancy tests............................................................................................. 86 
15.2.2 
Blood chemistry, hematology, and coagulation ........................................... 86 
15.2.3 
Urinalysis ..................................................................................................... 87 
15.2.4 
Screening laboratory .................................................................................... 87 
15.3 
Vital signs, physical examination, and ECG ........................................... 87 
16 
BIOSTATISTICAL METHODS ................................................................................. 88 
16.1 
Sample size calculation .............................................................................. 88 
16.2 
Analysis sets and types of analyses ........................................................... 89 
16.3 
Statistical analyses ..................................................................................... 90 
16.3.1 
General approaches ...................................................................................... 90 
16.3.2 
Primary and key secondary efficacy endpoint analyses .............................. 91 
16.4 
Part 1 to Part 2 transition procedures ..................................................... 93 
16.4.1 
General approach ......................................................................................... 93 
16.4.2 
“Activity” criteria and further issues to be considered ................................ 94 
17 
PATIENT STOPPING RULES AND OTHER REASONS FOR PATIENT 
WITHDRAWAL FROM TRIAL PARTICIPATION............................................... 97 
17.1 
Patient stopping rules ................................................................................ 97 
17.2 
Other reasons for patient withdrawal from trial participation ............. 97 
18 
INDEPENDENT DATA MONITORING COMMITTEE ........................................ 98 
19 
ETHICAL AND LEGAL REQUIREMENTS ........................................................... 99 
19.1 
Ethical conduct of the trial ........................................................................ 99 


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19.2 
Independent ethics committee or institutional review board ................ 99 
19.3 
Patient information and consent procedure ............................................ 99 
19.4 
Insurance coverage .................................................................................. 100 
19.5 
Submission to authorities ........................................................................ 100 
19.6 
Patient confidentiality .............................................................................. 100 
20 
CRITERIA FOR PREMATURE TERMINATION OF THE TRIAL AND 
CRITERIA FOR INITIALIZING AND CLOSING A TRIAL CENTER ............ 101 
20.1 
Trial safety stopping criteria................................................................... 101 
20.2 
Other criteria for halting or terminating the trial ................................ 101 
20.3 
Criteria for closing a trial center ............................................................ 102 
21 
TRIAL PROTOCOL, DOCUMENTATION AND ARCHIVING OF DATA ...... 102 
21.1 
Amendments to the protocol ................................................................... 102 
21.2 
Protocol deviations ................................................................................... 103 
21.3 
Data retention ........................................................................................... 103 
22 
DATA COLLECTION, MONITORING AND QUALITY ASSURANCE ........... 104 
22.1 
Data collection .......................................................................................... 104 
22.2 
Source data ............................................................................................... 104 
22.3 
Monitoring ................................................................................................ 105 
22.4 
Audits and inspections ............................................................................. 106 
22.5 
Data management procedures ................................................................ 106 
22.6 
Trial report and publications .................................................................. 107 
23 
TRIAL PERIODS ....................................................................................................... 107 
24 
REFERENCES ............................................................................................................ 108 
25 
APPROVAL AND SIGNATURES............................................................................ 111 
26 
APPENDICES ............................................................................................................. 113 
Appendix 1 
Central Laboratory Kits ............................................................ 113 
Appendix 2 
Local laboratory tests required at Screening ............................ 115 
Appendix 3 
Modified WHO Ordinal Scale for Clinical Status .................... 116 
 
 
 


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Table of tables 
Table 1: 
Schedule of assessments ................................................................................... 28 
Table 2: 
Administration of tablets .................................................................................. 67 
Table 3: 
Schedule of assessments ................................................................................... 71 
Table 4: 
Modified WHO Ordinal Scale for Clinical Status ............................................ 76 
 
Table of figures 
Figure 1: 
Trial flow chart ................................................................................................. 27 
Figure 2: 
Classification of COVID-19: disease states and potential therapeutic targets . 41 
 
 


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4 
Abbreviations and definition of terms 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BMI 
Body mass index 
BT 
Blinded treatment 
CA 
Competent authority 
cTn 
Troponin 
CFR 
Code of Federal regulations  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CYP 
Cytochrome P450  
DHODH 
Dihydroorotate dehydrogenase 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
ED50 
Effective dose 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EoS 
End-of-study 
EoT 
End-of-treatment 
EU 
European Union 
FA1 (2) 
Final analysis Part 1 (Part 2) 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
hCMV 
Human cytomegalovirus 
HCV 
Hepatitis C virus 
HIPPA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus(-antigen/antibody) 
IA2 
Interim analysis of Part 2 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee (IDMC) 


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IEC 
Independent ethics committee  
IFNγ 
Interferon gamma  
IgA(G) 
Immunogobulin A(G) 
IL 
Interleukin 
IMP 
Investigational medicinal product 
INV 
Invasive ventilation 
IRB 
Institutional review board 
IWRS 
Interactive web-based response system  
LDH 
Lactate dehydrogenase 
MA1 
Main analysis of Part 1 
NCI-CTCAE 
Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
OR 
Odds ratio 
PCT 
Prolactin 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol set 
RA 
Rheumatoid arthritis 
RBC 
Red blood cells 
RNA 
Ribonucleic acid 
RRT 
Renal replacement therapy  
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2  
SoC 
Standard of care 
SpO2 
Oxyhemoglobin saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNFα 
Tumor necrosis factor alpha 
UGT1A1 
UDP-glucuronosyltransferase 1A1 
ULN 
Upper limit of normal 
URAT1 
Urate anion transporter 1 
USA 
United States of America 
WHO 
World Health Organization  
 


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Drugs 
 
4SC-101 
Tablet or capsule formulation containing vidofludimus free acid 
IMU-838  
Tablet formulation containing vidofludimus calcium 
 


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5 
Introduction 
5.1 
Background COVID-19 
The World Health Organization (WHO) declared severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection (causing coronavirus disease 2019, COVID-19) a pandemic on March 
11, 2020. [3] Main clinical symptoms include fever, cough, myalgia or fatigue, expectoration, and 
dyspnea. [4] While most patients do not experience severe symptoms, one meta-analysis found that 
approximately 18% of cases were severe. [5] Fatality rates are estimated to be approximately 4-7% 
at this time. [4,5]  
Figure 2: 
Classification of COVID-19: disease states and potential therapeutic targets 
 
Taken from [6]. 
 
Two distinct but overlapping pathological pathways appear to be involved in the course of the 
disease. The first is triggered by the virus itself and the second comprises the host response. 
A 3-stage classification of the disease was proposed by Siddigi and Mehra. [6] The initial stage 
occurs at the time of inoculation and early establishment of the disease. For most people, this 
involves an incubation period associated with mild and often non-specific symptoms such as 
malaise, fever and a dry cough. Treatment at this stage is primarily targeted towards symptomatic 
relief. Should a viable antiviral therapy be proven beneficial, targeting selected patients during this 
stage may reduce duration of symptoms, minimize contagiousness and prevent progression of 
severity. 


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In the second stage of established pulmonary disease, viral multiplication and localized 
inflammation in the lung is the norm. During this stage, patients develop an interstitial lung disease 
(viral pneumonia), with cough, fever and possibly hypoxia. Treatment would primarily consist of 
supportive measures and available antiviral therapies. If hypoxia ensues (Stage IIb), it is likely that 
patients will progress to requiring mechanical ventilation and, in that situation, the use of anti-
inflammatory therapy may be useful. 
A minority of COVID-19 patients will undergo transition into the third and most severe stage of 
illness, which manifests as an extra-pulmonary systemic hyperinflammation syndrome. In this 
stage, markers of systemic inflammation appear to be elevated, including cytokines and interleukin 
(IL). In this stage, shock, vasoplegia, respiratory failure and even cardiopulmonary collapse are 
discernable. Systemic organ involvement, even myocarditis, would manifest during this stage. 
Tailored therapy in Stage III hinges on the use of immunomodulatory agents to reduce systemic 
inflammation before it overwhelmingly results in multi-organ dysfunction. 
5.2 
IMU-838  
5.2.1 
Background 
Vidofludimus free acid (SC12267) was previously developed by 4SC AG using capsules or tablets 
containing amorphous vidofludimus (4SC-101). Immunic AG acquired all rights and data of 
SC12267 and has developed a new pharmaceutical form containing the calcium salt of 
vidofludimus (INNM: vidofludimus calcium) in a new pharmaceutical formulation (tablets 
containing a specific polymorph).  
Both formulations depend on the same active moiety, i.e., vidofludimus which is released from the 
tablets in the gut and enters the blood stream. Hence, the 2 formulations share the same mechanism 
of action, pharmacology, and toxicology. Vidofludimus calcium may exhibit, however, superior 
pharmaceutical properties compared with the former vidofludimus free acid film-coated tablet. 
At this time and counting both formulations, more than 500 human subjects and patients have been 
exposed to the active moiety vidofludimus. 
5.2.2 
Mode of action 
IMU-838 is a small molecule investigational drug (vidofludimus calcium) under Phase 2 
development as an oral tablet formulation for the treatment of relapsing-remitting multiple 
sclerosis, inflammatory bowel disease and other chronic inflammatory and autoimmune diseases. 
IMU-838 selectively inhibits the human enzyme dihydroorotate dehydrogenase (DHODH), a key 
enzyme of pyrimidine de novo biosynthesis. Highly metabolically activated cells, such as 
hyperactivated lymphocytes in chronic inflammatory diseases, malignant transformed cells in 
cancer as well as virus infected cells, are highly dependent on DHODH. [1] In these cells, the 


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extraordinary demand of nucleotides cannot be sufficiently supported by recycling of nucleotides 
and therefore, the de novo synthesis of pyrimidines needs to be activated. 
Inhibition of de novo pyrimidine biosynthesis is a well-recognized antiviral mechanism. The 
presumptive explanation is attributed to the direct depletion of host nucleosides necessary for 
replication of the viral genome; however, secondary activation of the innate immune response has 
also been described as a relevant downstream mechanism. Therefore, DHODH inhibition 
ameliorates and blocks the viruses’ ability to “hijack” the human host cell mechanisms of 
ribonucleic acid (RNA) production as a means to virus replication. This is a host cell mechanism 
with the advantage that it has broad viral activity, is not influenced by resistances or mutations of 
the virus and can be combined with other antiviral drugs targeting the virus itself. This direct, 
broad-spectrum antiviral effect has been observed in various virus infected cells, such as influenza 
virus infections, cytomegalovirus infections and even hemorrhagic fever-causing viruses, such as 
Lassa virus. Treatment with IMU-838 may also avoid virus reactivation of further clinically 
relevant viruses. 
In addition to its antiviral activity, IMU-838 exhibits strong anti-inflammatory activities by 
selectively targeting activated lymphocytes, which express DHODH at high levels to satisfy their 
need for de novo pyrimidine synthesis. Resting lymphocytes and bone marrow cells satisfy their 
pyrimidine requirements through a DHODH-independent salvage pathway. The metabolic stress 
secondary to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release 
including IL-17 (IL-17A and IL-17F) and interferon gamma (IFNγ), and to an increased apoptosis 
in activated lymphocytes. [2] IMU-838-mediated DHODH inhibition does not induce unselective 
immunosuppression.  
One key advantage of DHODH inhibition is that it primarily targets metabolically active cells, and 
therefore may not negatively impact “normal” cells in a substantial fashion. In addition, no 
increased rates of neutropenia or other major antiproliferative effects as compared to placebo have 
been observed.  
IMU-838 is further characterized by a short blood half-life of 30-40 hours making it ideal for once-
daily dosing and resulting in only little accumulation after daily dosing (steady state concentrations 
are reached within 4-8 days with an accumulation factor of 2). Importantly due to the short blood 
half-life, the wash-out period for IMU-838 is considerably shorter than for teriflunomide. 
5.2.3 
Non-clinical studies 
Pharmacodynamics 
Vidofludimus strongly inhibits activated lymphocytes and reduces the release of pro-inflammatory 
cytokines and other physiologic effects of activated lymphocytes in in-vivo studies.  


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Vidofludimus demonstrated broad-spectrum antiviral activity in-vitro at concentrations below 
therapeutic blood levels achieved in treated patients.  
• In cell culture experiments vidofludimus inhibited the viral replication of the human 
immunodeficiency virus (HIV) and hepatitis C virus (HCV).  
• Reverse transcriptase activity and the appearance of the specific HIV antigen p24 was 
evaluated in human peripheral blood mononuclear cells (seronegative for HIV and hepatitis 
B virus) that were infected in vitro with HIV-191US005 and incubated with various 
vidofludimus concentrations. These experiments demonstrated a median effective dose 
(ED50) of vidofludimus of approximately 2 µM. 
• In a human hepatoma cell line (Huh7) harboring an HCV sub genomic replicon, vidofludimus 
reduced replicon levels with a median ED50 of 4.64 µM. 
• Vidofludimus was active against viruses of the herpes family. In an infection model of human 
fibroblasts infected with human cytomegalovirus (hCMV), vidofludimus showed an activity 
of around 7.4 µM. This activity was within the same range of Ganciclovir which is used in 
clinical practice to treat hCMV. 
• Vidofludimus demonstrated activity against mammalian Arena virus infections, the RNA 
virus causing human hemorrhagic fever diseases like Lassa fever, with an IC50 (concentration 
causing 50% inhibition) of 2.8 µM. In this case, DHODH inhibition mediated effects were 
independent of IFN signaling. 
Based on in-vitro data, vidofludimus was primarily metabolized via cytochrome P450 (CYP)2C8 
with smaller contributions by CYP2C9. Vidofludimus is primarily eliminated via feces (about 
70%).  
Vidofludimus mildly to moderately inhibits several transport systems, including the urate anion 
transporter 1 (URAT1), the breast cancer resistance protein, the organic anion transporters 1 and 
3, the organic anion transporting polypeptides 1B1 and 1B3, and the bile salt export pump. 
5.2.4 
Clinical trials 
So far, no clinical trials investigating the antiviral activity of vidofludimus have been performed. 
However, several studies were or are investigating vidofludimus in the treatment of autoimmune 
and chronic inflammatory diseases. 
Two clinical trials investigated the beneficial effects of 4SC-101, the previous vidofludimus free 
acid formulation, in patients with rheumatoid arthritis (RA). 4SC-101 improved various clinical 
parameters versus placebo. A pronounced effect was observed for inflammatory parameters.  
In a small Phase 2 trial in patients with corticosteroid-dependent inflammatory bowel disease 
(Crohn’s disease and ulcerative colitis), 4SC-101 showed beneficial effects in the remission 


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maintenance therapy. Compared with historical placebo data, 4SC-101 treatment showed a 
significantly higher response rate (88.5% total response) as well as a corticosteroid sparing effect.  
No 4SC-101-associated clinically significant adverse reactions were observed at doses of <70 mg 
once daily including the potential target organs liver and kidney as identified in non-clinical or 
early clinical trials. At higher 4SC-101 doses (>70 mg/day or single doses of 210 mg) potential 
drug-related increases of red blood cells (RBC) in urine and hematurias were observed (see also 
Section 8.3).  
Two Phase 1 clinical trials were performed for calcium vidofludimus (IMU-838). In Trial P1-IMU-
838-SAD, doses from 10 to 40 mg IMU-838 resulted in dose-linear blood pharmacokinetics (PK) 
under fasted conditions. For the 30 mg dose (the dose expected to be closest to an effective dose), 
the terminal plasma half-life was approximately 40 hours and the median concentration peaked at 
5 hours. Comparing single dosing of 10 mg under fasted and fed conditions, no detrimental effect 
of food intake was found. Single oral doses of 10 to 40 mg IMU-838 were well tolerated. No 
adverse events (AEs) of e.g., hematuria or clinically significant RBC in urine high were observed 
in that clinical trial. 
In Trial P1-IMU-838-MAD, repeated oral dosing of IMU-838 over 14 days in doses from 30 to 50 
mg resulted in dose-proportional blood PK under fasted conditions. Geometric mean half-life at 
steady state ranged from 28.6 to 30.4 hours. Overall, median peak concentration following multiple 
oral doses of IMU-838 occurred between 2 to 3 hours after the first and after repeated dosing. 
Steady-state levels were reached within about 4 days for 25 mg IMU-838, within 6-8 days for 30 
mg, within about 6 days for 40 mg, and within about 8 days for 50 mg IMU-838. Repeated once-
daily oral doses of 30 to 50 mg IMU-838 over 14 consecutive days were well tolerated. Mild or 
moderate treatment-emergent adverse events (TEAEs) were reported by 31 subjects (59.6%); 
overall 53 TEAEs, reported by 29 subjects (55.8%) were considered drug-related. The number of 
subjects with drug-related TEAEs or the number of drug-related TEAEs did not increase with 
increasing dose.  
Most individual laboratory values were within the normal ranges. There were no clinically relevant 
differences between pre- and post-dose assessments and between the treatment groups for any 
parameter. 
Currently ongoing studies with IMU-838 include 2 double-blind, randomized, placebo-controlled 
Phase 2 trials in patients with ulcerative colitis (CALDOSE-1) and relapsing-remitting multiple 
sclerosis (EMPHASIS). The primary objective of the ulcerative colitis trial is to determine the 
optimal dose of IMU-838 to induce symptomatic remission and endoscopic response in patients 
with moderate-to-severe disease. The primary objective of the multiple sclerosis trial is to evaluate 
the efficacy of IMU-838 based on magnetic resonance imaging assessments in the treatment of 
relapsing-remitting multiple sclerosis. Results of an interim analysis of the ulcerative colitis trial, 


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analyzed by an unblinded independent Data Review Committee showed that none of the doses used 
(10 mg, 30 mg, or 45 mg) was likely ineffective or intolerable. In addition, there is an ongoing 
open-label investigator-sponsored trial using IMU-838 in patients with progressive sclerosing 
cholangitis conducted in the USA under an Investigator IND.  
5.2.5 
Safety of IMU-838 
At this time and counting both formulations, more than 500 human subjects and patients have been 
exposed to the active moiety of IMU-838, i.e., vidofludimus. Of these, 299 were dosed with 4SC-
101 and approximately 360 with IMU-838 (some of the studies are still blinded and total exposure 
to IMU-838 can therefore only be estimated).  
The safety analysis of all exposed subjects provided the following findings:  
• No deaths 
• No serious adverse event (SAE) during Phase 1 with IMU-838 
• The most frequent AEs for IMU-838 during Phase 1 were: 
o 
Headache  
o 
Flatulence  
o 
Common cold  
o 
Positive urine dipstick for hemoglobin 
IMU-838 is a selective DHODH inhibitor and did not inhibit any kinase (of a panel of over 100 
tested protein kinases) at blood concentrations that are found at therapeutic dose levels. However, 
IMU-838 inhibits organic anion transporters such as URAT1, which potentially could affect renal 
uric acid elimination. 
In conclusion, IMU-838 is expected to have a favorable safety profile, as in more than 400 patients 
(with RA, multiple sclerosis, or inflammatory bowel disease) or volunteers no increased events of 
diarrhea, nausea, alopecia or headache as well as no increases in abnormal liver function tests were 
observed. 
5.3 
Rationale for the trial  
Acute viral infections, such as influenza virus, Ebola virus, and SARS-CoV-2 are an increasing 
and probably lasting health risk. [7] Broad-spectrum antivirals are clinically needed for the 
effective control of emerging and re-emerging viral infectious diseases. [9] However, besides 
intensive efforts to find therapeutic antiviral agents to manage such emergencies, reports on 
specific and effective drugs or vaccines with low toxicity are rare. [8] Thus, currently, there are no 
effective treatments against the new coronavirus SARS-CoV-2. 


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Literature data 
Strong activity of DHODH inhibitors against SARS-CoV-2 in vitro were recently reported by 
Xiong et al. [9] However, established DHODH inhibitors show either an unfavorable PK profile 
(leflunomide/teriflunomide) or intolerable toxicity (leflunomide/Brequinar) and thus are not 
suitable as acute antiviral treatments. New DHODH inhibitors seem promising, although for most 
no animal or human safety data are available.  
Xiong et al. [9] also demonstrated that a combination of DHODH inhibitors with antiviral drugs 
may improve therapeutic effects. Direct-acting antivirals, which target the viral replication cycle, 
are primarily effective in the early phase of infection while DHODH inhibitors which target a host 
cell factor, may also be effective in middle-to-late phases of infection or in patients with advanced 
respiratory disease. 
DHODH inhibition selectively targets activated inflammatory and virus infected cells because 
normally growing cells are not substantially affected (see Section 5.2.2). For normally dividing 
cells, DHODH inhibition does not produce general immunosuppression. It was shown for 
teriflunomide that patients can be even vaccinated under therapy. [10, 11] DHODH inhibition by 
IMU-838 did not suppress bone marrow cells or inhibit fast-growing cells. In preclinical and 
clinical studies, IMU-838 did not show any off-target effects, such as neutropenia, diarrhea or 
alopecia, at rates that were above placebo.  
A strong antiviral effect of DHODH inhibitors was described for several RNA and 
deoxyribonucleic acid viruses including Ebola [12,13], HIV [14], HCV [14], hCMV [15,16] and 
Influenza [14] viruses. While DHODH inhibitors are effective up to 12-16 hours after infection in 
in-vitro assays, other antiviral drugs can inhibit viral infection only up to 4 hours. [14,17]. DHODH 
inhibitors show a direct and an indirect antiviral effect both of which are linked to blocking 
pyrimidine de novo synthesis. In the direct pathway, the reduction of pyrimidine neosynthesis 
interferes with the viral transcription and replication. [14] However, the main antiviral effect might 
rather be an indirect effect via the induction or amplification of interferon-stimulated genes due to 
the reduced pyrimidine synthesis. [18] A large fraction of these genes plays a role in the host innate 
immune defense to viruses. While these genes are normally induced by interferons, the 
upregulation of these genes by DHODH inhibitors is independent of interferons. [12,18-20]  
Antiviral activity of IMU-838 against SARS-CoV-2  
Antiviral activity against SARS-CoV-2 of IMU-838 was investigated in-vitro in Vero 76 cells in a 
cytopathic effect assay. The virus was prepared in test media (Minimum Essential Media with 2% 
fetal bovine serum and gentamicin) to achieve the lowest possible multiplicity of infection that 
would yield >80% cytopathic effect within 5 days. Plates were infected prior to preparation and 
addition of compounds. IMU-838 was dissolved in dimethylsulfoxide to achieve a 100 mM stock 
and was serially diluted two-fold in media and added to the 80-100% confluent cell layer in 
triplicates, reaching a final concentration in the well starting from 100 µM down to 0.78 µM. 


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Controls in infected cells were M128533 (a protease inhibitor) as positive control and no treatment 
as negative control. The positive control performed as expected. 
IMU-838 exhibited antiviral activity with an EC50 (concentration that prevents 50% of virus 
induced cell death in virus infected cells) of 5.7 µM. For reference, the average trough levels of 
IMU-838 at steady state conditions is expected to be approximately 17 µM using the dosing 
regimen of 45 mg IMU-838 proposed for this trial. 
Conclusion 
Based on these data and the pharmacodynamics of vidofludimus, IMU-838 may represent a novel 
and efficacious oral treatment option for COVID-19 combining a broad antiviral activity with a 
selective anti-inflammatory effect. It is also important that IMU-838 is not known to cause any 
neutropenia for a patient population where decrease of neutrophils and lymphocytes is a critical 
feature of the disease. 
6 
Investigators, trial administrative structure, and committees 
The clinical trial is funded by Immunic AG and it is planned to include about 10 to 45 centers in 
the European Union, Bosnia and Herzegovina, Moldova, North Macedonia, Russia, Ukraine, and 
USA (and as back up countries: Croatia and Serbia). Prof. Neera Ahuja, Stanford University, 
School of Medicine will be the coordinating investigator. 
The Sponsor will reserve the right to define maximum number of patients per site and country to 
ensure a balance per site and country regarding enrolled patients. For Part 1, the number of patients 
per center is limited to 100 patients, and the number of patients per country is limited to 160 
patients. These limits may be re-evaluated if the trial is expanded into Part 2. 
The Sponsor, Immunic AG, will be responsible for the overall supervision and administration of 
the trial. Data management, statistical analysis and medical writing services will be done by FGK 
Clinical Research GmbH, München, Germany (a contract research organization [CRO]). Further 
vendors include: 
• LKF - Laboratorium für Klinische Forschung GmbH, Schwentinental, Germany: central 
clinical safety laboratory 
• SCRATCH Pharmacovigilance GmbH & Co. KG, Butzbach, Germany: pharmacovigilance 
services. 
• Covance Central Laboratory Services, Geneva, Switzerland and Indiana, USA: central 
virology laboratory 
Outside vendors will also be used for global and local project management, monitoring services, 
pharmacokinetics and IMP labeling, packaging, and distribution. 


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An Independent Data Monitoring Committee (IDMC) will be established to safeguard the 
interests of trial participants and to provide recommendations on trial conduct and sample size (for 
more details refer to Section 18). The IDMC will also fulfill the designated functions of a Data 
Safety Monitoring Board. 
Addresses and telephone numbers of main responsible parties involved in the conduct of the trial 
are provided in Section 2. 
7 
Trial objectives and endpoints 
Objective 
Endpoint 
Primary 
 
• To evaluate the efficacy of IMU-838 plus 
investigator’s choice of standard of care 
therapy (SoC) vs placebo plus SoC in the 
treatment of coronavirus disease 2019 
(COVID-19) based on the need for 
invasive ventilation (INV) up to 28 days 
• Proportion of patients without any need* 
for INV until end-of-study (EoS) 
Key secondary 
 
• To evaluate the efficacy of IMU-838 
(+SoC) vs placebo (+SoC) in the treatment 
of COVID-19 based on surviving patients 
without respiratory failure, the duration of 
hospitalization in intensive care unit (ICU) 
and all-cause mortality up to 28 days 
• Proportion of patients surviving without 
respiratory failure (defined as any need of 
ICU, 
INV, 
high-flow 
oxygen 
or 
extracorporeal membrane oxygenation 
[ECMO*] until EoS) 
• Duration of ICU treatment until EoS 
• 28-day all-cause mortality 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary 
 
Efficacy 
• To evaluate the efficacy of IMU-838 
(+SoC) vs placebo (+SoC) in the treatment 
of COVID-19 based on a variety of further 
variables and time points (e.g., clinical 
status, renal impairment, oxygenation, 
hospitalization, concomitant vasoactive 
treatments, clinical recovery) 
 
 
• Time to clinical improvement, defined as 
the time from first dose of investigational 
medicinal 
product 
(IMP) 
to 
an 
improvement of at least 2 points on the 
WHO 9-category ordinal scale [21], or live 
discharge from hospital without oxygen 
supplementation, whichever comes first 
• Duration of hospitalization (for US sites 
only: or treatment in special outpatient 
setting in lieu of hospitalization due to 
resource restraints) 
 
• Proportion of patients 
• free of renal-replacement therapy 
(RRT)* until EoS  
• free of ECMO* until EoS 
• free of INV until Days 6 and 14* 
• free of RRT until Days 6 and 14*  
• free of ECMO until Days 6 and 14* 
• with improvement of at least 2 points 
(from randomization) on the 9-category 
WHO ordinal scale [21] on Days 6, 14, 
and 28 
 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Efficacy (continued) 
• Proportion of patients  
• with 
auxiliary 
oxygen 
therapy* 
(including all types of oxygen therapy) 
until Days 6, 14, and 28 
• with clinical recovery defined as  
• Axillary temperature ≤36.6 ℃, or 
oral temperature ≤37.2 ℃, or rectal 
or tympanic temperature ≤37.8 ℃; 
and 
• Respiratory frequency ≤24 times/min 
without oxygen inhalation; and 
• Oxygen saturation ≥98% without 
oxygen inhalation 
• With clinical improvement, defined as 
an improvement of at least 2 points on 
the WHO 9 category ordinal scale [21], 
or live discharge from hospital without 
oxygen supplementation, whichever 
comes first 
• Change in daily clinical patient status on 
the WHO 9-category ordinal scale [21]  
• Duration of INV 
• Duration of ECMO 
• Duration of RRT 
• Duration of auxiliary oxygen therapy 
(including all types of oxygen therapy) 
• Duration of hospitalization for survivors 
• Rate of ICU* admission until Days 6, 14, 
and 28 
• Hospital-free days 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Efficacy (continued) 
• Time from IMP treatment initiation to 
death  
• Time to first prescription of INV 
• Time to first prescription of RRT 
• Time to first prescription of ECMO 
• Time to first prescription of INV, RRT, 
and ECMO 
• Time to ICU admission 
• Cumulative dose of vasoactive therapies 
and days (daily until Day 14) with 
vasoactive therapies (until Day 14) 
• Time to clinical recovery 
Pharmacokinetics 
To evaluate trough plasma levels of 
IMU-838 
 
• Morning trough plasma levels of IMU-838 
on Days 0, 1 through 6, 14, and 28 
• Correlation of trough levels (quartiles) to 
selected clinical outcomes 
Safety 
To evaluate safety and tolerability of 
IMU-838  
 
• AEs and SAEs 
• Vital signs 
• Clinical laboratory parameters (blood 
chemistry, hematology, and urinalysis) 
• Electrocardiogram (ECG) parameters 
• Temperature 
 
 
 
 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Disease markers 
To explore blood levels of disease markers 
 
• D-dimer 
• Lactate dehydrogenase (LDH) 
• C-reactive protein (CRP)  
• Troponin I (cTn) 
• Procalcitonin (PCT) 
• Correlation of disease markers to selected 
clinical outcomes 
 
The analysis for all endpoints includes 
absolute values and absolute change from 
Baseline over time; for LDH log transformed 
values will be used.  
Virologic markers, biomarkers, and 
serologic markers 
To explore viral titers, measures of viral 
virulence and inflammatory markers 
 
Virologic markers 
• Severe Acute Respiratory Syndrome 
Coronavirus Virus (SARS-CoV-2) mean 
viral load - log10 copies in spontaneous 
sputum and nasopharyngeal swab samples 
• Decrease of SARS-CoV-2 viral load 
• Time course of SARS-CoV-2 viral load 
• Qualitative 
virologic 
clearance 
in 
spontaneous sputum and nasopharyngeal 
swab samples (= 2 consecutive negative 
SARS-CoV-2 
reverse 
transcriptase 
polymerase chain reaction [RT-PC] tests 
at least 24 hours apart) 
• Rate of conversion to a negative SARS-
CoV-2 (qualitative) test on Days 6, 14 and 
28 
• Time to conversion to a negative SARS-
CoV-2 (qualitative) test 
 


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Trial objectives and endpoints (continued) 
Objective 
Endpoint 
Secondary (continued) 
 
Virologic markers, biomarkers, and 
serologic markers (continued) 
 
Biomarkers 
• Interleukin (IL)-17, IL-1ß, IL-6, interferon 
gamma (IFNγ), tumor necrosis factor 
alpha (TNFα) 
  
Serologic markers 
• IgA and IgG antibodies against SARS-
CoV-2 
• Time to appearance of IgA and/or IgG 
antibodies 
• Proportion of patients with IgA and/or 
IgG antibodies on Days 6, 14, and 28 
 
The analysis for all endpoints includes 
absolute values, relative and absolute change 
from Baseline over time, if applicable.  
* Patients who are assessed by the investigator to have a medical need of the respective treatment (i.e., INV, ECMO, RRT, 
ICU, hospitalization) but do not receive these treatments for other reasons will be counted for this endpoint.  
 
8 
Trial design and design rationale 
8.1 
Overall trial design 
The trial consists of 2 independent parts: a Phase 2 proof-of-activity phase (Part 1) with the option 
to continue enrollment (without interruption) to a confirmatory Phase 3 part (Expansion Phase, Part 
2). Part 2 will only be started after results from main analysis of Part 1 (MA1) has been analyzed 
and results indicate activity of IMU-838 in COVID-19.  
Both parts follow a multicenter, double-blind, placebo-controlled, randomized, parallel-group 
design to evaluate the safety and efficacy of IMU-838 as addition to investigator’s choice of SoC 
treatment in patients with COVID-19. Eligible patients will be centrally randomized 1:1 to twice-
daily (BID) oral 22.5 mg IMU-838 (45 mg/day + SoC) or placebo (+ SoC). Randomization will be 
stratified by age (< or ≥65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and 
Chloroquine, all other antivirals). 
Part 1 and Part 2 will be analyzed independently from each other. 


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The unblinded main analysis of Part 1 (MA1) will be performed after approximately 200 patients 
have completed Day 28/EoS, either as scheduled or prematurely, while enrollment continues. 
Based on the MA1 results the trial may be expanded into Part 2, if activity of IMU-838 is observed, 
or stopped, if no activity of IMU-838 or safety issues are observed. A further 30 patients are 
expected to be enrolled and treated in a double-blind manner until the results of the MA1 are 
available (when no activity of IMU-838 was found) or until the enrollment in Part 2 has 
commenced (if MA1 indicated proof-of-activity). A final analysis of Part 1 (FA1) will be 
performed after completion of Part 1, using all enrolled patients, i.e. about 230 patients. 
In addition, an early safety analysis will be performed and evaluated by an Independent Data 
Monitoring Committee (IDMC) after 30 patients in Part 1 have completed Day 28 to assess 
unblinded safety data.  
For US centers only: Enrollment into the trial will be paused after these 30 patients have reached 
Day 28 until the IDMC has evaluated safety stopping criteria. If the trial safety stopping criteria 
are not fulfilled, the enrollment in the trial will be resumed and the IDMC will continue with a full 
review of the available safety data. 
Further safety analyses can be initiated at any time by the IDMC or Sponsor when new safety 
signals are identified within this or other trials of IMU-838.  
Apart from assessing the IMU-838 activity, the MA1 will also be used to establish the sample size, 
endpoint selection as well as possible other trial adjustments (e.g. changes for study conduct due 
safety or changes in the study population) for Part 2. The IDMC will also review MA1 results and 
act as a consultative capacity to assist the Sponsor in sample size calculations, endpoint selection 
and other adjustments for Part 2. The final design of Part 2 will be submitted as protocol 
amendment to regulatory authorities, and enrollment in Part 2 will only start after approval of the 
amended Part 2 protocol. 
Part 2 of the trial, if performed, will use an adaptive sequential design with the IDMC reviewing 
unblinded data in an interim analysis during Part 2 (IA2) and providing the Sponsor with 
recommendations regarding modifications of sample size and trial conduct. The IA2 will be 
performed after approximately 50% of patients of the Part 2 sample size have been enrolled to 
adjust sample size and other trial features if needed. The final analysis of Part 2 (FA2) will be done 
after all patients have completed Part 2. 
Screening 
Patients can be screened for a maximum of 2 days (from Day -2 to Day 0) and eligible patients will 
be randomized on Day 0 and treated with IMP + SoC for 14 days. It is encouraged to screen 
potential participants immediately at the day of hospitalization (including informed consent, 
assessment of inclusion/exclusion criteria, screening laboratory tests all done locally, assessment 
of clinical and blood gas criteria) and randomize patients on the same day (Day 0). To assess 


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eligibility criteria, existing local laboratory values obtained within 48 hours of randomization can 
also be used, except for testing of positive status of SARS-CoV-2 infection where a 4-day window 
is allowed.  
IMP administration should start as quickly as possible after randomization and first IMP dose 
intended to be given in the evening of the screening day (Day 0). 
Blinded Treatment period (Day 0 to Day 13) and Day 14 (end-of-treatment) 
The first dose of IMP (2 tablets) should always be given on Day 0 (allowed range for first dose: 
12:00 noon on Day 0 to 02:00 a.m.). All further IMP doses are 1 tablet each in the morning and 
evening. For details of IMP administration see Section 11.1.5. Information about the status and 
patient care are continuously obtained and documented once or twice daily (see Table 3). Further 
examinations and tests, laboratory parameters, biomarkers, disease markers, and virologic 
parameters are to be assessed as outlined in Table 3.  
After the last IMP dose in the evening of Day 13, the end-of-treatment assessments will be done 
on Day 14 (see Table 3). Blood sampling for IMU-838 trough values must be performed in the 
morning around the time the morning dose was usually taken by the respective patient. Patients 
may then continue to receive SoC without any further restrictions on concomitant medications as 
during the 14-day BT period (see Section 11.2.1 and IMP-related exclusion criteria).  
The assessments to be performed in case of hospital discharge before Day 14 are described in 
Section 12.3. For centers in Bulgaria only: Patients must be hospitalized during the entire 
treatment period i.e., from Day 0 to Day 14. 
Day 28 Visit (EoS) 
The patient should return for the final trial visit on Day 28 (EoS). If IMP is prematurely 
discontinued for any reason, the EoS visit should always be conducted on Day 28 and no earlier 
EoS should be performed. If patients withdraw from IMP prematurely, they should be encouraged 
to allow the EoS visit as part of the follow-up. If the patient dies during the trial, the investigator 
should indicate that this visit was not performed. However, even if no EoS visit was performed, 
information about patient status should be reported on the EoS page in the case report form. If the 
patient refuses any EoS visit or the patient is lost to follow-up, it is permissive in this trial that the 
investigator contacts the patient, the family of the patient or the referring physician by phone or 
email to obtain status of life information, or is able to search in registers or publicly available 
information for such status of life information. 
Safety follow up 
Following the Day 28/EoS examination, the investigator will contact the patient regularly (at least 
once) by phone or email to obtain health data until Day 60. This should be documented as 
unscheduled visit in the eCRF. The patient should be asked to return for an on-site visit if the 
investigator deems this necessary for follow-up. 


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8.2 
Trial design rationale 
This is a placebo-controlled, double-blind, randomized trial, which is scientifically the strongest 
design. To mitigate any ethical concerns that may arise with the use of placebo, IMU-838 is 
evaluated as add-on therapy to SoC treatment as recommended by the WHO. [21] 
A treatment duration of 14 days was chosen for this trial as similar drug treatments for COVID-19 
had shown treatment effects within this treatment duration. [22] 
In addition, large studies from the Wuhan region of China had shown that the disease will lead to 
recovery or to death within an average of 22 days [23], thus an overall trial duration of 4 weeks 
seems appropriate. 
The distribution of male and female patients will be according to the natural distribution within the 
trial population, expecting more male than female patients. No corrective measures will be taken. 
However, as COVID-19 appears to affect women and men differently, the endpoints will be 
analyzed for sex-specific differences. This will be done without formal statistical testing. 
The primary endpoint is the proportion of patients without any need for INV until EoS.  
The most prominent feature of severe COVID-19 disease is the development of an interstitial lung 
disease that leads to hypoxia and respiratory failure which is a major contributor to mortality in 
this disease. Severely ill patients require invasive ventilation to have a chance for survival and INV 
causes a critical strain on healthcare resources. For these reasons, the avoidance of  
invasive ventilation should be the primary goal of drug therapy in hospitalized COVID-19  
patients. 
The clinical status will be assessed based on the WHO proposed disease severity scale. [21] 
To achieve balance across the key baseline factors participant inclusion will be stratified by age 
and use of antiviral therapy. 
An IDMC is established to allow an independent assessment of safety and efficacy data to assure 
that trial participants are not exposed to unnecessary or unreasonable risks because of their trial 
participation, and to ensure scientific integrity of the trial. 
8.3 
Risk-benefit assessment 
Risks 
Based on pre-clinical and clinical studies with the precursor drug 4SC-101, the single and multiple 
dose Phase 1 studies with IMU-838, and ongoing clinical trials with IMU-838 no serious adverse 
reactions are expected with IMU-838 at doses of <70 mg once daily. 
In clinical studies with 4SC-101, including 486 subjects of whom 299 received 4SC-101, no drug-
associated clinically relevant adverse reactions were observed at doses of <70 mg once daily. This 
included the potential target organs liver and kidney identified in animals or during early clinical 


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trials. In a large placebo-controlled, randomized clinical trial of 4SC-101 in patients with RA, the 
AE profile of 35 mg/day 4SC-101 was similar to the AE profile of placebo. [24] No increased rate 
of infections and infestations were seen in the treatment arm as compared to placebo in the same 
trial. Additionally, no signal for hepatotoxicity was observed. 
At high 4SC-101 doses (≥70 mg/day or single doses of ≥210 mg) potential drug-related decreases 
in blood uric acid and increases in urine RBC were observed, in very rare cases presenting as 
symptomatic hematuria during the first days of treatment. Laboratory findings were consistent with 
post-renal events and de novo precipitates in the urinary tract. However, no cases of symptomatic 
hematuria were seen at daily doses of 35 mg 4SC-101, the highest therapeutic dose used in previous 
clinical trials.  
The underlying mechanism leading to increased RBC in urine appears to be an increased uric acid 
elimination during the initial days after drug administration. By inhibition of the urate transport 
system URAT1, IMU-838 may decrease the tubular re-uptake of uric acid in kidneys, leading to 
an increase in the urinary excretion of uric acid. Increased urine uric acid may in turn result in 
microcrystallization of uric acid in acidic urine and may lead to the occurrence of RBC in urine. 
Although this may not regularly lead to clinically relevant AEs or laboratory abnormalities at 
therapeutic doses, it may be important for patients with risk factors (including increased serum uric 
acid or higher propensity for urinary concrements) or in patients with a history of gout.  
Thus, for patients with a history of nephrolithiasis, any underlying condition with a strong 
association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia, or 
history or clinical diagnosis of gout the protocol recommends a supplementation of either 2 x 
750 mg oral bicarbonate (daily) or 2 tablets of Neoralit SR three times daily during meals or half 
an hour after meals for these patients (Section 15.1.7). 
During clinical trials using the previous formulation 4SC-101, a single SAE of hepatitis was 
reported in a patient with Gilbert syndrome receiving 35 mg 4SC-101. Gilbert syndrome is a 
genetic disease characterized by a 70–80% reduction in the glucoronidation activity of uridine 
diphosphate-glucuronosyltransferase 1A1 (UGT1A1). IMU-838 is a moderate inhibitor of 
UGT1A1 which may have contributed to this AE. Patients with an elevation of total bilirubin above 
2 x upper limit of normal (ULN) will therefore be excluded from this clinical trial. 
A thorough analysis of the clinical data did not confirm a potential adverse effect of vidofludimus 
on liver function tests in patients other than those with Gilbert syndrome. However, patients with 
elevated alanine aminotransferase (ALT) and/or gamma glutamyl transferase (GGT) (˃5 x ULN) 
will be excluded from trial participation and liver enzymes and bilirubin will be regularly assessed 
throughout the trial.  
For more information please refer to the investigator’s brochure.  


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Benefits 
IMU-838 has currently not been clinically tested for its antiviral activity. However, beneficial 
effects are expected, based on pre-clinical findings demonstrating a broad-spectrum antiviral 
activity of IMU-838 in-vitro at concentrations that are below the therapeutic blood levels observed 
in treated patients. The antiviral activity of DHODH inhibition is further substantiated by numerous 
studies reported in the literature (see Section 5.3).  
IMU-838 as a DHODH inhibitor exhibits many advantages compared to other antiviral treatment 
options: It targets host cells which provides broad-spectrum antiviral activity, blocks viral 
replication and overcomes potential viral mutagenesis. It may as well act directly on the virus 
replication in the infected cells. Targeting virulence factors, such as cytokines, would specifically 
lead to a benefit for more severe cases. DHODH inhibition is also selective towards activated and 
infected cells and therefore does not cause broad and difficult-to-manage side effects seen with 
antimetabolites. 
Risk management 
Risk minimization procedures are implemented for this trial to minimize and assess potential risks 
to participating patients. These include, but are not limited to: 
• specific inclusion and exclusion criteria which ensure that patients who present with 
characteristics that may increase the risk for an adverse outcome are excluded 
• close monitoring of patients with Gilbert syndrome 
• a recommendation that patients with an increased risk for hematuria are supplemented with 
oral bicarbonate or oral Neoralit SR (see Section 15.1.7) 
• regular monitoring of liver enzymes  
In addition, the functions of a Data Safety Monitoring Board to periodically review and evaluate 
accumulated trial data for participant safety, trial conduct and progress, and, when appropriate, 
make recommendations to the Sponsor concerning the continuation, modification, or termination 
of the trial will be fulfilled by the IDMC. 
Risk-benefit assessment 
Considering the safety data available and the exposure of the active moiety in more than 500 human 
subjects and patients, the implemented risk minimization measures, the positive data in in-vitro 
assays, the promising data on antiviral effects of DHODH inhibitors in the literature, the expected 
benefits in the target population, and the urgent medical need for further treatment in SARS-CoV-
2 induced infections, the benefit-risk evaluation is considered favorable. 


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9 
Patient selection 
9.1 
Sample size 
Part 1: MA1 approximately 200 patients; an additional 30 patients are expected (total 
230 patients) until completion of Part 1  
Part 2:  determined based on the MA1, if applicable 
For sample size calculation see Section 16.1. 
9.2 
Inclusion criteria  
1. Male or female patients at least 18 years old (may only be extended to include children 
12 years or older after MA1 following approval of a protocol amendment) 
2. Admitted to the hospital or other medical in-patient treatment facility for treatment of 
COVID-19 
The hospitalization needs to be for medical reasons (treatment of COVID-19 disease) and 
cannot be for social reasons or due to housing insecurity. 
For US sites only: If the investigator would commonly hospitalize the patient but for 
healthcare resource reasons decides to treat the patient in a specially designed out-patient 
setting, then such patients are also allowed to enter the trial (please note that in this case 
the patient would be counted as clinical status category 3). The investigator then must assure 
that the patient has at least a twice daily assessment by qualified trial personnel and all 
laboratory assessments can be adequately performed as per protocol. The Sponsor reserves 
the right to discontinue this option via administrative letter if such assurances cannot be met 
by any site. 
3. SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-
PCR) test in a nasopharyngeal, oropharyngeal or respiratory sample at ≤4 days before 
randomization 
4. Moderate COVID-19 disease defined as fulfilling clinical status category 3 or 4 on the WHO 
9-point ordinal scale [21]: 
o 
Category 3: Hospitalized (see note above for US only), virus-positive, no oxygen 
therapy with the following condition: 
− 
The hospitalization needs to be for medical reasons (treatment of COVID-19 
disease) and cannot be for social reasons or due to housing insecurity 
o 
Category 4: Hospitalized, virus-positive, oxygen by mask or nasal prongs (excluding 
high-flow oxygen therapy) with the following conditions: 


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− 
Peripheral capillary oxyhemoglobin saturation (SpO2) >92% at maximum of 6 liters 
oxygen flow per minute 
− 
Stable respiratory rate ≤30 breaths/min at maximum of 6 liters oxygen flow per 
minute 
5. Presence of at least 1 symptom characteristic for COVID-19 disease i.e., fever, cough or 
respiratory distress 
6. Willingness and ability to comply with the protocol  
7. Written informed consent given prior to any trial-related procedure 
8. For women of childbearing potential: Application of a highly effective method of birth 
control (failure rate less than 1% per year when used consistently and correctly) together 
with a barrier method between trial consent and 30 days after the last intake of the IMP. 
Highly effective forms of birth control are those with a failure rate less than 1% per year 
and include: 
o 
oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraceptives associated with inhibition of ovulation 
o 
oral, injectable, or implantable progestogen-only hormonal contraceptives associated 
with inhibition of ovulation 
o 
intrauterine device or intrauterine hormone-releasing system 
o 
bilateral tubal occlusion 
o 
vasectomized partner (i.e., the patient’s male partner underwent effective surgical 
sterilization before the female patient entered the clinical trial and is the sole sexual 
partner of the female patient during the clinical trial) 
o 
sexual abstinence (acceptable only if it is the patient’s usual form of birth 
control/lifestyle choice; periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are no acceptable methods of contraception) 
Barrier methods of contraception include: 
o 
Condom  
o 
Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
gel/film/cream/suppository 
9. Male patients must agree not to father a child or to donate sperm starting at Screening, 
throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients 
must also  
o 
abstain from sexual intercourse with a female partner (acceptable only if it is the 
patient’s usual form of birth control/lifestyle choice), or 


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o 
use adequate barrier contraception during treatment with the IMP and until at least 
30 days after the last intake of the IMP, and 
o 
if they have a female partner of childbearing potential, the partner should use a highly 
effective contraceptive method as outlined in inclusion criterion 8 
o 
if they have a pregnant partner, they must use condoms while taking the IMP to avoid 
exposure of the fetus to the IMP 
9.3 
Exclusion criteria 
A patient will not be eligible for inclusion if any of the following criteria applies:  
Underlying disease-related exclusion criteria 
1. Involvement in the trial is not in the patient’s best interest according to the investigator’s 
decision, including the presence of any condition that would, in the assessment of the 
investigator, not allow the protocol to be followed safely 
Note: The investigator should particularly consider exclusion of patients at increased risk 
for serious or fatal AEs in case of worsening of the pulmonary perfusion. This includes, but 
is not limited to, pre-existing pulmonary hypertension, severe chronic respiratory disease, 
severely increased risk for thromboembolic complications and moderate to severe left 
ventricular ejection fraction (LVEF) dysfunction. In addition, other known risk factors of 
highest risk of mortality in COVID-19 patients should be considered. 
2. Presence of respiratory failure, shock, and/or combined failure of other organs that requires 
ICU monitoring in the near foreseeable future 
3. Critical patients whose expected survival time <48-72 hours 
4. Presence of the following laboratory values at screening: 
o 
White blood cell count (WBC) <1.0 x 109/L 
o 
Platelet count <100,000/mm³ (<100 x 109/L) 
o 
Total bilirubin>2 x ULN 
o 
Alanine aminotransferase (ALT) or gamma glutamyl transferase (GGT) >5 x ULN 
5. Participation in any other interventional clinical trial  
6. Hospitalization primarily for reasons other than COVID-19 (including primarily for 
concomitant conditions during ongoing SARS-CoV-2 infection) 
7. Anticipated transport to a different hospital or institution, in particular when such transport 
is anticipated for pending ECMO or RRT treatment 
8. Clinical suspicion of a bacterial superinfection at Screening 
IMP-related exclusion criteria 
9. Patients who cannot take drugs orally 


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10. Allergic or hypersensitive to the IMP or any of the ingredients 
11. Use of the following concomitant medications is prohibited from Screening to end of 
treatment with IMP in this trial (up to Day 14) if not indicated otherwise in this protocol: 
o 
Concurrent use of any mycophenolate mofetil or of methotrexate exceeding 17.5 mg 
weekly 
o 
Any medication known to significantly increase urinary elimination of uric acid, in 
particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid 
o 
Current treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, 
bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib 
o 
Any drug significantly restricting water diuresis, in particular vasopressin and 
vasopressin analogs 
o 
Use of rosuvastatin at daily doses higher than 10 mg 
o 
Arbidol and Colchicine  
o 
Any use of other DHODH inhibitors, including teriflunomide (Aubagio™) or 
leflunomide (Arava™) 
o 
Chloroquine and Hydroxychloroquine during the entire trial unless taken for indicated 
use before entering the trial 
12. Patients with clinically relevant conditions leading to hyperuricemia 
13. Use of any investigational product within 8 weeks or 5x the respective half-life before the 
date of informed consent, whichever is longer, and throughout the duration of the trial 
General exclusion criteria 
14. Patients who have a “do not intubate” or “do not resuscitate” order (unless the patient waives 
in writing this order and will allow intubation for the duration of the trial period)  
15. Patients with pre-existing end-stage liver disease (Child Pugh B and C score) 
16. Patients with known Gilbert syndrome (unless their indirect [unconjugated] bilirubin level 
is confirmed to be <1.2 x ULN, i.e. <1.1 mg/dL) 
17. Patients with known acute or clinically relevant chronic renal failure, patients currently on 
dialysis, as well as patients with an estimated glomerular filtration rate value 
<30 mL/min/1.73 m² body surface area according to the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation for adults (or the Schwartz bedside 
equation for children and adolescents, if applicable) 
18. History or presence of serious or acute heart disease such as uncontrolled cardiac 
dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled 
congestive heart failure (New York Heart Association [NYHA] class 3 or 4) 


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Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. 
Patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is increased. 
19. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable 
to provide consent for the trial 
20. Pregnant or breastfeeding  
21. An employee of an investigator or Sponsor or an immediate relative of an investigator or 
Sponsor 
22. Patients institutionalized due to judicial order 
10 
Randomization, blinding and unblinding procedures 
10.1 
Blinding 
Trial participants, the investigator and all other personnel directly involved in the conduct of the 
trial will be blinded to the individual treatment assignments. 
For the MA1 the IDMC and Sponsor will be unblinded, the blind will, however, be kept for patients 
and investigators until FA1. 
To maintain the blind, IMU-838 and placebo tablets will have identical appearance, shape and 
color, and will have identical labeling and packaging. To minimize the potential for bias, treatment 
randomization information will be kept confidential by the responsible personnel and will not be 
released to investigators, other trial center personnel, or the Sponsor’s designee(s).  
10.2 
Emergency unblinding 
The premature breaking of the blind will be restricted to emergency cases in which knowledge of 
the administered drug is necessary for treatment of clinically significant AEs. Whenever possible 
but not required in emergency situations, the investigator must contact the Sponsor or the medical 
monitor before breaking the blind and evaluate if the knowledge of the administered drug would 
have any impact on treatment decisions for the AE. If the blind is broken, the respective patient 
will be withdrawn from further treatment in this trial and a written explanation must be given by 
the investigator to the Sponsor immediately. Emergency unblinding, if necessary, will be 
conducted via the interactive web-based response system (IWRS) of the electronic case report from 
(eCRF). 


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10.3 
Patient identification 
A 7-digit patient identifier consisting of 2 digits each for country (YY), center (XX) and 3 digits 
for patient (ZZZ) i.e., YYXX-ZZZ will be assigned to each screened patient.  
10.4 
Randomization 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list with a 1:1 allocation. Randomization will be done by an IWRS within the eCRF. 
Patients will be assigned respective IMP kits. The investigators will be provided with technical 
options and password information to selectively break the code for an individual patient in case of 
emergency via the IWRS (back-up by phone maybe established).  
11 
Treatments 
11.1 
Investigational medicinal product 
All IMPs supplied by the Sponsor will be manufactured, tested, and released according to current 
Good Manufacturing Practice guidelines and local requirements.  
11.1.1 
IMU-838  
Name: 
IMU-838  
Manufacturer: 
Immunic AG 
Active ingredient: 
Vidofludimus calcium (IM90838) 
Inactive ingredients: 
Microcrystalline cellulose EP, polyvidon K25, crospovidone EP 
type A, talc, and magnesium stearate 
Formulation: 
Tablets containing a specific polymorph of vidofludimus calcium  
Matrix: 
White uncoated tablets, biconvex shape, diameter of 8 mm 
Dose strength: 
22.5 mg  
Total daily dose: 
45 mg 
 
11.1.2 
Placebo  
The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of 
inactive ingredients, and packaging. 


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11.1.3 
Packaging, labeling and dispensing 
All IMP will be packed and labeled according to applicable regulatory requirements.  
The labels will contain at least the following information: route of administration, trial code, 
randomization number, batch number, expiry date, and instructions for storage. 
IMU-838 and placebo tablets will be packaged in 30 mL polyethylene bottles containing 32 tablets.  
For patients discharged from the hospital before Day 14, the patient will be allowed to take the 
IMP home to complete blinded treatment (not applicable for centers in Bulgaria as all patients 
must be hospitalized between Day 0 and Day 14). 
11.1.4 
Storage and stability 
The investigator is responsible for the safe and proper handling and storage of the IMP at the 
investigational site. The IMP must be stored in a locked facility with access limited to the 
investigator and authorized personnel. The investigator must ensure that the IMP is administered 
only to patients enrolled in this trial. 
In stability studies, IMP was stable at ambient (25°C/60% relative humidity) and at accelerated 
storage conditions (40°C/75% relative humidity) and does not require any special storage 
conditions. However, the tablets should be protected from direct sun light, moisture, freezing, and 
extended periods of excessive heat (defined as any temperature above 40°C [104 F]). It should also 
be advised to keep the bottle tightly closed to protect tablets from moisture. 
11.1.5 
Treatment dose, dose selection, and administration  
Tablets will be taken BID with a glass of water (if possible); one tablet each in the morning (15 to 
50 min before a meal if applicable), and in the evening (2 hours after any meal if applicable).  
The 1st IMP dose on Day 0 should always be the “evening dose of Day 0”. To administer the 1st IMP 
dose as close as possible to time of randomization, the initial IMP dose (“evening dose of Day 0”, 
2 tablets to be given at once) can be administered between 12:00 noon on Day 0 to 02:00 a.m. on 
Day 1. The 2nd IMP dose is then given in the morning of Day 1, and dosing continues twice daily 
until the evening dose of Day 13 (last IMP dose). Except for the initial IMP dose (2 tablets), all 
other IMP doses will consist of 1 tablet. The timing of morning and evening doses (except for 
initial evening dose on Day 0) should be at the same time of the day, if possible (see Table 2). 


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Table 2: 
Administration of tablets 
 
Day 0 
Day 1 
Days 2 to 12 
Day 13 
Time 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
 
 
 
 
 
 
 
 
 
Number of tablets 
 
2 
1 
1 
1 
1 
1 
1 
 
 
 
 
 
 
 
 
 
Dose IMU-838 
 
45 mg 
22.5 mg 
22.5 mg 
22.5 mg 
22.5 mg 
22.5 mg 
22.5 mg 
 
 
# 
⃰ 
⃰ 
⃰ 
⃰ 
⃰ 
⃰ 
# Day 0: Loading dose of 45 mg IMU-838 once daily given in the evening of Day 0. 
⃰  Day 1- Day 13: dosing of 22.5 mg IMU-838 BID (twice daily). 
 
If the patient is intubated for ventilation, IMP is to be given via a gastric tube. The tablet has no 
coating and a homogeneous content and can be crushed into smaller pieces (if necessary) for dosing 
via gastric tube. 
If the patent is discharged from the hospital before Day 14, the patient will receive the IMP and 
will take the remaining doses of IMP at home (not applicable for centers in Bulgaria as all patients 
must be hospitalized between Day 0 and Day 14). 
The 45 mg dose used in this trial is on the higher end of doses used in completed and ongoing 
clinical trials. A daily dose of 50 mg IMU-838 was found to be safe in a 14-day Phase 1 clinical 
trial (Trial P1-IMU-838-MAD). The 45 mg dose is also used in the ongoing Phase 2 studies in 
multiple sclerosis (P2-IMU-838-MS) and ulcerative colitis (P2-IMU-838-UC). In an interim 
analysis of Trial P2-IMU-838-UC during which unblinded safety data were evaluated by an 
independent Data Review Committee, no safety signal was found, and the 45 mg dose was 
considered as not intolerable. Based on the overall safety data, 45 mg IMU-838 is considered a safe 
dose. To maintain IMU-838 drug levels as stable as possible, the dose of 45 mg IMU-838 is to be 
given as 22.5 mg dose BID in this trial. 
For patients with a hyperacute disease like COVID-19, it is imperative that therapeutic drug levels 
are quickly reached. Because of the short half-life (approximately 30 hours) and short time to 
maximum blood levels (3-4 hours after oral dosing) of IMU-838, therapeutic levels are reached 
rather quickly. In addition, the first dose (loading dose in the evening of Day 0) will be given as 45 
mg dose of IMU-838 (2 tablets of 22.5 mg IMU-838 taken at the same time). This will ensure that 
therapeutic drug levels are expeditiously reached in this hyperacute disease. 
The PK profile of IMU-838 based on the described dosing (loading dose of 45 mg IMU-838 on 
Day 0, then 22.5 mg IMU-838 BID for the remaining treatment days) should therefore result in a 
profile with a quick onset of therapeutic effects and stable therapeutic drug level over the 14-day 
treatment period. 


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11.1.6 
Drug accountability and patient compliance 
The IMP must not be used outside the context of this trial protocol. For patients discharged from 
the hospital the investigator must ask the patient to return excess IMP and all packaging materials 
(including empty containers) at Day 14 (see Table 3) for drug accountability. Unused IMP cannot 
be used outside the context of this trial protocol. Dispensed and returned IMP cannot be re-used 
for any other patients. 
The investigator or authorized staff must document the receipt, dispensing, and return of all IMP 
received during this trial. These records will include but are not limited to dates, quantities, batch 
numbers, patient identifiers, and unique interactive response technology codes, as applicable. The 
investigators must maintain records documenting that patients were provided with the IMP as 
outlined in the protocol. Furthermore, investigators will reconcile all IMP received from the 
Sponsor and administered to or returned from the patient. It is the responsibility of the investigator 
to reason any discrepancies in IMP accountability. Forms will be provided to ease accountability. 
At the end of the clinical trial, or as directed, all remaining and unused IMP must be accurately 
counted (final drug accountability) and destroyed according to the Sponsor’s instructions, i.e., to 
e.g., return all remaining and unused IMP to the Sponsor or Sponsor’s designee.  
11.2 
Prior and concomitant medications 
All medications administered within 2 days before the day of informed consent and until EoS must 
be documented in the corresponding section of the eCRF. Vasopressor dose will be documented 
separately. 
All medications taken by the patients after giving informed consent and all treatments given in 
addition to the IMP during the trial are regarded as concomitant treatments and must be 
documented in the eCRF. 
11.2.1 
Standard of care treatment and concomitant treatments 
Any treatments, medications and procedures that investigators would customarily use to treat 
COVID-19 in their clinical practice should be included in SoC treatment. The investigator’s choice 
of SoC can include supportive pharmaceutical treatments (including medications that are approved 
in other indications but that the investigator customarily uses in COVID-19 patients), medications 
with any approved antiviral indication, intravenous fluids, supplemental oxygen, noninvasive and 
invasive ventilation, antibiotic agents, vasopressor support, RRT, and ECMO. Investigational 
treatments not yet approved for commercial use in the respective country (for example obtained 
through an early access program) or parallel participation in different interventional trials are 
prohibited in this trial.  


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In addition, Arbidol and Colchicine are prohibited for centers in all countries. Chloroquine and 
Hydroxychloroquine are also prohibited for all centers in all countries unless already taken for 
indicated use before entering the trial. 
11.2.2 
Prohibited and restricted medication 
The use of the following medications and treatments will be prohibited from Screening to end-of-
treatment with IMP in this trial (up to Day 14) if not indicated otherwise in this protocol: 
• Concurrent use of any mycophenolate mofetil or of methotrexate exceeding 17.5 mg weekly 
• Any medication known to significantly increase urinary elimination of uric acid, in particular 
lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid 
• Current treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, 
bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib 
• Any drug significantly restricting water diuresis, in particular vasopressin and vasopressin 
analogs 
• Use of rosuvastatin at daily doses higher than 10 mg 
• Arbidol and Colchicine  
• Any use of other DHODH inhibitors, including teriflunomide (Aubagio™) or leflunomide 
(Arava™) 
• Chloroquine and Hydroxychloroquine are not allowed during the entire trial, unless already 
taken for indicated use before entering the trial 
Routine use of steroids is not recommended and should be reserved for patients with severe disease 
or with special circumstances. Concomitantly used steroids (e.g., required for pre-existing 
conditions) do not need to be discontinued when entering this trial, however, their use should be 
carefully considered. 
After the 14-day treatment period with IMP any drugs to treat the disease, including any anti-viral 
therapy, can be used at the investigator’s discretion. 
The concomitant administration of drugs metabolized for more than 70% by CYP2C8 (although 
not prohibited) should be carefully considered since it cannot be excluded that IMU-838 potentially 
increases their blood levels. Major substrates of CYP2C8 include:  
• amodiaquine (anti-malarial) 
• dasabuvir (anti-viral),  
• enzalutamide (anti-cancer) 
• montelukast (anti-asthmatic), and 
• pioglitazone and repaglinide (anti-diabetics) 


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The use of the potent CYP2C8 inhibitor rifampicin and strong and moderate CYP2C8 inducers 
gemfibrozil and trimethoprim as concomitant medication is not prohibited during this trial. 
However, alternatives to these drugs should be considered, and patients should be carefully 
monitored for any indication of toxicity. Given the known narrow therapeutic window of ibuprofen, 
the use of ibuprofen should be carefully considered or, if possible, therapeutic alternatives should 
be used. 
 
12 
Trial schedule 
12.1 
Schedule of assessment 
An overview of the trial conduct is provided in Table 3.  


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Table 3: 
Schedule of assessments  
 
Assessments 
 Screening  
Blinded treatmentl 
EoT 
EoS 
USV 
 
 D-2 to D0g  
D0g 
D1 - D5 
D6 
D7 - D13 D14  
D28 
 SFUp 
 
Pre Post 
 
 
 
 
 
±1 d 
 
 
Informed consent 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Demographics, incl. high 
risk factorsf 
 
• 
 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Local screening labs 
performed or taken from 
existing labsk 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of positive 
SARS-CoV-2 status 
 
•m 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
• 
 
 
 
 
 
 
 
 
 
Medical history 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/procedures 
 
• 
 
 
• 
• (daily) 
• 
• (daily) 
• 
 
• 
 
• 
Physical examination 
 
• 
 
 
 
 
• 
 
• 
 
• 
 
 
Continuous monitoring 
with documentation of  
 
 
 
 
 
 
 
 
 
 
 
 
 
Status hospitalization/ 
status ICUc 
 
 
 
 
 
 
 
 
• 
 
• 
 
• 
Survival status  
 
 
 
 
 
 
 
 
• 
 
•n 
 
 
O2 supplementation 
(incl. type of ventil.) 
 
 
 
 
 
 
 
 
• 
 
• 
 
•p 
Temperature 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
Vital signsr 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
Respiratory rate 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
SpO2 
 
 
 
 
 
 
 
 
• 
 
 
 
•p 
Score assessment 
(9-point WHO scale)b 
 
• 
 
 
 
 
 
 
• 
 
• 
 
•p 
Vasopressor dose 
 
 
 
 
 
 
 
 
• 
 
• 
 
 
Radiol. confirmation in 
clinical practice of 
interst. lung diseasei 
 
 
 
 
 
 
 
 
• 
 
 
 
 
Document confirmation 
of any new infectionsj 
 
 
 
 
 
 
 
 
• 
 
 
 
 
Use of RRT 
 
 
 
 
 
 
 
 
• 
 
• 
 
• p 
Use of ECMO 
 
 
 
 
 
 
 
 
• 
 
• 
 
• p 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Twice daily 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 
Once daily (evening) 


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Table 3: 
Schedule of assessments (continued) 
 
 
a 
Needs to be frozen at at least -20° C (-4° F) and sent to the central safety laboratory within 6 weeks. 
b 
Clinical status on a 9-category ordinal scale (as proposed by the WHO master protocol) 
c 
Including documentation of ICU admission and discharge times. 
Assessments 
 
Screening 
 
Blinded treatmentl 
EoT 
EoS 
USV 
 
 D-2 to D0g 
 
D0g 
D1- D5 
D6 
D7 - D13 D14  
D28 
 SFUp 
 
Pre Post 
 
 
 
 
 
±1 d 
 
 
Lab assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Hematology 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Coagulationa 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Urinalysis 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Disease markersa 
 
 
 
• 
 
• (daily) 
• 
• (daily) 
• 
 
• 
 
 
Biomarkersa 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
IMU-838 trough 
levelsa 
 
 
 
• 
 
• (daily) 
• 
 
•o 
 
• 
 
 
SARS-CoV-2 viral 
load and SARS-CoV-2 
status (qualitative)e 
 
 
 
• 
 
• (Days 2 
& 4 only) 
• 
• (Days 8, 
10 & 12 
only) 
• 
 
• 
 
•p 
Serology: SARS-CoV-
2 antibodiesh 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Immune cell subtyping 
(US only)q 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Lab Kits used 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kit A 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Kit B 
 
 
 
 
 
• (daily) 
 
• (daily) 
 
 
 
 
 
Kit C 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Kit PK 
 
 
 
• 
 
• (daily) 
• 
 
•o 
 
• 
 
 
Kit D 
 
 
 
• 
 
• (daily) 
• 
• (daily) 
• 
 
• 
 
•p 
Kit E 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
•p 
Immune cell 
subtyping (US only)q 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 
 
• 
 
 
 
 
 
 
 
 
• 
 
• 
ECG 
 
 
 
• 
• 
• (only 
Day 3) 
• 
 
• 
 
• 
 
 
IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of tablets 
 
 
 
- 
2 
 
 
 
 
 
 
 
 
Accountability 
 
 
 
 
 
 
 
 
• 
 
 
 
 
SoC treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 tablet each morning + evening 


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d 
Existing local lab values obtained within 48 hours of randomization as well as locally obtained screening lab values can be 
used for assessment of eligibility. 
e 
At each time point only 1 nasopharyngeal swab and 1 sputum sample each will be taken. The viral load test will also be used 
as qualitative test (i.e. may be evaluated as absence or presence of virus in the quantitative SARS-CoV-2 assessments). 
Samples need to be frozen at at least -20° C (-4° F) and sent to the central virology laboratory within 7 days on dry ice. 
f 
Includes: Age≥65; cardiovascular disease (including hypertension), pre-existing pulmonary disease, diabetes, current 
treatment for malignancy or within the previous 3 years, immunosuppression (due to ongoing use of immunosuppressive 
drugs or existing disease leading to impaired immune status), body mass index. 
g 
Screening, randomization and first IMP administration can be performed the same day (Day 0). If screening is performed on 
Day 0, treatment will start with the evening dose. 
h 
Plasma sample for serology SARS-CoV-2 (IgG and IgA detection) should be frozen at at least -20° C (-4° F) and sent to the 
central safety laboratory within 6 weeks. 
i 
Confirmation of radiographic evidence of pulmonary infiltrates by chest X-ray or CT (only if done within the scope of routine 
clinical practice). 
j 
Confirmation of presence of any new viral or non-viral infection (this is not a protocol-required procedure, only documentation 
when done within the scope of routine clinical practice). Site of infection and source of culture will be recorded. 
k 
As performed during routine clinical practice in the center. Must include white blood cell count, platelet count, total bilirubin, 
alanine aminotransferase or gamma glutamyl transferase, serum creatinine, for women of childbearing potential: blood 
pregnancy test, and if the patient has known Gilbert syndrome: indirect [unconjugated] bilirubin.  
l 
For assessments, if patients will be discharged from the hospital before Day 14, see Blinded Treatment period (Day 0 to 
Day 13) and Day 14 (end-of-treatment). For centers in Bulgaria only: Patients must be hospitalized during the entire 
treatment period. 
m 
Within 4 days of randomization. 
n 
If no EoS visit was performed, information about patient status should be reported on the EoS page in the case report form. If 
the patient is lost to follow-up, the investigator must contact the patient, the patient’s family or the referring physician by 
phone or email to obtain survival status, or it must be possible to search in registers or publicly available information for these 
survival data. 
o 
 Blood sampling must be performed in the morning around the time the morning dose was usually taken by the respective 
patient. 
p 
Safety follow up assessments must be performed regularly (at least once) by phone or email between Day 28/EoS and Day 60 
and documented as an unscheduled visit in the eCRF. The patients should be asked to return for an on-site visit if the 
investigator deems this necessary for follow-up. The assessments not to be done if the visit is performed as a telephone or 
email contact in the scope of the safety follow up are marked as •p 
q 
Optional for centers in the USA only: 2 blood samples will be collected to evaluate immune cell subtypes and immune 
reactions for future research studies. This will be shipped directly to a US research site and not to the central laboratory. 
Shipment needs to be done at ambient temperature and immediately the same day after sampling. 
r 
Height and weight only to be measured at D0, pre-dose. 
 
AE = adverse event, CT = computed tomography, cont. = continued, D = day, ECG = electrocardiogram, ECMO = extracorporeal 
membrane oxygenation, EoS = end-of-study, EoT = end-of-treatment, ICU = intensive care unit, Ig = immunoglobulin, 
IMP = investigational medicinal product, incl. = including, interst. = interstitial, pre(post) = pre(post) IMP, RRT = renal-
replacement therapy, Radiol. = radiological, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, SFU = safety follow 
up, SoC = standard of care, SpO2 = peripheral capillary oxyhemoglobin saturation, ventil. = ventilation, USV = unscheduled visit, 
WHO = World Health Organization. 
 
12.2 
Screening (Day -2 to Day 0) and Day 0 
Patients for whom written informed consent (for consent procedures see Section 19.3) was obtained 
will undergo the assessments shown in Table 3. Patients will be screened for eligibility based on 
the trial’s inclusion and exclusion criteria. The infection with SARS-CoV-2 must have been 
confirmed by RT-PCR within 4 days of randomization. To assess eligibility existing local 
laboratory values obtained within 48 hours of randomization will be used.  
Whenever possible, screening, randomization and 1st IMP administration should be performed on 
the same Day (Day 0). In this case the Day 0 assessments (see Table 3) will be performed, as soon 


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as the eligibility is confirmed. Treatment will then start with the evening dose. For dosing 
recommendations how to dose on initial days see Section 11.1.5. 
12.3 
Blinded treatment period (Day 0 to Day 13) and Day 14 (end-of-treatment) 
Patients will undergo the assessments and procedures as detailed in Table 3. Blood samples to 
assess IMU-838 trough levels will be taken pre-dose on Day 0 before first IMP dose is given. If 
patients will be discharged from hospital during the BT, they will be asked to return for a visit at 
Day 6 and Day 14, whatever is applicable (not applicable for centers in Bulgaria as all patients 
must be hospitalized between Day 0 and Day 14). Treatment will be stopped at Day 13 with the 
evening dose on that day as the last IMP administration. After the last IMP dose in the evening of 
Day 13, the end-of-treatment (EoT) assessments will be done on Day 14 (see Table 3). Blood 
sampling for IMU-838 trough values must be performed in the morning around the time the 
morning dose was usually taken by the respective patient. 
For centers in Bulgaria: Patients must be hospitalized during the entire treatment period i.e., from 
Day 0 to Day 14. 
For centers in countries other than Bulgaria: If applicable, the patient will be asked to return all 
remaining IMP and its packaging (including empty bottles) to the trial center at Day 14 for IMP 
accountability checks. 
In case of hospital discharge before Day 14, the following assessments should be done between 
hospital discharge and until Day 14 (patients should return for clinic visits at Day 6, if discharged 
before Day 6, and Day 14): 
• On the day of hospital discharge: 
o 
All trial-related assessments and procedures are completed as per Table 3 and finalized 
(evening assessments should be done, even when patient is discharged during the day) 
o 
The date and time of hospital discharge need to be documented 
• Day 6 and Day 14: 
o 
The full lab assessments to be performed on Days 6 or 14, respectively (as indicated in 
Table 3) 
o 
Physical examination and ECG 
o 
Documentation of concomitant medications/procedures, AEs, temperature, vital signs, 
respiratory rate, type of oxygen supplementation, survival status, hospitalization status, 
assessment of WHO ordinal scale [21] (only once daily assessment required) 
o 
Return of IMP by patients and drug accountability (Day 14 only) 
If the patent is discharged from the hospital before Day 14, the patient will receive the IMP and 
will take the remaining doses of IMP at home. 


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12.4 
Unscheduled visit 
Unscheduled visits may be performed at any time during the clinical trial and will generally include 
the assessments listed in Table 3. Depending on the reason for the unscheduled visit, further 
appropriate assessments maybe done according to the investigator’s discretion. Results of the 
assessments and any change in concomitant medications will be recorded in the eCRF. After an 
unscheduled visit, the regular scheduled visits must continue according to Table 3. 
12.5 
End-of-study (EoS, Day 28) and premature termination 
Patients will undergo the assessments and procedures shown in Table 3.  
In case of premature discontinuation, assessments of the EoS visit should be performed at Day 28 
for the respective patients, whenever possible. Patients who were discharged (for centers in 
Bulgaria only: between Day 14 and 28), will be asked to return at Day 28 for EoS assessments. If 
the patient dies during the trial, the investigator should indicate that this visit was not performed, 
however should fill out all information about patient status to be performed at the EoS visit. If the 
patient refuses any EoS visit or is lost to follow-up, at least the survival status should be ascertained 
e.g., by calling the patient, his/her relatives, or referring physician, or by searching registers or 
publicly available information for survival status information.  
In case of premature withdrawal from the trial or IMP, reasons, circumstances and findings will be 
fully described on the corresponding page in the eCRF respecting the patient’s rights.  
12.6 
Safety follow-up  
Following the D28/EoS examination, the investigator will contact the patient regularly (at least 
once) by phone or email to obtain health data until Day 60. This should be documented as an 
unscheduled visit in the eCRF. The patients should be asked to return for an on-site visit if the 
investigator deems this necessary for follow-up. 
13 
Efficacy and baseline assessments and procedures  
13.1 
Demographics and other baseline assessments 
During screening, demographics (including sex, age, height, weight, race, and ethnicity), presence 
of high-risk factors, a complete medical history, confirmation of SARS-CoV-2 infection status, 
and previous and concomitant therapy will be collected.  
High risk factors include: Age ≥65, cardiovascular disease (including hypertension), pre-existing 
pulmonary disease, diabetes, current treatment for malignancy or within the previous 3 years, 
immunosuppression (due to ongoing use of immunosuppressive drugs or existing disease leading 


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to impaired immune status), and body mass index (BMI). The BMI will be calculated from patient’s 
height and weight. 
13.2 
Clinical disease severity assessment 
The clinical disease severity will be assessed based on the WHO Ordinal Scale for Clinical Status 
[21, and Table 4]. The WHO scale is a 9-category ordinal scale and was developed to have a 
standardized measure of the COVID-19 disease severity. The scale comprises patient status 
(outpatient or hospitalized), virus status (infected yes or no), limitation of activities, oxygen 
support, and organ support. For the clinical assessment in this trial the WHO scale is slightly 
modified. 
Table 4: 
Modified WHO Ordinal Scale for Clinical Status 
Patient state 
Descriptor 
Score 
Uninfected or no longer infectious 
No clinical or virological evidence of infection 
0 
Mild Disease 
Ambulatory, virus-positive, no limitation of activities 
1 
Ambulatory, virus-positive, limitation of activities 
2 
Moderate Disease 
Hospitalized, virus-positive, no oxygen therapy 
3 
Hospitalized, virus-positive, oxygen by mask or nasal prongs 
4 
Severe Disease 
Hospitalized, virus-positive, non-invasive ventilation or high-
flow oxygen 
5 
Hospitalized, virus-positive, intubation and mechanical 
ventilation 
6 
Hospitalized, virus-positive, ventilation plus additional organ 
support (pressors, RRT, ECMO) 
7 
Dead 
Death 
8 
ECMO = extracorporeal membrane oxygenation, RRT = renal replacement therapy. 
Based on [21]. 
 
13.3 
Clinical and patient status assessments 
The following will be recorded regularly, once or twice daily, during the course of the trial (see 
Table 3): 
• Hospitalization and ICU admissions 
• Survival status  
• Score assessment (WHO scale, see Section 13.2)  
• Use of invasive and non-invasive ventilations, auxillary oxygen supplementation (including 
type of ventilation e.g., ECMO), and RRT 
• Vital signs and temperature 


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• Respiratory rate and SpO2 (see Section 13.4) 
• Vasoactive therapy (type and dose) 
• Confirmation of radiographic evidence of pulmonary infiltrates by chest X-ray or computer 
tomography (if done within the scope of routine clinical practice)  
• Documentation of presence of any new viral or non-viral infection (e.g., if blood cultures and 
sputum gram stain and culture are done within the scope of routine clinical practice). Site of 
infection and source of culture will be documented. 
13.4 
Assessment of respiratory rate and oxygen saturation 
To assess the respiration of the patient, peripheral capillary oxyhemoglobin saturation (SpO2) will 
be repeatedly reported (Table 3). Respiration rate will be assessed according to hospital staff's 
current clinical practice. 
14 
Pharmacokinetics, disease markers, and biomarkers 
All laboratory samples for IMU-838 plasma trough levels, disease markers and biomarkers must 
be handled and labeled according to the respective laboratory manual i.e., virologic samples 
according to the manual from the central virology laboratory, all other samples according to the 
central safety laboratory manual.  
14.1 
Plasma trough levels of IMU-838 
IMU-838 plasma trough level concentrations will be determined by validated direct liquid 
chromatography tandem-mass spectrometry. This method determines the concentration of the 
active moiety vidofludimus contained in IMU-838. Details of the assay will be described in a 
separate bioanalytical report.  
Plasma samples for IMU-838 trough levels will be assessed centrally at Nuvisan. Samples will be 
collected and subsequently stored at at least -20°C (-4°F) at the site, and shipped to the central 
laboratory as frozen samples, as appropriate. Investigators will be provided with detailed written 
instructions how to collect, handle, store, and ship the samples.  
Blood samples to assess IMU-838 serum trough values will be collected in all patients as specified 
in the schedule of assessments in the morning before the first IMP dose (Table 3).  
Patients are required to withhold intake of the IMP until after the blood sample collection. Plasma 
trough will be assessed using Lab Kit PK. 


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14.2 
Disease markers 
The following blood biomarkers will be evaluated: 
• D-dimer 
• LDH 
• CRP 
• cTn 
• PCT 
Disease markers are part of Lab Kit B, must be frozen at at least -20°C (-4°F) and sent within 6 
weeks (for more details on lab kits see also Appendix 1). 
14.3 
Biomarkers 
The following biomarkers will be evaluated (in blood samples if not indicated otherwise): 
• Serial viral load assessed by RT-PCR in spontaneous sputum and nasopharyngeal swab 
(samples must be frozen at at least -20°C [-4°F] and sent within 7 days, Lab Kit D)* 
• Qualitative virus assessment: SARS-CoV-2 status (qualitative) in sputum and 
nasopharyngeal swab as derived from the viral load assessment (i.e. may be evaluated as 
absence or presence of virus in the quantitative SARS-CoV-2 RT-PCR assessments) 
• Biomarkers: IL-17, IL-1ß, IL-6, IFNγ, and TNFα (assessed with Lab Kit C, samples must be 
frozen at at least -20°C [-4°F] and sent within 6 weeks) 
• Serology: IgA and IgG antibodies against SARS-CoV-2 (Lab Kit E, samples must be frozen 
at at least -20°C [-4°F] and sent within 6 weeks) 
For more details on lab kits, storage and shipment conditions see Appendix 1. 
For the sputum sample, no induced sputum should be attempted. If spontaneous sputum cannot be 
obtained, this should be noted and no sample needs to be sent. 
* At each time point indicated in Table 3 only 1 nasopharyngeal swab and 1 sputum sample will 
be taken. The results of the viral load test will also be used for the qualitative assessment. 
For centers in the USA: 2 additional blood samples as indicated in Table 3 will be collected to 
evaluate immune cells and immune reactions for future research studies. Shipment needs to be 
done at ambient temperature and immediately the same day after sampling. Samples will be 
shipped directly to a US research site and not to the central laboratory. This blood collection is 
optional and only for patients agreeing to the extra biomarker assessment on the ICF. 


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15 
Safety assessments 
15.1 
Adverse events documentation and reporting 
15.1.1 
Definitions 
15.1.1.1 
Adverse events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the IMP, 
whether or not related to the IMP. 
Overdosing, defined as intake of more than twice the intended dose, will not be considered an AE 
but must be documented as protocol deviation. However, symptoms associated with overdose are 
considered adverse drug reactions (ADR, for definition see below).  
Untoward medical experiences occurring during pre-treatment periods do not meet the above-
mentioned definition of AE. Nevertheless, they have to be documented in the same way as AEs, if 
they occur in the safety monitoring period, i.e., between signing the informed consent form and 
completion of the EoS visit. Should they already be present at Screening and don’t worsen later 
on, they will only be documented as medical history. 
A surgery or procedure scheduled to occur during the trial will not be considered an AE if the 
surgery or procedure will be performed for a pre-existing condition and the surgery or procedure 
was planned prior to trial entry. However, if the pre-existing condition deteriorates unexpectedly 
during the trial (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the surgery or procedure is being done will be considered an AE. 
Diagnostic medical or non-surgical procedures will not be considered as AEs. Hospital admission 
for social, quarantine or convenience reasons will also not be recorded as AE. 
AEs that occur between signing the informed consent form and the time when the patient first 
administers the IMP (Day 0) are defined as pre-treatment AEs. 
Treatment-emergent adverse events are defined as any event not yet present prior to the first 
intake of IMP or any event already present that worsens in either intensity or frequency following 
exposure to the IMP. 
A continuous event with changing intensities will be considered as one event of the most severe 
intensity documented. A continuous event with a changing seriousness will also be considered as 
one event, but the start and stop date of the time the event is serious must be separately documented. 
Clearly separated episodes of an event will be considered as separate events. 


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15.1.1.2 
Adverse drug reactions and unexpected adverse drug reactions 
All AEs judged by either the reporting investigator and/or the Sponsor as having a reasonable 
causal relationship to the IMP qualify as ADR. The expression reasonable causal relationship 
means to convey in general that there is evidence or argument to suggest a causal relationship. 
An unexpected ADR is an adverse reaction, the nature or severity of which is not consistent with 
the applicable product information (e.g., investigator’s brochure for an unapproved investigational 
product or package insert or summary of product characteristics for an approved product). Reports 
that add significant information on specificity or severity of a known, already documented AE 
constitute unexpected AEs, too. For example, an event more specific or more severe than described 
in the reference document would be considered ‘unexpected’. Specific examples would be: acute 
renal failure as a labeled AE with a subsequent new report of interstitial nephritis or hepatitis with 
a subsequent report of autoimmune hepatitis. 
15.1.1.3 
Serious adverse events 
An SAE is any untoward medical occurrence that, at any dose: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 
• results in a congenital abnormality or birth defect 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These will usually 
also be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. In addition, new malignancies that occur during 
the participation in the trial are defined as important medical events and must be reported as SAEs.  
An SAE requires that the underlying event is considered an AE as defined in Section 15.1.1.1. 


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Hospitalizations due to a surgery or procedure during the trial will not be considered an SAE if the 
surgery or procedure will be performed for a pre-existing condition and the surgery or procedure 
was planned prior to trial entry. However, if the pre-existing condition deteriorates unexpectedly 
during the trial (e.g., surgery performed earlier than planned), then the deterioration of the condition 
leading to hospitalization will be considered an SAE. Hospital admission for social, quarantine, or 
convenience reasons will not be recorded as SAE. Hospitalization and death due to COVID-19 are 
anticipated clinical events of the underlying disease and cannot be used as reason for SAE 
classification without an underlying AE leading to hospitalization or death (see also Section 
15.1.6). 
15.1.1.4 
Suspected unexpected serious adverse reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction (SAR) 
that is unexpected or for which the development is uncommonly (unexpected issue) observed 
during a clinical trial and for which there is at least a reasonable possibility of a causal relationship 
with the IMP. 
15.1.2 
Classification of adverse events 
Classification of AEs will be performed by the investigator. 
Causality 
The causal relationship between the AE and the administration of the IMP or trial procedure will 
be assessed as follows: 
• Related: 
Implies a reasonable possibility of a causal relationship between the 
event and the IMP or procedure. This means that there are facts 
(evidence) or arguments to suggest a causal relationship. 
• Not related: 
Implies no reasonable possibility of a causal relationship between the 
event and the IMP or procedure. This means that there are neither facts 
(evidence) nor arguments to suggest a causal relationship. 
 
Severity 
The severity of AEs will be graded according to the National (US) Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0. If not specifically defined 
in the NCI-CTCAE, the following grading applies:  
Grade 1: 
mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 


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Grade 2: 
moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)* 
Grade 3: 
severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
 
Outcome categories 
Recovered: 
The patient has fully recovered from the event or the condition has 
returned to the level observed at Baseline 
Recovering: 
The patient has recovered from the event, but the condition has not 
returned to the level observed at Baseline 
Not recovered: 
The event is ongoing at the time of reporting and the patient has still 
not recovered 
Recovered 
with sequelae: 
As a result of the AE, the patient suffered persistent and significant 
disability/incapacity (e.g., became blind, deaf or paralyzed) 
Fatal: 
The patient died due to the event. If the patient died due to other 
circumstances than the event, the outcome should be stated 
otherwise (e.g., not recovered or recovering) 
Unknown: 
If the outcome is not known or not reported 
15.1.3 
Documentation of adverse events 
All AEs occurring between the time written informed consent was obtained and until the end of 
the safety follow-up period (safety observation period) must be recorded. Information on AEs will 
be derived by non-directive questioning of the patients in general terms at each visit if possible 
(e.g., "How do you feel?” or “How have you been since the last questioning?"), by patients’ 
spontaneous reports, or by observation. Adverse events also may be detected when they are 
volunteered by the patient during or between assessments and/or visits or through physical 
examination, laboratory test, or other assessments. 
 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 


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All AEs that occur during the safety observation period of the trial as described above will be 
recorded in the patient’s AE section of the eCRF and will include the following information: a 
description of the AE, date of onset and resolution, severity, relationship to the IMP, relationship 
to trial procedure, action taken, and outcome. For SAEs, the SAE form must be completed (see 
Section 15.1.4). 
15.1.4 
Documentation and reporting of immediately reportable adverse events 
Any SAE that occurs during this trial will be reported (via the "Serious Adverse Event Form") to 
the Sponsor immediately (i.e., within 24 hours). The information will include at least the following 
data: 
• Name, address, and telephone number of the reporting investigator 
• Investigational product(s) 
• Trial code 
• Patient identification number, sex, and date of birth 
• Description of the AE, measures taken and outcome (at the time of reporting) 
• Assessment of causality to the IMP by the investigator 
Reports will be addressed to:  
SCRATCH Pharmacovigilance GmbH & Co. KG 
Schlossstrasse 25, 35510 Butzbach, Germany 
E-mail: 
safety-immunic@scratch-pv.com  
Telephone: +49 6033 74535 50 
Fax: 
+49 6033 74535 59 
The sponsor ensures to keep detailed records of all AEs which are reported to him by the 
investigator or investigators. Reporting of SUSARs to the independent ethics committee (IEC) or 
institutional review board (IRB) and regulatory authorities will follow pertinent national 
legislation. 
The Sponsor will inform as soon as possible and following pertinent national legislation the 
regulatory authorities and the IECs or IRBs about any event that necessitates reconsideration of the 
benefit-risk-ratio of the IMP. These events are in particular: 
• single cases of expected SARs with an unexpected outcome, 
• an increased incidence of expected SARs considered clinically significant, 
• SUSARs occurring after a concerned person has completed the trial, 


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• events related to the conduct of the trial or the development of the tested IMP possibly 
affecting the safety of the concerned persons. 
All additional measures deemed necessary through new findings and taken by the Sponsor or the 
investigator to protect the safety of the persons concerned and their triggering circumstances will 
be reported as soon as possible to the concerned regulatory authorities and the IECs or IRBs, if 
applicable. 
Periodic safety reporting to regulatory authorities and the IECs will follow pertinent national 
legislation. 
In the event of a fatality, the "Trial participant’s insurer" will be informed by the Sponsor’s 
designee within 24 hours of gaining knowledge of the event. In case of other SAEs, the "Trial 
participant’s insurer" will be informed promptly. 
15.1.5 
Follow-up of adverse events 
All SAEs judged to be related to the IMP must be followed by the investigator until the patient has 
recovered, recovered with sequelae, died, or until the investigator determines that the patient’s 
condition is stable, whichever occurs first. All other AEs must be followed by the investigator until 
the conditions mentioned above are met or until the end of the safety follow-up period, whichever 
comes first, and until all AE-related queries for the patient have been resolved. The investigator 
will take all appropriate and necessary therapeutic measures required for resolution of the AE, if 
applicable. All efforts to collect follow-up information must be documented in the source data. 
Follow-up information should be supplied on the respective forms of the eCRF.  
During and following a patient’s participation in this trial, the investigator must ensure that 
adequate medical care is provided to a patient for any AEs related to the trial, including clinically 
significant laboratory values. 
 
15.1.6 
Handling of anticipated clinical events of COVID-19 
Typical COVID-19-related symptoms present at Baseline (examples such as fever, dyspnea, viral 
pneumonia, or hypoxia) and continuing during the trial without clinically unusual worsening* 
are considered anticipated clinical events of the underlying condition and will not be collected as 
AEs. In addition, disease characteristics and severity will be regularly captured within the scope of 
the clinical status assessment. Death, hospitalization, and use of ventilation, ECMO, or dialysis due 
to COVID-19 or its complications (which all are recorded as clinical endpoints for this trial) are not 
considered AEs (see Section 15.1.2) and should not be considered medically significant events by 
itself for the assessment of SAEs. 


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Any clinically unusual worsening* of COVID-19-related disease symptoms present at trial 
inclusion and any clinically relevant changes in clinical laboratory parameters, vital signs or 
other findings during physical examination which are considered unusual for COVID-19 disease 
and where a relationship to drug treatment cannot be excluded should be recorded as AEs. 
* “Unusual worsening” means that, in terms of type or severity of symptoms, time frame or symptom 
fluctuations, the course of the disease progression is different from that in most patients with the same 
general conditions (disease status, age, health status, concurrent diseases). 
15.1.7 
Further safety precautions 
Patients known or suspected to have Gilbert syndrome should be carefully monitored, and any 
clinically relevant increase in bilirubin, in particular indirect bilirubin, in these patients should be 
carefully considered in terms of benefit-risk assessment. 
A daily supplementation of either 2 x 750 mg oral bicarbonate or 2 tablets of Neoralit SR three 
times daily during meals or half an hour after meals is recommended for patients with 
• Known history of nephrolithiasis  
• Underlying condition with a strong association of nephrolithiasis, including hereditary 
hyperoxaluria or hereditary hyperuricemia 
• History or clinical diagnosis of gout 
15.1.8 
Pregnancies 
Should a pregnancy occur in a female patient, or in a female partner of a male patient, it must be 
reported to the Sponsor within 24 hours of the first awareness of the event and be recorded on the 
appropriate pregnancy form. The trial participation of patients who become pregnant during the 
trial after signing the informed consent will be discontinued immediately. 
A pregnancy is not regarded an AE unless there is a suspicion that the IMP may have interfered 
with the effectiveness of a contraceptive method. Whenever possible, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality, maternal and/or new-born complications) must be followed up and documented even 
if the patient was discontinued from the trial. All reports of congenital abnormalities or birth defects 
are SAEs. Spontaneous miscarriages will also be reported and handled as SAEs. Elective abortions 
without complications will not be handled as AEs. 
Pregnancy follow-up will be recorded on the pregnancy form and will include an assessment of the 
possible relationship of the IMP to any pregnancy outcome. 


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15.2 
Safety laboratory investigations 
Clinical safety laboratory tests will be performed at the times indicated in the schedule of 
assessments (Table 3).  
Given that this is an acute treatment situation, existing local or locally obtained laboratory values 
obtained within 48 hours of randomization can be used to assess patient eligibility. However, all 
laboratory samples required in this trial will be sent to the central laboratory. Results will be 
available to the investigator within 1-3 days. The investigator is free to use local laboratory values 
for urgent treatment decisions. Reference ranges must be supplied by the local laboratory and used 
to assess the laboratory data for clinical significance. 
All laboratory samples sent to the central laboratory must be clearly and fully labeled according to 
the central laboratory manual. The laboratory reports received from the central laboratory via email 
or fax will be printed, reviewed, signed, and dated by the investigator, and filed at the center. The 
laboratory results will be additionally imported into the eCRF.  
Abnormal results will be assessed by the investigator and classified as clinically significant 
(yes/no). Clinically significantly abnormal values must be reported as AE, if not already clinically 
significantly abnormal at Baseline (i.e., pre-dose on Day 0) or if there are known circumstances 
unrelated to a disease or the medication (such as patient activities or sample handling) that are a 
likely explanation for the abnormal value. 
Persistent clinically significant abnormal values must be followed up using local laboratory values 
until the cause is determined or until they returned to normal or to the level observed at Baseline 
(for follow-up of clinically significant laboratory values reported as AEs, see Section 15.1.5). 
15.2.1 
Pregnancy tests 
Female patients of childbearing potential, i.e., not postmenopausal (where postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause) or not surgically sterile, 
must have a local negative pregnancy test before the first intake of the IMP. A blood pregnancy 
test is required at Screening. Any local urine pregnancy test must be followed up with a 
confirmatory local blood pregnancy test. 
For follow-up procedures in case of pregnancy see Section 15.1.8. 
15.2.2 
Blood chemistry, hematology, and coagulation 
Blood chemistry, hematology and coagulation assessments will be performed as scheduled in 
Table 3. For more details an assessments, storage and shipment conditions please refer to 
Appendix 1. 


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Abnormal results will be classified as clinically significant (yes/no). Clinically significantly 
abnormal values, which were not clinically significantly abnormal at Screening, must be reported 
as AE. 
Blood samples will be collected, handled and stored according to the instructions provided by the 
central laboratory (or local laboratory if applicable). Coagulation samples will be collected and 
stored at at least -20°C at the site and shipped within 6 weeks to the central laboratory for analysis. 
Dry ice shipments may be delayed for up to 2 weeks if another patient is expected to finish the 
respective visit. 
15.2.3 
Urinalysis 
Urine assessments will be performed as scheduled in Table 3. For more details an assessments, 
storage and shipment conditions please refer to Appendix 1. 
Urinalysis will be done centrally (see Section 6). Abnormal results will be classified as clinically 
significant (yes/no). Clinically significantly abnormal values must be reported as AE, if not already 
clinically significantly abnormal at Screening. 
The handling and collection of urine samples will be detailed in the Laboratory Manual. 
15.2.4 
Screening laboratory 
For screening local laboratory test will be used, these should include:  
• Positive SARS-CoV-2 test (done locally or obtained within 4 days before randomization by 
another laboratory) 
• Negative blood pregnancy test 
• Hematology and blood biochemistry: white blood cell count, platelet count, total bilirubin, 
ALT, and GGT 
15.3 
Vital signs, physical examination, and ECG  
Vital signs, routine physical examinations, and ECG will be performed as scheduled in Table 3. 
Vital signs 
Vital signs will include height and weight (both only at Screening), body temperature (ºC), pulse 
rates, systolic and diastolic blood pressures. Height in centimeters and weight in kilograms will be 
recorded without shoes. 
Blood pressure (systolic and diastolic), and pulse must be measured with the patient in a seated 
position (if possible), after at least 5 minutes at rest. 
Body temperature can be measured axillary, oral, rectal or tympanic, but should always be 
measured by the same method for a patient. 


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Changes in vital signs judged by the investigator as clinically significant will be reported as an AE. 
Physical examination 
Physical examinations will cover the following body systems: general appearance, skin, neck 
(including thyroid), throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, 
neurological systems, and, if applicable, others.  
Any new clinically significant finding compared to Screening must be documented as AE. 
Any clinically significant finding at Screening Visit 1 must be documented in the medical history 
section of the eCRF. 
12-lead electrocardiogram 
The 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) will be recorded in supine position after at 
least 5 minutes at rest (if applicable) using the local standard ECG machine. The ECG will be 
analyzed qualitatively (normal or abnormal, if abnormal clinically significant [yes/no]). The heart 
rate, PQ-, QRS-, and QT-intervals, as well as the heart rate-corrected QTc interval (according to 
Bazett’s formula) will be determined. All procedures will be done according to local practice. Any 
findings from ECGs collected after the IMP administration will be captured as AEs if, in the 
opinion of the investigator, there was a clinically significant change from Screening. 
16 
Biostatistical methods 
16.1 
Sample size calculation 
Part 1 
As no formal hypothesis testing will be conducted in Part 1, no formal sample size calculation is 
deemed necessary. In previous protocol versions, a pooling of p-values of Part 1 and Part 2 was 
planned and a sample size of N = 200 enrolled patients (100 per group) was calculated. It is 
assumed that with the previously planned sample size a robust estimation of all efficacy and safety 
parameters can be conducted. Thus, no adaptations in sample size for Part 1 are necessary. 
Previously, the following assumptions were made:  
3-stage group sequential adaptive test design with O’Brien and Fleming shaped boundaries 
Information rate for Part 1 analysis: 0.2 
O’Brien and Fleming alpha level for end of Phase 2 analysis: <0.0001  
Primary endpoint: Proportion of patients without any need for invasive ventilation 
Randomization ratio: 
 
 
1:1 (45 mg/day IMU-838:placebo) 
Power:  
 
 
80% 
Global significance level:  
 
 
0.05, 1-sided 


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Proportions of patients with need for INV  
for 45 mg/day IMU-838: 
 
 
32% 
for placebo: 
 
 
 
40% 
Number of patients (Part 1): 
 
 
188 
Considering a 6% drop-out rate, a total of 200 patients (100 per group) were to be enrolled. 
Part 2 
If the trial is expanded to Part 2, the sample size of Part 2 will be determined based on the results 
of MA1. 
The Part 2 (Phase 3, Expansion Phase) trial will be designed to keep a global 1-sided alpha level 
of 0.025 (one-sided). A 2-stage group sequential test adaptive design with O’Brien and Fleming 
shaped boundaries will be used. Stage 1 will be IA2 applying an overall information rate of 50% 
and using an alpha of 0.0026. The use of group sequential boundaries within the context of an 
adaptive design is enabled using the inverse normal method, combining the p-values of both stages 
with weights based on the sample sizes. Statistical analysis methods that control for the Type I 
error will be used. 
16.2 
Analysis sets and types of analyses 
Safety analysis set 
The safety analysis set (SAF) will consist of all randomized patients who received at least one dose 
of IMP, i.e., any dose of IMU-838 or placebo. If it is uncertain if the patient has received any IMP, 
the patient will be included in the SAF. The analyses based on the SAF will be conducted on an 
“as treated” basis, i.e., all patients will be analyzed by the treatment they received. 
Full analysis set 
The full analysis set (FAS) will consist of all randomized patients who received at least one dose 
of IMP, i.e., any dose of IMU-838 or placebo. The analyses based on the FAS will be conducted 
on an intention-to-treat procedure, i.e., all patients will be analyzed by the groups to which they 
were randomized to. 
Per-protocol set 
All patients of the FAS will also be included in a per-protocol (PP) set if they did not violate any 
major protocol criteria. Protocol deviations will be identified and classified for each patient during 
a blind data review. 
Assignment of analysis sets to analyses and allocation of patients 
All efficacy analyses will be based on the FAS. The primary and the key secondary efficacy 
endpoints only will be additionally analyzed for the PP set. The analysis of the primary and the key 


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secondary efficacy endpoints using the FAS will be considered the primary analysis. All other 
analyses will be exploratory. Safety analyses will be based on the SAF. 
The allocation of patients to the analysis sets for the final analysis will be done during a blind data 
review meeting.  
16.3 
Statistical analyses 
16.3.1 
General approaches 
For qualitative variables, the frequencies (absolute and relative) will be calculated. Quantitative 
parameters will be described by declaring the mean value, standard deviation, minimum, first 
quartile, median, third quartile, and maximum. The treatment groups will be separately tabulated. 
A detailed description of the statistical analyses for all scheduled analyses (i.e., early safety 
analysis, MA1 and FA1, and interim and FA2) will be provided in a statistical analysis plan and 
will be finalized before the respective data (e.g. MA1/FA1, IA2, FA2) will be analyzed. 
In Part 1, all endpoints will be analyzed descriptively. In addition, exploratory confidence intervals 
will be calculated for the primary and key secondary endpoints (and for other endpoints as 
appropriate) using an alpha of 0.1 (2-sided). No formal statistical tests will be conducted. 
The Part 2 (Phase 3 Expansion Phase) trial will be designed to keep a global 1-sided alpha level of 
0.025 (1-sided). A 2-stage group sequential test adaptive design with O’Brien and Fleming shaped 
boundaries will be used. Stage 1 will be the IA applying an overall information rate of 50% and 
using an alpha of 0.0026. The use of group sequential boundaries within the context of an adaptive 
design is enabled using the inverse normal method, combining the p-values of both stages with 
weights based on the sample sizes. Statistical analysis methods that control for the Type I error will 
be used. 
In Part 2, the primary and key secondary endpoints will be tested confirmatory. Results of other 
endpoints will be considered exploratory, even when statistical tests are performed.  
Confirmatory hypothesis testing of key secondary endpoints will be done only after the test of the 
primary efficacy endpoint was significant. Testing will be done strictly hierarchically in the given 
order to ensure the family wise error rate. Confirmatory hypothesis testing in the pre-defined order 
will stop once the first non-significant test result is obtained.  
The FAS (all randomized patients who received at least one dose of IMP; as randomized) will be 
the primary analysis population. The PP analysis set and the set of only surviving patients until 
EoS will be applied as secondary/sensitivity analysis for the primary and key secondary endpoints, 
if applicable. 


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16.3.2 
Primary and key secondary efficacy endpoint analyses 
In the following the analyses for the primary and key-secondary endpoints are described for Part 1. 
Since Part 1 and Part 2 will be independent parts, these endpoints may be changed for Part 2 after 
the MA1 analysis. More details and/or changes for evaluation in Part 2 will be specified in a 
protocol amendment and respective SAP when MA1 results are available. 
Primary endpoint 
The primary endpoint of the trial i.e., the proportion of patients without any need for INV until 
EoS. The “need for INV” (considered positive for the primary endpoint) will include patients:  
1. placed on any INV method during the trial 
2. who had an active “do not intubate” or “do not resuscitate” order established during the trial 
conduct or refused intubation for any reason but were assessed by the investigator to have a 
medical need for INV 
3. who had a medical need for INV as assessed by the investigator but for reasons of medical 
resource exhaustion or due to triage decisions by the hospital had not received INV, or  
4. who died mainly due to respiratory failure but had a need for INV as assessed by the 
investigator or before such needed INV could have been started  
Patients who are lost to follow-up or discontinue the trial on or before Day 13 (last treatment day) 
due to any reason other than death and discontinue with a last observed WHO clinical status no 
lower than that at Screening, and patients who die and do not fall under Number 4 of the above-
mentioned criteria will be considered treatment failures for the primary endpoint. A sensitivity 
analysis will be performed for patients who discontinued before EoS, using the available 
information on INV. 
Invasive ventilation involves any instrument penetrating via the mouth (e.g., endotracheal tube), 
nose, or the skin (e.g., tracheostomy tube through a stoma) to serve as an artificial airway, and the 
manual or mechanical ventilation of the patient through such artificial airway. 
For clarification, bilevel positive airway pressure (trademarked as BiPAP™ or VPAP™ by 
different manufacturers) and continuous positive airway pressure are not considered INV as they 
do not involve intubation. However, for classification of patient clinical status these methods are 
considered non-invasive ventilation (WHO Status 5, Table 4). 
In Part 1, the primary endpoint will be displayed with frequency tables per stratification factor age 
(< or ≥65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and Chloroquine, all 
other antivirals) and overall. In addition, an odds ratio (OR) with an exact 2-sided 90% confidence 
interval will be conducted. The OR will be calculated adjusted for the stratification factors age 
(< or ≥65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and Chloroquine, all 
other antivirals).  


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Key secondary endpoints 
Proportion of patients surviving without respiratory failure 
Respiratory failure will be defined as the need of ICU, INV, high-flow oxygen or ECMO. Patients 
who are lost to follow-up or discontinue the trial on or before Day 13 (last treatment day) due to 
any reason other than death, and patients who discontinue with a last observed WHO clinical status 
no lower than that at Screening are considered respiratory failures. A sensitivity analysis will be 
performed for patients who discontinued before EoS, using the available information. Statistical 
analysis will follow the analysis of the primary endpoint. 
Duration of ICU treatment until Day 28  
The duration of ICU treatment until Day 28 will be analyzed in decimal days.  
For patients who were transferred to ICU, the duration of ICU treatment will be calculated as [Time 
of discharge from ICU (date:hh:mm) - time of admission to ICU (date:hh:mm) + 1] / 1440. For 
patients who were discharged from ICU but readmitted the time from first admission until last 
discharge will be used. The time from investigator’s decision to admit a patient to ICU until a 
patient is admitted will not be considered. 
If the investigator decides that there is the medical need to admit a patient to the ICU but the patient 
is not admitted due to patient refusal, unavailability of ICU or due to rationing or triage decisions, 
the start time of ICU hospitalization will use the investigator’s decision. The end of ICU duration 
will be imputed as Day 28 or, if ICU hospitalization occurs at a later study period, until end of 
actual ICU hospitalization. 
The following imputation of concurrent events in the preferred analysis of ICU duration, creating 
the most conservative assessment approach will be performed: a) for all death cases that have no 
recorded or known ICU hospitalization in this trial, start date will be imputed as date/time of death, 
end date will be imputed as Day 28 b) if ICU treatment is known and started before the date of  
death, start date will be the actual ICU submission, end date will be imputed as Day 28. 
For patients who are lost to follow-up or discontinue the trial on or before Day 13 (last treatment 
day) due to any reason other than death and patients who discontinue with a last observed WHO 
clinical status no lower than that at Screening, the following approach will be performed: a) for 
cases that have no recorded or known ICU hospitalization in this trial, start date will be imputed as 
date/time of discontinuation, end date will be imputed as Day 28 b) if ICU treatment is known and 
started before the date of study discontinuation, start date will be imputed as actual ICU 
submission, end date will be imputed as Day 28. 
As sensitivity analyses, ICU duration imputation on available data will be done as follows:  
• for patients who died, the study period of 28 days will be recorded as ICU treatment duration,  
• for patients who discontinued the study prematurely or for patients who died before EoS, the 
available information on ICU treatment duration until day of discontinuation will be used. 


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In Part 1, the ICU duration will be displayed with basic statistics per stratification factor age (< or 
≥65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and Chloroquine, all other 
antivirals) and overall. In addition, an exact 2-sided 90% confidence interval for the median of 
differences between treatment groups (location shift) will be conducted adjusted for the 
stratification factors age and antiviral therapy.  
28-day all-cause mortality 
28-day all-cause mortality will be derived as percentage of patients who died due to any cause from 
time of 1st IMP administration until EoS. In Part 1, 28-day all-cause mortality will be displayed 
with frequency tables per stratification factor age (< or ≥65 years) and antiviral therapy (no 
antivirals, Hydroxychloroquine and Chloroquine, all other antivirals) and overall. In addition, an 
OR with exact 2-sided 90% confidence interval will be conducted. The OR will be calculated 
adjusted for the stratification factors.  
Patients who discontinued the trial before Day 28 due to any other reason than death will be 
considered as deaths, unless survival status can be obtained by the investigator through other means 
(see Section 12.4).  
In a sensitivity analysis, patients who discontinued before EoS due to reasons other than death, will 
be considered as survived, unless the investigator has any information of patient death after 
discontinuation. 
In Part 2, the primary endpoint (as selected during MA1) and the key secondary endpoints that 
include proportion of patients (e.g. patients without respiratory failure, 28-day all-cause mortality) 
will be evaluated for superiority of IMU-838 vs placebo with an exact Cochran-Mantel-Haenszel 
test, adjusted for the stratification factors age and antiviral therapy. In addition, logistic regression 
analyses will be conducted including the covariates age, antiviral therapy, sex, and country. The 
distribution of primary endpoint or any key secondary endpoint containing duration measurements 
(e.g. duration of ICU treatment) will be analyzed with the van Elteren test (stratified by age and 
antiviral therapy). In addition, time-to-event analyses using Kaplan Meier methodology and a 
stratified log rank test (stratification factors age and antiviral therapy) will also be performed. All 
tests will be performed 1-sided keeping a global alpha level of 0.025 (1-sided). 
16.4 
Part 1 to Part 2 transition procedures  
16.4.1 
General approach 
The MA1 (unblinded) will be performed after approximately 200 patients have completed Day 28, 
either as scheduled or prematurely, while enrollment continues.  
Based on the MA1 results the trial may be expanded into Part 2, if activity of IMU-838 is observed, 
or stopped, if no activity of IMU-838 is observed. A further 30 patients are expected to be enrolled 


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and treated in a double-blind manner until the results of the MA1 are available (when no activity 
of IMU-838 was found) or until the enrollment in Part 2 has commenced (if MA1 indicated proof-
of-activity). Criteria to assess activity of IMU-838 that will guide the decisions to expand the trial 
are based on efficacy, virology and biomarker endpoints and are defined in Section 16.4.2 below. 
The IDMC will also review MA1 results and act as a consultative capacity to assist the Sponsor in 
decision making, sample size calculations, endpoint selection and other adjustments for Part 2. 
A final analysis of Part 1 (FA1) will be performed after completion of Part 1, pooling all enrolled 
patients, i.e. about 230 patients for any outcome evaluated in the MA1. 
The sample size of Part 2 will be estimated based on the MA1 results. Possible other adjustments 
(e.g., modifications to endpoints, concomitant medications and to SoC, inclusion of children, and 
other adjustments) will be considered and discussed between the Sponsor and the IDMC. Part 2 
will use an adaptive sequential trial design. An unblinded IA will be performed by the IDMC after 
approximately 50% of patients have been enrolled (based on the Part 2 sample size) to re-assess 
sample size based on available safety and efficacy data. The Part 2 of the trial will be designed to 
keep a global 1-sided alpha level of 0.025. A 2-stage group sequential test adaptive design with 
O’Brien and Fleming shaped boundaries will be used. The IA during Part 2 is assumed a Stage 1 
analysis applying an overall information rate of 50% and using an alpha of 0.0026. 
The use of group sequential boundaries within the context of an adaptive design is enabled by using 
the inverse normal method, combining the p-values of both stages with weights based on the sample 
sizes.  
16.4.2 
“Activity” criteria and further issues to be considered 
The activity of IMU-838 will be evaluated based on the following endpoints: 
• Proportion of patients without any need for INV until EoS (primary endpoint) 
• Proportion of patients surviving without respiratory failure (defined as any need of ICU, INV, 
high-flow oxygen or extracorporeal membrane oxygenation [ECMO] until EoS, key 
secondary) 
• Duration of intensive care unit (ICU) treatment until EoS (key secondary) 
• 28-day all-cause mortality (key secondary) 
• Rate of ICU admission until Day 28  
• Duration of INV  
• Proportion of patients with improvement of at least 2 points (from randomization) on the 9-
category WHO ordinal scale 
• Time to first prescription of INV 
• Duration of hospitalization 


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• Time to ICU admission 
• Time from IMP treatment initiation to death 
• Analysis of virologic data: 
o Time to conversion to a negative SARS-CoV-2 (qualitative) test 
o Decrease of SARS-CoV-1 viral load 
o Time course of SARS-CoV-1 viral load  
• Analysis of biomarkers: relative change from Baseline in interleukin (IL)-17, IL 1ß, IL-6, 
interferon gamma, and tumor necrosis factor alpha 
IMU 838 will be considered active when one of the following applies:  
• A moderate, descriptive effect on the primary endpoint: observed treatment effect is close to 
or higher than the assumed 20% relative difference between IMU-838 and placebo (e.g., 40% 
for IMU-838 and 32% for placebo group) 
• A mild, descriptive effect on the primary endpoint and a moderate effect in at least one of the 
key secondary endpoints, defined as follows:  
o Mild effect in primary endpoint: at least a 10% relative difference between IMU-838 and 
placebo in favor of IMU-838 (e.g. 40% for IMU-838 group and 36% for placebo), AND 
o Moderate effects in at least one of the key secondary endpoints, defined as. 
− a 10% relative difference in the proportion of surviving patients without respiratory 
failure in favor of IMU-838,  
− the duration of ICU treatment until EoS is at least about 1.5 days shorter with IMU-838 
(median values) than placebo,  
− the proportion of patients who died is at least 8% (relative difference) lower with 
IMU-838 than placebo 
• A mild, descriptive effect on the primary endpoint as well as a moderate effect in at least 
three secondary endpoints plus one virologic endpoint as listed above: observed treatment 
effect is at least a 5% relative difference between IMU-838 and placebo for the primary 
endpoint. In addition, moderate effects within the secondary endpoints are observed and in 
addition at least one of the virologic endpoints should show a recognizable beneficial effect 
of IMU 838 
In all 3 scenarios, the assessed clinical endpoints, virologic data, and/or biomarker must show an 
overall general pattern that is consistent with IMU-838 having clinical activity in COVID-19 
patients. 


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A robust trend of IMU-838 activity versus placebo must be observed. If none of the above criteria 
is met without any robust trend on efficacy endpoints of IMU-838 versus placebo, Part 2 will not 
be initiated, and enrollment of Part 1 will be stopped.  
If clinical activity of IMU-838 is confirmed, the following will additionally be evaluated 
• Re-evaluation of the primary and key secondary endpoints 
• The sample size for Part 2 based on the MA1 
o Assumptions:  
− 
2-stage group sequential test design with O’Brien and Fleming shaped boundaries 
− 
Information rate for IA2: 0.50 
− 
O’Brien and Fleming alpha level for IA2: 0.0026  
− 
Primary endpoint: Proportion of patients without any need for INV (if not changed 
after MA1) 
− 
Randomization ratio: 1:1 (45 mg/day IMU-838:placebo) 
− 
Power: 80% 
− 
Global significance level: 0.025, 1-sided 
− 
Proportions in primary endpoint as observed during MA1A drop-out rate as observed 
during MA1 will be considered 
• Re-evaluation of inclusion and exclusion criteria 
• Inclusion of children and adolescents 12 years or older 
• Modifications on dose and/or treatment duration  
• Modifications on allowed or prohibited concomitant medications and medications to be 
considered for standard of care  
• Safety review 
o Any safety signal which require a change in trial conduct  
o Are additional safety analyses before the next IDMC meeting required? 
• Are any other adjustments to the trial conduct (not previously covered) needed? 
• Re-evaluation of the number of patients per country and center  
If activity and safety of IMU-838 is confirmed, enrollment will be stopped, when Part 2 is initiated, 
and FA1 will be performed.  


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17 
Patient stopping rules and other reasons for patient withdrawal 
from trial participation 
17.1 
Patient stopping rules 
Any SAE of Grade 3 or 4, when in the investigator’s opinion the benefits do not outweigh the risk 
for continuing in the trial. 
17.2 
Other reasons for patient withdrawal from trial participation 
Participation in the trial is voluntary and patients may withdraw from the trial at any time and for 
any reason. However, all patients will be encouraged to complete the trial and have EoS assessment 
performed (Day 28) (also refer to Section 12).  
Patients must be withdrawn from the trial for any of the following reasons:  
• Patient withdraws consent due to 
o 
AE(s) 
o 
COVID-19 related clinical events  
o 
other reason (to be specified)  
for all patient withdrawals it should be recorded whether the patient agrees to all non-
interventional follow-up procedures 
• Investigator decision due to  
o 
AE(s), which in the opinion of the investigator may jeopardize the patient’s health or 
may compromise the trial objectives 
o 
relevant non-compliance with the protocol, which in the opinion of the investigator 
may jeopardize the trial integrity or scientific goals of the trial 
o 
reasons other than AE or non-compliance (to be specified) 
• Lost to follow-up (including transfer of patient to a different medical institution inaccessible 
to the investigator) 
• Death 
o 
Primarily related to COVID-19 and its complications 
o 
Not primarily related to COVID-19 and its complications 
• Pregnancy 
• Treatment with prohibited concomitant medication (see Section 11.2, Prohibited and 
restricted medication) 
• Violation of inclusion or exclusion criteria noted only after randomization 


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• The trial is terminated by the Sponsor 
The primary reason for discontinuation from the trial is to be recorded in the source documents and 
on the early termination page of the eCRF. 
If the patient withdraws consent, no further evaluations should be performed and no attempts 
should be made to collect additional data. However, the patient may allow to continue non-
interventional follow-up procedures. 
Patients who prematurely discontinue the trial will be treated according to the investigator’s 
discretion and standard treatment guidelines, irrespective of the reason for withdrawal, and will not 
be replaced. 
Reasonable efforts will be made to contact any patient lost to follow up, to complete assessments 
(including an EoS assessment) and to retrieve any outstanding data and IMP and supplies. 
If the IMP will be prematurely discontinued, the primary reason for discontinuation is to be 
recorded in the appropriate section of the eCRF. Patients who discontinue therapy with IMP will 
be encouraged to continue with trial-related assessments (including EoS visit) until their trial 
completion. 
18 
Independent Data Monitoring Committee  
An IDMC will be established including at least 3 members: an independent clinical virologist (or 
clinical infectious disease expert), an independent statistician, and an independent 
pharmacovigilance expert. The independent virologist will serve as Chair. However, additional 
independent experts may be added, as needed. 
The IDMC will have access to efficacy and safety data and information regarding the quality of 
the data as outlined in the IDMC Charter. 
The IDMC will have at least 4 planned formal meetings 
• Inaugural meeting (at the start of the trial to discuss function and roles) 
• Meeting for the early safety analysis 
• Meeting for MA1 
• Meeting for IA2, if applicable 
More details on their responsibilities are outlined in Section 8.1. 
If at the IA2 the IMU-838 therapy arm proves to be statistically significantly more beneficial, the 
patient enrollment will be stopped. 
The IDMC may hold ad hoc teleconference meetings to discuss safety or trial conduct information 
as needed, or when new safety signals are observed in this trial or in other trials of IMU-838.  


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Further details on responsibilities and the working procedures of the IDMC will be specified in an 
IDMC charter. 
19 
Ethical and legal requirements 
19.1 
Ethical conduct of the trial 
The trial will be conducted in a manner consistent with all applicable regulatory authority and 
IRB/IEC regulations (e.g., International Council for Harmonisation [ICH] Guideline for Good 
Clinical Practice [GCP, CPMP/ICH/135/95], the Declaration of Helsinki [in its currently 
acknowledged version], for centers in the USA: IRBs [21 CFR 56], and Obligations of Clinical 
Investigators [21 Code of Federal regulations [CFR] 312]) as well as in keeping with applicable 
local law(s) and regulation(s). The investigator must also comply with all applicable privacy 
regulations (e.g., USA: Health Insurance Portability and Accountability Act of 1996 [HIPAA]; 
European Union: General Data Protection Regulation [25]). 
Financial disclosure by the investigator(s) pursuant to 21 CFR Part 54 will be obtained. 
19.2 
Independent ethics committee or institutional review board 
Before the initiation of the clinical trial, the final protocol, any amendments if applicable, the 
patient information sheet and consent form, as well as any additional documents which are required 
by national regulations and the IEC or IRB will be submitted to the competent IEC or IRB for 
review. A favorable opinion for the clinical trial must be obtained from the IEC or IRB before any 
patient is enrolled at a center. 
If appropriate, any additional requirements imposed by the IEC or IRB will be followed. 
Amendments to the trial documents will be notified to, or approved by, the IEC or IRB before 
implementation, if applicable. 
19.3 
Patient information and consent procedure 
Before any clinical trial-related activities are performed, the investigator (or authorized designee) 
must review the informed consent form and explain the trial to potential trial participants. The 
investigator must ensure that the patient is fully informed about the aims, procedures, potential 
risks, any discomforts, and expected benefits of the clinical trial. Before consenting, the patient 
must be left with ample time to consider and ask questions. It must be emphasized that participation 
is voluntary and that the patient has the right to withdraw from the clinical trial at any time without 
prejudice. The patient and the investigator must then sign and date the consent form before the 
conduct of any trial procedures.  


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A copy of the patient information and informed consent form will be given to the patients for their 
records. The rights and welfare of the patients will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
clinical trial. 
If amendments to the final trial protocol affect the patient’s participation in the clinical trial (e.g., 
a change in any procedure), the patient information and informed consent form must be updated to 
incorporate this modification, and patients must agree to sign the amended form indicating that 
they re-consent to participate in the clinical trial. 
For sites in the United States of America: The investigator will comply with all applicable state 
and federal requirements, including the requirement of the HIPAA Privacy Rule. The authorization 
to use and disclose protected health information for research is part of the informed consent form, 
and a signed copy of the informed consent form must be placed in the trial record. Patients from 
whom additional blood samples will be collected to immune cell subtyping for further research 
studies will have to provide their consent to that optional additional procedure in the ICF. 
19.4 
Insurance coverage 
Insurance coverage for damages emerging from the clinical trial will be provided according to 
applicable legal requirements. During the informed consent procedure, the investigator must 
inform the patient accordingly. Insurance details will be provided to the patient within the patient 
information sheet. 
19.5 
Submission to authorities 
Documents required for the trial application will be submitted to the responsible competent 
authority (CA). The trial will not start until this authority has authorized the trial. Amendments to 
the trial protocol or to any other documents that must be reviewed by the CA will also be submitted 
to the CA in accordance with the regulatory requirements. If applicable, approval of the amendment 
must be awaited before implementing any changes. 
19.6 
Patient confidentiality 
The trial protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the clinical trial, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
Personal patient data will be kept confidential in compliance with the General Data Protection 
Regulation [25], the HIPAA Privacy Rule, and other applicable international and national 
requirements.  
The investigator must ensure that the confidentiality and anonymity of trial participants will be 
maintained and that their identities are protected from unauthorized parties. In eCRFs, 


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compensation documentation, or any other documents submitted to the Sponsor or Sponsor’s 
designee, patients must be identified only by their identification codes; it is not allowed to use their 
names, addresses, telephone numbers, or similar information. The investigator will keep the 
original of the Patient Identification Log (including complete name and date of birth of each 
patient) in his/her file. The investigator must maintain these documents in strict confidence. 
To allow compliance with GCP, all patients will be asked for consent regarding the access to their 
personal clinical trial-related data for monitoring, audits, and inspections as well as regarding 
transmission and storage of their pseudonymous data; a respective statement will be part of the 
informed consent form. Professionals getting access to source data for monitoring, audits and 
inspections are bound to preserve strict confidentiality. 
20 
Criteria for premature termination of the trial and criteria for 
initializing and closing a trial center 
20.1 
Trial safety stopping criteria 
The trial will be stopped during the early and potential additional safety analyses when the 
following stopping criteria are fulfilled: 
• ≥10% of patients experience at least one SAE Grade 3, or 
• ≥5% of patients experience at least one SAE Grade 4 
As outlined in Section 15.1.1.3, any SAE requires an underlying event that is considered an AE. 
Please consider the definitions in Section 15.1.6 when potentially COVID-19 related clinical events 
are considered an AE.  
20.2 
Other criteria for halting or terminating the trial 
The Sponsor reserves the right to halt or terminate the trial at any time. Reasons for termination 
include but are not limited to: 
• Potential health risk for the patients 
• High withdrawal rate 
• New scientific knowledge becomes available that makes the objectives of the trial no longer 
feasible or valid 
• Insufficient enrollment of patients 
• The IDMC requests termination of the clinical trial based on review of all clinical and 
laboratory data 
• The Sponsor, Regulatory Agency or an IEC or IRB requests the termination of the clinical 
trial 


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20.3 
Criteria for closing a trial center 
A trial center may be closed for the following reasons: 
• The center is unable to recruit sufficient patients within the agreed time frame 
• The center does not respond to trial management requests 
• Multiple significant protocol deviations or substantial non-compliance 
• The approval of the IEC or IRB in charge of the clinical trial is permanently revoked 
• Additional local criteria might be established by written agreements between the Sponsor 
and the trial center 
The Sponsor will notify the relevant CA, IEC(s), IRB(s) and investigator(s) in writing about the 
termination of individual centers or the entire trial. 
The investigator may terminate his/her participation prematurely. If the investigator decides to 
terminate his/her participation before the trial is completed, he/she will notify the Sponsor in 
writing stating the reasons for the early termination. In terminating the trial, the Sponsor and the 
investigator will ensure that adequate consideration is given to the protection of the patients’ 
interests.  
The investigator will notify the relevant CAs, IEC(s), or IRB(s) in writing, if required, submit a 
copy of that notification to the Sponsor and return all IMPs and all related trial material, as 
applicable, to the Sponsor. Concerned eCRFs will be archived at the site. Authorization to access 
and edit the eCRF will be removed from the investigator and all authorized delegates. 
21 
Trial protocol, documentation and archiving of data 
21.1 
Amendments to the protocol 
Any change to the protocol concerning the purpose of the trial, the trial design, or the patient’s 
eligibility can only be made in the form of a written amendment to the trial protocol. Such 
amendments must be discussed and signed by the Sponsor and the investigator before 
implementation.  
Substantial amendments, i.e., amendments likely affecting to a significant degree 
• the safety or physical or mental integrity of the patients of the trial 
• the scientific value of the trial 
• the conduct or management of the trial, or 
• the quality or safety of any IMP used in the trial 


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will be submitted to the CA and IEC or IRB for approval and favorable opinion as required by 
applicable regulations. If such amendments affect the patient’s participation in the clinical trial 
(e.g., a change in any procedure), the patient information and informed consent form must be 
updated to incorporate this modification, and patients enrolled at the time of implementation of the 
amendment must re-consent to their participation in the clinical trial. 
Non-substantial changes, e.g., minor corrections of administrative nature and/or rephrasing, which 
do not meet the above criteria for being substantial, are considered editorial changes. The IEC or 
IRB and CA do not need to be notified of such minor corrections. Non-substantial amendments 
will be signed by the Sponsor only. 
If new events occur related to the conduct of the trial or the development of the tested IMP that 
may affect the safety of the patients, the Sponsor and the investigator will take appropriate safety 
measures to protect the patients against any immediate hazard. The Sponsor will immediately 
inform the CA and IEC or IRB of the new events and the measures taken. 
21.2 
Protocol deviations 
A protocol deviation is a failure to follow, intentionally or unintentionally, the requirements of the 
protocol. As required by national regulation or guidelines, reports of deviations will be provided 
to the IEC or IRB. 
In emergency circumstances, deviations from the protocol may proceed without prior consultation 
with the Sponsor and favorable opinion of the IEC or IRB, if the rights, safety and well-being of 
the patients need to be protected. Such deviations will be documented and reported to the Sponsor 
and the IEC or IRB as soon as possible in accordance with national regulations. 
All protocol deviations will be listed. If concerned patients are evaluable for data analysis will be 
discussed in a data review meeting prior to statistical analyses. 
21.3 
Data retention 
The trial center and the Sponsor or Sponsor’s designee(s) will maintain all trial records according 
to ICH GCP and applicable regulatory requirement(s). Records will be retained until at least 2 years 
after the last approval of a marketing application in an ICH region, until there are no pending or 
contemplated marketing applications in an ICH region, until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the tested IMP, and at least 15 years after the 
end of the trial, whichever period is longer. The final report will be kept for another 5 years after 
the tested IMP was taken off the market according to legal stipulations. The documents will be 
archived for a longer period, if required by the applicable regulatory authorities or if agreed with 
the Sponsor. It is the responsibility of the Sponsor to inform the investigators when these 
documents need not to be retained any longer. 


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The medical files of trial patients must be retained in accordance with local legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
22 
Data collection, monitoring and quality assurance 
22.1 
Data collection 
All data will be collected on an eCRF separately for each patient. eCRFs will be provided as a 
regulatory compliant, electronically secure and protected web-based database, and will be handled 
in accordance with the instructions provided. An audit trail will record all entries and corresponding 
changes. 
All entered data will go through programmed edit checks (see Section 22.5). 
The trial sites will be provided with secure access to and training on the eCRF.  
All data generated after the patient provided informed consent must be recorded in the eCRF. The 
investigator is responsible for ensuring accurate and proper completion of the eCRF. 
Only investigators and authorized designees will enter and edit data via a secure network and a 
secure access system. Completed data for each visit will be approved by the investigator or 
authorized designee using an electronic signature to confirm the accuracy of the data. Any change 
or addition will be recorded by an electronic audit trail system. 
The investigator or designee must carefully answer queries issued by data management. 
22.2 
Source data 
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial that are necessary for the 
reconstruction and evaluation of the trial (see ICH GCP E6 R2, 1.51). Source records should be 
stored for a time period as defined by local regulations. 
The investigator must keep a patient file (medical file, original medical records) on paper or 
electronically for every patient included in the trial.  
It must be possible to identify each patient by using this patient file. Dates and authors of all source 
data entry and changes must be clearly identifiable. 
Documents and data to be considered source data will be identified and agreed with the investigator 
in advance of the first visit. The location of all source data will be documented and filed in the 
Investigator Site File (source data location form or equivalent). 


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Electronic patient files will be printed whenever the monitor performs source data verification, if 
applicable. Printouts must be signed and dated by the investigator and filled at the center as required 
for other source data documents.  
22.3 
Monitoring 
Critical data will be identified to ensure patients’ safety and the reliability of trial results. The extent 
and details of monitoring including source data verification will be specified in the monitoring 
plan. All critical data require source verification by the monitor.  
The trial center must not enroll any patient before the initiation was performed and final eligibility 
of the center is confirmed by the monitor and Sponsor. Depending on the pandemic situation of the 
centers site qualification and site initiation visits might be performed in a remote setting. During 
the trial, regular monitoring visits will be performed according to ICH GCP, the Sponsor’s 
designee’s or local CRO’s standard operating procedures, and local regulations. The frequency and 
kind of monitoring visits will depend amongst other factors on the trial site’s recruitment rate and 
current pandemic situation in each country and trial center.  
Risk-based monitoring including reduced source data verification, triggered monitoring, 
centralized monitoring, and targeted monitoring will be conducted [26-29]. The extent and details 
of this monitoring methods will be defined in the monitoring plan. 
Due to the current COVID-19 pandemic situation, physical monitoring visits at the centers may 
not be feasible or restricted for some time, and either a combined remote and on-site monitoring or 
full remote monitoring visit will be conducted during these periods. The Sponsor authorizes the 
designated local CROs to include remote monitoring visits according to the applicable guidelines 
and regulations into the monitoring activities. In line with local laws and regulations remote source 
data verification might be part of the remote monitoring visits and if so, has to be agreed between the 
Sponsor designee, the investigator and additional investigational staff at each center. The relevant trial 
documents (e.g., monitoring plan) will be adjusted to reflect these activities that will be held during the 
period when standard monitoring visits are not possible.  
Options for remote monitoring - in compliance with the local, country specific regulations, 
requirements and relevant guidelines - might be phone calls, audio/videoconferencing, and sharing 
of medical records (e.g., direct access to Electronic Health Records [30, 31] sharing 
redacted/blinded medical records in a secured way, etc.), depending on the center’s capability to 
contribute. 
The ICH-GCP requirements and applicable data protection and privacy regulations must be met in any 
case and for any selected monitoring approach. As part of the informed consent form, the patients need 
to agree to a remote monitoring of data. 


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The investigators must permit the monitor access to the patient’s medical records and all other 
applicable source documents. Throughout the trial, all data captured in the eCRF will only be 
identified by patient number. The data will be pseudonymized correspondingly in all data analyses. 
It is the investigators’ obligation to assure documentation of all relevant data in the patient’s file, 
such as medical history and concomitant diseases, date of trial enrolment, visit dates, results of 
examinations, administrations of IMP and any concomitant medication, and AEs. 
22.4 
Audits and inspections 
During the trial, audits may be performed by independent auditors. Audits of clinical research 
activities will be performed in accordance with corresponding standard operating procedures to 
ensure compliance with the principles of GCP. 
Regulatory authorities may wish to conduct an inspection. If an inspection is requested, the 
investigator must inform the Sponsor or Sponsor’s designee immediately. 
The investigator must allow auditors or inspectors access to source data and documents and will 
answer any questions. 
Depending on the COVID-19 pandemic situation of the centers with regards to center accessibility, 
remote audits might be considered in line with local laws and regulations and without adding 
additional burden to center staff. 
22.5 
Data management procedures 
All data management activities will be conducted by the Sponsor’s designee following their 
standard operating procedures. 
Details on data handling will be described in the data management plan. Data entered into the eCRF 
will be validated through online edit checks and offline checks run by the data manager or designee 
according to the data validation plan. For all identified discrepancies, the data manager will raise a 
query in the electronic data capture application. The appropriate investigational personnel will 
answer the queries in the eCRF, which will be audit trailed by the electronic data capture 
application. 
The Sponsor’s designee will handle the data cleaning process, query process, and coding. 
For the MA1, FA1, and FA2, the respective database will be locked when it is considered complete 
and accurate and after all changes following the data review meeting (if applicable) are included 
(i.e., all data cleaning activities performed). All changes will be tracked (audit trail). Sponsor 
approval prior to database lock is mandatory.  


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22.6 
Trial report and publications 
The results of Part 1 (MA1 and FA1) and Part 2 (FA2) of the trial will be each summarized in a 
clinical trial report according to the ICH E3 Note for guidance on structure and content of clinical 
trial reports. 
The main conclusions of the early safety analysis, MA1 and IA2 will be submitted to investigators 
as well as to regulatory authorities and IECs, as appropriate, within the timeframes defined per 
national regulation or by the IEC or IRB.  
The preparation and submission of abstracts of manuscripts including the trial results must be in 
line with the process specified in the investigator’s clinical trial agreement and shall be organized 
by the Coordinating Investigator. The publication or presentation of any trial results shall comply 
with all applicable privacy laws, for example, the USA’s HIPAA and he European Union’s General 
Data Protection Regulation [25]. 
23 
Trial periods 
Part 1: 
Phase 2 (Proof-of-Activity Phase, Part 1): 
Estimated start (first patient in): 
May 2020 (actual 12-Jun-2020) 
Estimated recruitment period: 
4 months 
Estimated end of trial (last patient out): 
Nov 2020 
Optional Phase 3 (Part 2): 
To be defined after MA1, if applicable 
 
The end of the trial is defined as last patient last visit in the entire trial. 
 


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24 
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22. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in 
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9/8/2020
Neera Ahuja, MD


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Principal investigator agreement page for the protocol 
I agree: 
o To assume responsibility for the proper conduct of the clinical trial at this site, and to 
conduct the trial in compliance with national law, the valid version of the Declaration of 
Helsinki, the GCP-guidelines, the present trial protocol including its amendments, and 
with any other trial conduct procedures provided by the Sponsor or authorized 
representatives. 
o Not to implement any deviations from or changes to the protocol (including protocol 
amendments) without agreement from the Sponsor and prior review and favorable opinion 
from the ethics committee and approval from the competent authority, if applicable, except 
where necessary to eliminate an immediate hazard to the patient(s), or for administrative 
aspects of the clinical trial (where permitted by all applicable regulatory requirements). 
o That I am familiar with the appropriate use of the investigational medicinal product as 
described in this protocol and any other information provided by the Sponsor including, 
but not limited to, the current investigator’s brochure or equivalent document provided by 
the Sponsor. 
o To ensure that all persons assisting me with the clinical trial are adequately informed about 
the investigational medicinal product and of their trial-related duties and functions. 
o That I have been informed that certain regulatory authorities require the Sponsor to obtain 
and supply details about the investigator’s ownership interest in the Sponsor or the trial 
product, and more generally about his/her financial ties with the Sponsor. The Sponsor 
will use and disclose the information solely for the purpose of complying with regulatory 
requirements. 
 
 
 
 
 
Principal investigator name (print) 
 
 
 
 
 
 
 
 
Principal investigator signature 
 
Date 


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26 
Appendices 
Appendix 1 
Central Laboratory Kits 
A-Table 1: 
Central Laboratory Kits 
Lab Kit 
Designation 
(Laboratory) 
Parameters 
Storage/shipping 
conditions 
Kit A 
 
(Central 
safety 
laboratory) 
Hematology 
 
Full differential blood cell count erythrocytes, leucocytes, differential 
leucocyte count (neutrophils, eosinophils, basophils, lymphocytes, 
monocytes), hemoglobin, hematocrit, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), platelets. 
Biochemistry 
 
Liver function monitoring: aspartate amino transferase, alanine amino 
transferase, alkaline phosphatase, gamma glutamyl transferase, total 
bilirubin, unconjugated (indirect) and conjugated (direct) bilirubin.  
Renal function monitoring: creatinine, uric acid, blood urea nitrogen 
(BUN). Estimated glomerular filtration rate (eGFR) will be calculated 
according to the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation for adults and according to the Schwartz bedside 
equation for children and adolescents.a 
Other parameters: Sodium (Na), potassium (K), magnesium, chloride 
(Cl), inorganic phosphate (P), calcium (Ca), creatine phosphokinase, 
amylase, lipase, total protein, albumin, glucose, hemoglobin A1c, 
triglycerides, cholesterol, ferritin 
Urinalysis 
pH, nitrites, hemoglobin, protein, albumin, glucose, ketones, creatinine. 
Microscopic examination of the urine sediment only for cases when 
positive hemoglobin test is detected 
Ambient shipment 
on day of 
sampling 
Kit B 
 
(Central 
safety 
laboratory) 
D-dimer, lactate dehydrogenase (LDH) and C-reactive protein (CRP) 
Troponin I (cTN) 
Procalcitonin (PCT) 
NT-proB-type Natriuretic Peptide (BNP) 
At least -20°C 
(-4°F) on site, dry 
ice shipment 
within 6 weeks 
Kit C 
 
(Central 
safety 
laboratory) 
Everything included in Kit B plus: 
 
Coagulation: Prothrombin time, partial thromboplastin time, and 
international normalized ratio (INR) 
Interleukin (IL)-17, IL-1ß, IL-6, interferon gamma (IFNγ), and tumor 
necrosis factor alpha (TNFα) 
At least -20°C 
(-4°F) on site, dry 
ice shipment 
within 6 weeks 
Kit PK 
(Central 
safety 
laboratory) 
Trough level IMU-838 
At least -20°C 
(-4°F) on site, dry 
ice shipment 
within 6 weeks 
 


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A-Table 1: 
Central Laboratory Kits (continued) 
Lab Kit 
Designation 
Parameters 
Storage/shipping 
conditions 
Kit D 
(Central 
virology 
laboratory) 
SARS-CoV-2 status (qualitative)b and viral load by reverse transcriptase 
polymerase chain reaction (RT-PCR) in nasopharyngeal swab and 
spontaneous sputum 
At least -20°C 
(-4°F) on site, dry 
ice shipment 
within 7 days 
Kit E 
(Central 
safety 
laboratory) 
IgA and IgG antibodies against SARS-CoV-2 
At least -20°C 
(-4°F) on site, dry 
ice shipment 
within 6 weeks 
a 
Fadrowski JJ, Neu AM, Schwartz GJ, Furth SL. Pediatric GFR estimating equations applied to adolescents in the general 
population. Clin J Am Soc Nephrol 2011;6(6):1427-35. 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children 
with CKD. J Am Soc Nephrol 2009;20(3):629-37. 
b 
Qualitative assessment of SARS-CoV-2 status may be evaluated as absence or presence of virus in the quantitative SARS-CoV-
2 RT-PCR assessments. 
 
 
 


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Appendix 2 
Local laboratory tests required at Screening 
The following local laboratory tests are required at Screening to check for eligibility 
• White blood cell count 
• Platelet count  
• Total bilirubin 
• Alanine aminotransferase (ALT) or gamma glutamyl transferase (GGT) 
• Serum creatinine 
• For women of childbearing potential: blood pregnancy test 
• If the patient has known Gilbert syndrome: indirect [unconjugated] bilirubin 
• SARS-CoV 2 qualitative test (within 4 days before randomization) 
 
For exclusion criterion 17, the estimated glomerular filtration rate value (eGFR) must be calculated 
as follows: 
• For adults according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation 
GFR [mL/min/1.73 m²] = 141 x min(Scr/κ,1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if 
female] x 1.159 [if black] 
where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates 
the maximum of Scr/κ or 1. 
• For children and adolescents (12 to 17 years) according to the Schwartz bedside equation 
GFR [mL/min/1.73 m²] =0.413 x (height/Scr) 
where Scr is serum creatinine (mg/dL) and height expressed in centimeters.  


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Appendix 3 
Modified WHO Ordinal Scale for Clinical Status 
 
Patient state 
Descriptor 
Score 
Uninfected or no longer 
infectious 
No clinical or virological evidence of infection 
0 
Mild Disease 
Ambulatory, virus-positive, no limitation of activities 
1 
Ambulatory, virus-positive, limitation of activities 
2 
Moderate Disease 
Hospitalized, virus-positive, no oxygen therapy 
3 
Hospitalized, virus-positive, oxygen by mask or nasal 
prongs 
4 
Severe Disease 
Hospitalized, virus-positive, non-invasive ventilation 
or high-flow oxygen 
5 
Hospitalized, virus-positive, intubation and 
mechanical ventilation 
6 
Hospitalized, virus-positive, ventilation plus 
additional organ support (pressors, RRT, ECMO) 
7 
Dead 
Death 
8 
ECMO = extracorporeal membrane oxygenation, RRT = renal replacement therapy. 
Based on [21].