Conditions: Acute Kidney Injury (AKI)
Keywords: AKI
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
The purpose of the clinical study is to assess safety, tolerability and pharmacokinetics of RMC-035 for the prevention and treatment of acute kidney injury (AKI) in patients undergoing cardiac surgery.

Detailed description:
This is a study with two parallel treatment groups where subjects are randomized to receive RMC-035 or a matching placebo in a double-blind fashion. The study will comprise of a screening visit, followed by CABG and/or valve replacement on Day 1, double-blind treatment period and a follow-up period up to Day 30.

Arms:
arm 1: Participants will receive RMC-035 intravenously arm 2: Participants will receive matching placebo solution intravenously

Interventions: intervention 1: RMC-035 intervention 2: Placebo
Intervention descriptions: intervention 1: Multiple dosing during 48 hours following cardiac surgery intervention 2: Multiple dosing during 48 hours following cardiac surgery

Protocol document:
SAP_004.pdf: 
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The content of this Statistical Analysis Plan is confidential and may not 
be passed to any third party without permission of Guard Therapeutics International AB. 
STATISTICAL ANALYSIS PLAN 
A Phase 1b study of RMC-035 in subjects undergoing Cardiac Surgery 
Sponsor Code: 20-ROS-04 
mc Code: mc451 
EudraCT No.: 2020-004107-14 
Sponsor: Guard Therapeutics International AB 
Evaluation: KLIFO GmbH, Munich 
Final Version 1.0 of June 11th, 2021 
Previous Version(s): None 


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DOCUMENT HISTORY 
 
 
Version 
Number 
Version Date 
Main reason for 
new version 
Summary of changes 
1.0 
11-06-2021 
Final Version 
Not applicable 


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TABLE OF CONTENTS 
1 
GENERAL 
6 
2 
EFFICACY AND SAFETY VARIABLES 
7 
2.1 
General procedures 
7 
2.1.1 Time definitions and handling of visits 
7 
2.1.2 Change from baseline 
8 
2.1.3 Safety laboratory parameters: Technical failure and values reported as ‘< x’ or ‘> 
x’ 
8 
2.2 
Primary Endpoint 
8 
2.3 
Secondary Endpoints 
8 
2.4 
Exploratory Endpoints 
9 
3 
STATISTICAL ANALYSIS SETS 
12 
3.1 
All Subjects Screened (SCR) 
13 
3.2 
Randomised Subjects (RND) 
13 
3.3 
Safety Analysis Set (SAF) 
13 
3.4 
Full Analysis Set (FAS) 
13 
3.5 
PK Analysis Set (PK) 
13 
4 
STATISTICAL EVALUATION 
14 
4.1 
General 
14 
4.2 
Study Patients 
14 
4.2.1 Disposition of Patients 
14 
4.2.2 Protocol Deviations 
14 
4.2.3 Demographic and Other Baseline Characteristics 
16 
4.2.4 Treatment Compliance 
17 
4.2.5 Concomitant Treatment 
17 
4.3 
Safety, Tolerability and Pharmacokinetics Evaluation 
18 
4.3.1 Primary Evaluation 
18 
4.3.2 Secondary Evaluation 
19 
4.3.2.1 
Safety Evaluation 
19 
4.3.2.2 
ADA Evaluation 
21 
4.3.2.3 
PK Evaluation 
21 
4.4 
Evaluation of exploratory endpoints 
23 
4.5 
Missing Values 
23 


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5 
INTERIM ANALYSIS 
24 
6 
CHANGES FROM PROTOCOL 
24 
7 
SUMMARY TABLES AND DATA LISTINGS 
24 
7.1 
Summary Tables 
24 
7.2 
Data Listings 
25 
7.3 
Figures 
26 
8 
SIGNATURES 
27 
9 
APPENDICES 
29 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
8OH-dG 
8 hydroxy 2 deoxyguanosine 
A1M 
Alpha-1-microglobulin 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration time curve 
AUCτ 
Area under the curve from 0 to t, where t is the last measurable sample 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration 
Cmax 
Maximum (peak) concentration observed 
CO 
Cardiac output 
Ctrough 
Lowest concentration reached by a drug before the next dose is administered 
CrCl 
Creatinine clearance 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CVP 
Central venous pressure 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
GFR 
Glomerular filtration rate 
h 
hour(s) 
ICU 
Intensive care unit 
IGFBP7 
Insulin like growth factor binding protein 7 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IRR 
Infusion related reaction 
ISR 
Infusion site reactions 
IV 
Intravenous 


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Abbreviation 
Definition 
KDIGO 
Kidney Disease Improving Global Outcome 
KIM-1 
Kidney injury molecule-1 
L-FAPB 
Liver-type fatty acid-binding protein 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
NCA 
Non-compartmental analysis 
NGAL 
Neutrophil gelatinase associated lipocalin 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
PK 
Pharmacokinetic 
PT 
Preferred term 
PTR 
Peak to trough ratio 
Rac (AUC) 
Accumulation ratio calculated from AUCτ,ss and AUCτ 
after single dosing 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCr 
Serum Creatinine 
SD 
Standard deviation 
SOC 
System organ class 
SS 
Steady state 
SvO2 
Mixed venous saturation 
TEAE 
Treatment emergent adverse event 
TIMP2 
Tissue inhibitor of metalloproteinases 2 
t½ 
Elimination half-life 
 
 
1 GENERAL 
This Statistical Analysis Plan (SAP) specifies the statistical methods to be applied in the 
analysis of this study. It was written by the responsible biostatistician prior to 
unblinding/closure of the database according to SOPs of KLIFO GmbH. This SAP is based 
upon the Study Protocol (version 2.0 of 22-Dec-2020) and contains a specification of the 
statistical methods described therein. The SAP was written without knowledge of the 
randomisation code. 
The primary objective of this phase 1b study is to evaluate the safety and tolerability of RMC- 
035 in subjects undergoing non-emergent, on-pump Coronary Artery Bypass Graft (CABG) 
and/or valve surgery. 
For this purpose, this trial has been designed as a phase 1b, randomised, double-blind, parallel 
treatment group clinical study. 


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The patients are randomised to receive RMC-035 or a matching placebo in a 2:1 ratio in a 
double-blind fashion. 
A total of 7 visits are scheduled as follows: 
• Screening: 
Visit 1 (Day -1) 
• Treatment period: 
Visit 2 (Baseline, Day 1) 
Visit 3 (Day 2), 
Visit 4 (End of Treatment [EOT], Day 3) 
• Safety follow-up period: Visit 5 (Day 4) 
Visit 6 (Day 7) 
Visit 7 (End of Study [EOS], Day 31) 
 
2 EFFICACY AND SAFETY VARIABLES 
 
2.1 
General procedures 
 
2.1.1 
Time definitions and handling of visits 
A total of 7 visits with investigations are planned including a screening visit. 
In general, variables will be analysed according to the visit as documented in the eCRF. 
Details of the scheduled visits and time windows will be as follows: 
 
Visit 
Visit No. 
Scheduled for 
Visit Day 
Time 
window 
[days] 
Documented 
in eCRF as 
Presented 
in the 
analysis 
as time 
point 
Screening 
Visit 1 
Day -1 
-5 
SCREENING 
Screening 
Treatment 
(Baseline) 
Visit 2 
Day 1 
±0 
Day 1 (TRT) 
Baseline 
(Day 1) 
Treatment 
Visit 3 
Day 2 
±0 
Day 2 (TRT) 
Day 2 
Treatment 
(EOT) 
Visit 4 
Day 3 
±0 
Day 3 (EOT) 
Day 3 
(EOT) 
Follow-up 
Visit 5 
Day 4 
±0 
Day 4 (FU) 
Day 4 
(FU) 
Follow-up 
Visit 6 
Day 7 
±1 
Day 7 (FU) 
Day 7 
(FU) 
Follow-up 
(EOS) 
Visit 7 
Day 31 
±3 
Day 31 (FU; 
EOS) 
Day 31 
(FU, EOS) 
Some measurements are performed at baseline at various time points. These time points will 
be presented in the analyses as follows. 


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o Baseline (pre-surgery) 
o Day 1 (start first IMP infusion) 
o Day 1 (15 min) 
o Day 1 (30 min) 
o Day 1 (1 h) 
o Day 1 (2 h) 
o Day 1 (3 h) 
o Day 1 (4 h) 
o Day 1 (5 h) 
o Day 1 (6 h) 
o Day 1 (12 h) 
where time point in () is time since start of first IMP infusion. 
 
2.1.2 
Change from baseline 
For continuous variables assessed at any time point after baseline, the absolute change from 
baseline will be calculated as [value at the time point] – [baseline value]. Relative change [%] 
will be calculated by dividing the absolute change by the baseline value and multiplication with 100 
to obtain a percentage. Baseline value will be the last available value pre-surgery. If the pre-
surgery baseline value is missing at Visit 2, the screening value will be used, if applicable. If 
any of the two values (i.e. baseline value or value at the respective time point) is missing, the 
absolute and relative change from baseline will be missing as well. 
 
2.1.3 
Safety laboratory parameters: Technical failure and values reported as ‘< x’ or ‘> 
x’ 
In case a value is assessed as technical failure by the investigator, the value will be set to missing 
for summary tables and prior to the calculation of changes between visits. 
Values reported as ‘< x’ or ‘> x’ will be set to ‘x’ for quantitative analyses (e.g. for the 
calculation of mean values in summary tables and for the calculation of changes between visits). 
This means that values below the lower limit of quantification will be set to the lower limit of 
quantification for quantitative analyses. 
 
2.2 
Primary Endpoint 
The primary objective of this study is to evaluate the safety and tolerability of RMC-035 in 
subjects undergoing non-emergent, on-pump Coronary Artery Bypass Graft (CABG) and/or 
valve surgery. Therefore, the primary endpoint is the nature, frequency and severity of Adverse 
Events (AEs). 
 
2.3 
Secondary Endpoints 
In addition to the primary endpoint described in Section 2.2 the following endpoints will be 
analysed: 
 
• Clinically significant changes in safety laboratory tests (hematology, biochemistry, 


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urinalysis) 
• Changes in vital signs (blood pressure, heart rate, respiratory rate) 
• Changes in 12-lead ECG 
• Pharmacokinetics of RMC-035 in plasma: Cmax, Ctrough, tmax 
• Pharmacokinetics of RMC-035 in plasma after fourth dose: AUCτ, Cmax, Ctrough, PTR, 
Rac(AUC), t1/2 
• Presence and titers of Anti-Drug-Antibodies (ADA) 30 days after surgery 
• Characteristics of ADA developed 30 days after surgery with regards to isotype, 
neutralizing capacity and cross-reactivity with endogenous alpha-1-microglobulin 
 
2.4 
Exploratory Endpoints 
• Post-baseline changes in specific categories of biomarkers: 
o Renal tubular damage and stress markers, e.g. 
 KIM-1, TIMP2, IGFBP7, IL-18, L-FAPB, NGAL (urine) 
 KIM-1, NGAL and A1M (plasma or serum) 
o Oxidative stress markers e.g. 
 8OH-dG (serum and urine) 
o Inflammatory cytokines e.g. 
 IL-6 and IL-8 (plasma) 
o Cardiac biomarkers, e.g. 
 NT-proBNP and Troponin T 
• Concentration of RMC-035 in urine 
Evaluation of exploratory biomarkers and urine concentration of RMC-035 may be performed 
and reported separately. Cardiac biomarkers NT-proBNP and Troponin T will be reported as 
per this SAP. 
• Post-baseline changes in hemodynamic assessments, including cardiac output (CO), mixed 
venous saturation (SvO2) and central venous pressure (CVP) (i.e., right ventricular 
pressure systolic/diastolic, pulmonary artery pressure systolic/diastolic), 
• Presence of major adverse kidney event at 30 days (MAKE30), defined as a composite of 
either death, dialysis or ≥ 25% eGFR reduction. 
Presence of MAKE30 is ‘Yes’, if at least one of the following apply: 
- Death, which will be documented as an AE with seriousness ‘Serious - results in death’ 
- Dialysis, which is ‘Yes’, if at least at one visit the question ‘Was dialysis started since 
last visit?’ is ‘Yes’. 
- ≥ 25% eGFR reduction from baseline to Visit 7, where eGFR criterion is considered 
fulfilled if eGFR reduction is ≥ 25% based on any of the following eGFR equations: CKD- 
EPI (SCr), CKD-EPI (Cys C), CKD-EPI (SCr and Cys C). 
Presence of MAKE30 will be No, if the following apply: 
- No AE with seriousness ‘Serious - results in death’ documented AND 


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- At each documented visit the question ‘Was dialysis started since last visit?’ is ‘No’ 
AND 
- < 25% eGFR reduction from baseline to Visit 7, where eGFR criterion is considered 
fulfilled if eGFR reduction is < 25% based on any of the following eGFR equations: CKD- 
EPI (SCr), CKD-EPI (Cys C), CKD-EPI (SCr and Cys C). 
Otherwise MAKE30 will be ‘not evaluable’. 
• Percent increase (from baseline to all subsequent time points) and maximum percent 
increase in SCr and Cystatin C (and corresponding estimated GFR values based on any of 
the following eGFR equations: CKD-EPI (SCr), CKD-EPI (Cys C), CKD-EPI (SCr and 
Cys C)) over the time points visit 3, 4, 5 and 6. 
At all time points of visit 1 to 7 when clinical chemistry blood samples are taken, eGFR 
will be calculated in mL/min/1.73 m² using any of the following eGFR equations: CKD- 
EPI (SCr), CKD-EPI (Cys C), CKD-EPI (SCr and Cys C). The eGFR value based on 
CKD-EPI equation for SCr will be calculated by the laboratory and entered in the eCRF. 
The eGFR value based on CKD-EPI equation for SCr and Cystatin C will be calculated in 
the eCRF directly and the third eGFR value, which is based on the CKD-EPI equation for 
Cystatin C only, will be calculated within the process of data derivation as follows: 
 
𝐶𝐶𝐶𝐶𝐶𝐶 − 𝐸𝐸𝐸𝐸𝐸𝐸 (𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐶𝐶) = 133 𝑥𝑥 ೦ 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐴𝐴 
0.8 ೦ 
 
𝑥𝑥 0.995𝑎𝑎𝑎𝑎𝑎𝑎 𝑥𝑥 𝐵𝐵 
Where Scys is serum Cystatin C in mg/L, age is measured in years and A and B are as 
follow: 
 
Female 
Male 
Scys ≤ 0.8 
A = -0.499 
Scys ≤ 0.9 
A = -0.499 
B = 0.932 
B = 1 
Scys > 0.8 
A = -0.499 
Scys > 0.9 
A = -0.499 
B = 0.932 
B = 1 
 
• Post-baseline AUC of Serum Creatinine (SCr) and Cystatin C levels (and corresponding 
eGFR values) from baseline to 48 hours, 72 hours and Visit Day 7 post-surgery 
AUC of Serum Creatinine and Cystatin C levels (and corresponding eGFR values) will be 
calculated as follows: 
AUCs are calculated according to the linear trapezoidal rule. Actual times when the samples 
were taken are used for the calculation, except for the 0h and the last sample of the respective 
AUC (i.e., 48 hours sample, 72 hours sample, or 6 days post-surgery sample), where the 
following will apply: In order to calculate for example a 48h AUC (τ=48h), the start time of 
first IMP administration will be used for the 0h measurement, whereby the 0h measurement 
will be the respective parameter (Serum Creatinine, Cystatin C or the corresponding eGFR 
values) of the pre-surgery clinical chemistry sample. 48h after start of first IMP 
administration will be used for the 48h measurement. The other AUCs will be calculated 
analogously. 


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If the actual time is not given, the scheduled time is used. 
Missing values will be interpolated. 
AUCs are not calculated and a profile is considered as not evaluable, if either 
o in case the baseline value is missing or 
o in case the last value of the respective AUC (i.e., 48 hours value, 72 hours value, 
or Visit Day 7 post-surgery value) is missing or 
 
• Severity of AKI defined as the following: 
o Stage 1: SCr 1.5 to 1.9 times baseline within 7 days, OR increase of ≥0.3 mg/dL (≥ 
26.5 µmol/L) within 48 hours OR urine output <0.5 mL/kg/h for 6 to <12 
consecutive hours 
o Stage 2: SCr 2.0-2.9 times baseline within 7 days OR urine output <0.5 mL/kg/h 
for ≥ 12 consecutive hours 
o Stage 3: SCr 3.0 times baseline within 7 days, OR increase in SCr 5.0 mg/dL (≥353.6 
µmol/L), OR initiation of renal replacement therapy OR urine output <0.3 mL/kg/h 
for ≥24 consecutive hours OR anuria for ≥12 hours, where initiation of renal 
replacement therapy is ‘Yes’, if at least at one visit the question ‘Was dialysis 
started since last visit?’ is ‘Yes’ in the first 7 days. Anuria is defined as urine output 
<100 mL per day (over a 24h time period). 
For assessment for urine output values from the time urine collection is started, i.e. 
before surgery, will be used and only hourly recording of urine output until 48 hours 
after start of 1st IMP infusion will be included. For calculation of urine output in 
mL/kg/h weight at the respective visit will be used. If no valid value for weight is 
available at the respective visit, the last valid value of weight from a previous visit will 
be used. 
For AKI stage 1 the urine output criterion is assessable, if at least one time window of 
at least 6 consecutive hours with valid urine output values is available. Otherwise urine 
output criterion for stage 1 is not assessable. 
For AKI stage 2 the urine output criterion is assessable, if at least one time window of 
at least 12 consecutive hours with valid urine output values is available. Otherwise urine 
output criterion for stage 2 is not assessable. 
For AKI stage 3 the urine output criterion is assessable, if at least one time window of 
at least 24 consecutive hours with valid urine output values is available. Otherwise urine 
output criterion for AKI stage 3 is not assessable. The anuria criterion is assessable, if 
one time window of at least 36 hours with valid urine output values is available. 
Otherwise the anuria criterion is not assessable. 
If the urine output criterion is not assessable for the respective stage of AKI severity, 
the assessment of AKI severity will be based on the remaining criteria of the respective 
stage. In addition for AKI stage 3, if the anuria criterion is not assessable, the assessment 
of AKI severity will be based on the remaining criteria of AKI stage 3. 
The highest stage of AKI severity will be tabulated. 
• Duration and persistence of AKI defined as either of the following 


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o The number of days from start of AKI (KDIGO definition) where either SCr increase 
≥ 0.3 mg/dL above pre-AKI reference point (first comparison is versus pre-surgery 
baseline, or a reference value after baseline if AKI occurs after 48 hours post-
surgery) or if SCr increase is ≥ 1.5 times baseline or dialysis in the first 7 days, or 
up to discharge if prior to 7 days. Number of days will be counted until SCr value 
will drop below the threshold of the AKI definition (stage 1 or higher) and other 
parts of the AKI definition are not fulfilled either (e.g. urinary output criteria). 
Possible end dates will be at any of the study visits. Duration of AKI [days] will be 
calculated as end date of AKI minus start date of AKI +1. If AKI will persist at last 
documented visit in the eCRF, the date of last documented visit will be used as end 
date of AKI for calculation of a continuous variable. For calculation of a categorical 
variable the duration will be set to ‘ongoing’. 
The continuous variable of duration of AKI will be presented in a summary table for 
continuous variables. Additionally, the categorical variable of duration of AKI will 
be presented in a summary table for categorical variables using the following 
categories: 1-3, 4-7, 8-14, 15-21, 21+ and ‘ongoing’. 
o Persistent AKI defined as AKI (KDIGO definition) for >48 hours 
• Length of index Intensive Care Unit (ICU) stay and index hospital stay 
o Index ICU stay (in Days) defined as the duration of stay in the ICU immediately 
following surgery or recovery room post-surgery until ICU discharge 
It will be calculated as date of discharge from ICU – date of admission to ICU after 
surgery/recovery room + 1. 
o Index hospital stay (in Days) is defined as the duration of stay in the hospital from 
admission to hospital discharge for the index surgery 
It will be calculated as date of discharge from hospital – date of admission to hospital 
+ 1. 
• Nature of patient discharge facility (e.g. home, skilled nursing facility, rehabilitation 
center) 
 
3 STATISTICAL ANALYSIS SETS 
The evaluation of the primary endpoint and the safety analysis of the secondary endpoints will 
be performed using the Safety Analysis Set (SAF). The Full Analysis Set (FAS) will be used 
for the evaluation of the exploratory endpoints and the evaluation of PK endpoints will be 
performed using the PK Analysis Set (PK). All analysis sets will be based on actual treatment 
as the primary objective of this phase I clinical trial is to evaluate the safety and tolerability of 
RMC-035 and the FAS, which is defined to allow for exploratory SCr-based efficacy 
evaluations, will be used for exploratory analysis only. 
In addition to SAF, FAS and PK the all subjects screened (SCR) and all subjects randomised 
(RND) analysis sets are defined in Section 3.1 and 3.2 and will be used for listings and selected 
overview summary tables, for completeness of presentation of all data documented in the eCRF. 
A subject classification document will be prepared which details subject inclusions into the 
analysis sets. The document will be completed before unblinding of study statistician, 
pharmacokineticist and other persons participating in the blind data review meeting. Subject 


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classification will be performed (if feasible) during this meeting. 
In case subjects will be replaced according to protocol section 7.3.1, both, subjects to be 
replaced and replacing subjects will be analysed and allocated to the corresponding analysis 
sets. 
 
3.1 
All Subjects Screened (SCR) 
The set of all subjects screened will include all patients with data documented at the screening 
visit. This set will be used to calculate the proportion of patients screened but not randomised 
and the frequencies of the reasons for non-randomisation. 
 
3.2 
Randomised Subjects (RND) 
All subjects who have been randomised at Day -1, independent of whether they have received 
any IMP or not. This analysis set will be used for data listings. 
 
3.3 
Safety Analysis Set (SAF) 
The Safety Analysis Set will consist of all randomised subjects who have received at least 1 
dose of IMP. SAF will be used for safety endpoints. 
 
3.4 
Full Analysis Set (FAS) 
The Full Analysis Set will consist of all randomised subjects who have received at least 1 dose 
of IMP and with at least one post-dose SCr (eGFR) assessment. FAS will be used for 
exploratory endpoints. 
 
3.5 
PK Analysis Set (PK) 
PK Analysis Set will be used for the PK evaluation and will consist of all randomised subjects 
with no relevant protocol deviations affecting the evaluation of the PK parameters. 
Protocol deviations affecting the evaluation of the PK parameters may include: 
• AEs that may interfere with IMP use or effect and/or sampling: 
A list of patients with such AEs will be provided by medical expert of pharmacovigilance 
KLIFO A/S before blind data review meeting. 
• Insufficient pharmacokinetic samples which do not enable calculation of reliable 
pharmacokinetic parameters: 
Information about insufficient PK samples will be provided by PK laboratory or PK expert 
before or during blind data review meeting. 
• Other major protocol deviations which are assessed to significantly affect PK assessments 
(e.g. failure to properly use the IMP) 
 
Further details of protocol deviations will be discussed in the blind data review meeting, where 
protocol deviations will be classified as minor and major. Patients with major protocol 
deviations will be excluded from the PK analysis set. 


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4 STATISTICAL EVALUATION 
 
4.1 
General 
The statistical analysis will be performed using the software package SAS® version 9.4 or 
higher (SAS Institute Inc., Cary, NC 27513, USA). 
Patient listings will be generated for all data items collected in the eCRF and paper-based forms. 
Relevant data of screening failures (i.e. of patients not eligible for treatment because of 
violations of in- or exclusion criteria) will also be listed. 
All statistical analyses will be descriptive. Continuous data will be summarised using 
descriptive statistics including the arithmetic mean, the standard deviation, median, minimum, 
maximum, and the number of patients with non-missing values. Except for PK analysis where 
number of patients with non-missing values, arithmetic mean, SD, CV, median, minimum, 
maximum, geometric mean, geometric CV% will be used. 
Categorical data will be summarised using absolute and relative frequencies. 
Any changed in the planned statistical analysis will be documented in the study report. 
 
4.2 
Study Patients 
 
4.2.1 
Disposition of Patients 
• Number of patients screened, randomised, number of patients included in each analysis 
set, and reasons for exclusion from analysis sets 
• Completion of treatment period, reason for premature discontinuation of treatment 
• Completion of follow-up period, reason for premature discontinuation 
• Completion of full study, reason for premature discontinuation 
Completion of full study is reached, if the treatment period and the follow-up period are 
completed. 
If multiple reasons of premature discontinuation are given, these will be presented by all 
observed combinations. 
• Study duration: Last visit of the study will be the last visit where a visit date has been 
documented 
 
4.2.2 
Protocol Deviations 
Protocol deviations affecting the evaluation of the PK parameters are defined in Section 3.5. All 
protocol deviations (documented in the protocol deviation log of the project management) will be 
listed and the following additional aspects will be tabulated: 
• Violations of any eligibility criteria 
• Compliance with scheduled time windows, assessed based on the 
 
o Difference between the dates of Screening visit and Baseline visit, 
o Difference between the dates of Baseline visit and of each subsequent visit of the 
complete study period 


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The following table will show the calculated differences categorised as ‘Less than 
scheduled time window’, ‘Scheduled time window’ and ‘More than scheduled time 
window’ per visit. The differences will be categorised as follows: 
 
Visit 
Less than scheduled 
time window 
Scheduled time 
window 
More than scheduled 
time window 
Visit 1 
<-7 
[-7; -2] 
>-2 
Visit 2 
- 
- 
- 
Visit 3 
<1 
1 
>1 
Visit 4 
<2 
2 
>2 
Visit 5 
<3 
3 
>3 
Visit 6 
<5 
[5; 7] 
>7 
Visit 7 
<27 
[27; 33] 
>33 
 
o Differences between start time of first IMP administration at Baseline and start time 
of each subsequent IMP administration will be calculate in hours and presented in a 
listing. 
o Compliance with the schedule of PK sampling will be analysed using a listing (CSP 
V1.0 Table 4 may serve as template for this listing). This will provide for each IMP 
administration differences between start time of first PK sampling (pre- dose) and 
time of corresponding IMP administration and differences between time of IMP 
administration and time of all corresponding subsequent PK samplings calculated in 
minutes (for PK samples planned to be taken pre-dose or up to 1 hour after 
corresponding IMP administration) or hours (for samples planned to be taken 2 
hours after corresponding IMP administration or later). See CSP V1.0 Table 4. 
• Compliance with scheduled IMP dose and overall compliance with scheduled IMP doses 
For the 1st IMP dose, compliance with scheduled dose will be ‘yes’, if the value of eGFR 
is ≥60 mL/min/1.73m2 at baseline and the patient has received a dose of 1.3 mg/kg of IMP 
at the respective time point, or if the value of eGFR is 30 to <60 mL/min/1.73m2 at baseline 
and the patient has received a dose of 0.65 mg/kg of IMP at the respective time point. For 
the 2nd IMP dose, compliance with scheduled IMP dose will be ‘yes’, if the dose is the same 
as the first IMP dose and compliance with scheduled IMP dose for the 
1st IMP 
administration is ‘yes’. 
For the 3rd, 4th and 5th IMP dose compliance with scheduled dose will be ‘yes’, if the value 
of CrCl(/eGFR) is ≥60 mL/min(/1.73m2) and the patient has received a dose of 1.3 mg/kg 
at the respective time point, or - if the previous received dose was lower than 1.3 mg/kg - 
the patient has received the previous received dose. Compliance with scheduled dose will 
also be ‘yes’, if the value of CrCl(/eGFR) is 30 to <60 mL/min(/1.73m2) and the patient has 
received 0.65 mg/kg at the respective time point, or - if the previous received dose was 0.43 
mg/kg - the patient has received a dose of 0.43 mg/kg. Compliance with scheduled dose 
will also be ‘yes’, if the value of CrCl(/eGFR) is <30 mL/min(/1.73m2) and the patient has 
received a dose of 0.43 mg/kg at the respective time point. 
Compliance with the respective scheduled IMP dose will be ‘no’ otherwise. 


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Overall compliance with scheduled IMP doses will be ‘yes’, if compliance with scheduled 
dose is ‘yes’ for each IMP administration. 
Overall compliance with scheduled IMP doses will be ‘no’, if compliance with scheduled 
dose is ‘no’ for at least one IMP administration. 
 
4.2.3 
Demographic and Other Baseline Characteristics 
The following demography data, medical/surgical history, disease characteristics and baseline 
characteristics will be shown for SAF and PK: 
• Demographic data at screening: 
o Gender 
o Age (years) 
o Age group (18-69 years of age and ≥70 years of age) 
o Age group (18-64 years of age, 65-84 years of age and ≥85 years of age) 
o Ethnicity (Hispanic or Latino, non-Hispanic or Latino) 
o Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White) 
o Height (cm) 
o Weight (kg with one decimal) 
o Body Mass Index (BMI) 
BMI will be calculated for every Visit as follows: 
(body weight at Visit [kg]) / (body height at Screening [cm]/100)2 and will be rounded to one 
decimal. In case of missing body height at Screening BMI will be not available. 
• Medical/surgical history and disease characteristics 
Medical history, disease characteristics, relevant past and current diseases documented on 
the medical history form in the eCRF will be coded using MedDRA and will be classified 
by System Organ Class (SOC) and Preferred Term (PT). 
Frequency (number and percentage) of subjects with diseases / symptoms / findings per 
treatment group will be summarised by SOC and PT. 
Surgical history will be analysed analogously. 
• Renal function at baseline 
To analyse renal function at baseline, eGFR (based on serum creatinine with CKD-EPI 
equation) will be presented in a summary table per treatment group. Additionally eGFR at 
baseline will the categorised follows: 
o eGFR<60mL/min/1.73m2 
o eGFR≥60mL/min/1.73m2 


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Number and percentage of patient in each category will be tabulated per treatment group. 
• Physical examination at screening: 
This will be summarised by presenting absolute and relative frequencies of patients with 
any pathological findings (yes/no). 
 
4.2.4 
Treatment Compliance 
Compliance will be analysed using descriptive statistics and will be analysed per IMP 
administration for the following: 
• 
IMP dose 
• 
Total infusion volume [mL] 
• 
Infusion rate [mL/min] 
• 
Duration of administration: Stop time of IMP administration – Start time of IMP administration. 
If any of the two values is missing, the duration of administration will be missing as well. 
• 
Irregularities in IMP administration 
In addition, the 
• 
Overall number of infusions per subject 
• 
Any dose reduction in subject due to creatinine clearance (CrCL) or eGFR <30 mL/min or 30 
to <60 mL/min (yes/no) 
Any dose reduction is ‘yes’, if at least one of the 3rd, 4th or 5th IMP infusions was administered 
and the patient received a lower dose than the one received at 1st IMP administration on at least 
one of these administrations. 
Any dose reduction is ‘no’, if the dose received at 1st IMP administration was given throughout 
the treatment phase. 
Otherwise any dose reduction is ‘not evaluable’. 
• 
Any irregularities in any IMP administration (yes/no) per subject 
will be summarised per treatment group. 
 
4.2.5 
Concomitant Treatment 
Concomitant therapies will be coded and frequencies will be calculated by the first and the 
second level of the Anatomical Therapeutical Chemical (ATC) classification. The following 
summary tables will be provided, all summaries will be presented by treatment group and overall 
based on SAF: 
• 
All documented therapies (prior or during the study) 
• 
Concomitant therapies administered during the treatment period 
• 
Concomitant therapies administered during the follow-up period 
Medications are classified as prior if the stop date is before or on the day for obtaining informed 
consent. 
A therapy will be included in the summary table of a study period, unless the therapy end date 


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is prior to the beginning of the study period and unless the therapy onset date is after the end 
date of the study period. A concomitant therapy can be included in more than one summary 
table. 
The following start and end dates of the study period will be used for this purpose: 
• 
Treatment period: date of Visit 2; date of Visit 4 (EOT) 
• Safety follow-up period: date of Visit 4 (EOT) +1; date of Visit 7 (EOS) 
Handling of incomplete therapy dates: 
If month and year or only the year of the therapy end date is available and before the month and 
year or the year of the start date of the study period, the therapy will not be allocated to the 
study period. 
If month and year or only the year of the therapy start date is available and after the month and 
year or the year of the end date of the study period, the therapy will not be allocated to the study 
period. 
If a therapy start date is missing, the concomitant medication will be allocated to all study 
periods, in which the patient participated, prior the therapy end date. If a therapy end date is 
missing, the therapy will be allocated to all study periods, in which the patient participated, 
depending on the therapy start date. If both therapy start date and therapy end date is missing, 
the therapy will be allocated to all applicable study periods. 
 
4.3 
Safety, Tolerability and Pharmacokinetics Evaluation 
The evaluation of safety and tolerability will be performed for the SAF and the evaluation of 
PK will be performed for the PK analysis set. 
No statistical hypotheses are planned to be tested in this study. 
 
4.3.1 
Primary Evaluation 
The primary endpoint of this study is described in section 2.2. The nature, frequency and 
severity of AEs will be analysed for the evaluation of safety and tolerability of RMC-035 in 
subjects undergoing non-emergent, on-pump CABG and/or valve surgery. 
AEs will be coded using MedDRA and will be classified by System Organ Class (SOC) and 
Preferred Term (PT). 
Additionally, AEs will be categorized as 
• pre-treatment, 
• treatment-emergent, 
• post-treatment. 
AEs are assigned to one of the above categories using the start date of the AE and the dates of 
first and last administration of IMP. 
Treatment-emergent AEs (TEAEs) are defined as AEs occurring after the first IMP 
administration, with onset date on or after the day of first administration of IMP, and occurring 
up to four days after last IMP administration. 
Pre-treatment AEs are defined with an onset date prior to the day of first IMP administration, 
for patients with a documented screening visit. 


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Post-treatment AEs are defined as AEs with onset day at least five days after last IMP 
administration. 
In case of an incomplete AE start date, the AE will be categorized as treatment-emergent (worst 
case). In case an investigator comment on the AE page provides different information 
concerning the timing of AE onset, the AE onset will be categorized based on this comment. 
Adverse Events of Special Interest (AESI) in this study are defined as Injection Site Reaction 
(ISR) or Infusion Related Reaction (IRR) adverse events. 
The incidence of the following categories of AEs will be analysed for the SAF: 
• Number (%) of subjects with at least one TEAE 
• Number (%) of subjects with at least one treatment-emergent SAE 
• Number (%) of patients with at least one non-serious TEAE 
• Number (%) of patients with at least one treatment-emergent AESI 
• Number (%) of subjects with at least one treatment-emergent AEs reported as related 
(possible/probable) to IMP 
• Number (%) of patients with at least one treatment-emergent AEs leading to withdrawal 
of IMP 
An overview summary table will present the number (%) of subjects for all of the above 
categories by treatment group. 
In addition, separate summary tables will be generated for each of the above categories. These 
will present the number of events and number (%) of patients with an AE in the respective 
category classified in SOCs and PTs. 
An overview summary table will present the number (%) of patients with at least one TEAE by 
seriousness, severity (Common Terminology Criteria for Adverse Events (CTCAE) grade), 
causality, measures (AE treatment and action taken to IMP) and outcome. 
In addition, summary tables for TEAEs will present the number (%) of patients with each SOC 
and PT grouped by seriousness, severity, causality, measures and outcome. 
Individual patient listings will be provided for AEs, SAEs, AESI, AEs reported as related 
(possible/probable) to IMP and for AEs leading to withdrawal of IMP. AEs will be flagged in 
these patient data listings as pre-treatment, treatment-emergent and post-treatment, according 
to the definitions provided at the beginning of this section. 
Patient data listings will display the duration of each AE. In case of a complete AE start date 
and a complete AE end date the duration of an AE will be calculated as (AE end date) - (AE 
start date) + 1. Otherwise, the duration of an AE will not be determined. 
 
4.3.2 
Secondary Evaluation 
 
4.3.2.1 Safety Evaluation 
The safety evaluation will be based on SAF. Summary tables will be provided containing the 
following: 


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• Physical examination; the overall assessment of any changes to any body system 
compared to screening examination (“No”, “Clinically non-significant changes and/or 
improvements only”, “Clinically significant deteriorations or new findings”) will be 
summarised at Day 3 (EOT) by treatment group. In addition, a shift table between the 
overall assessment at Day 3 (EOT) and the variable “Did the physical examination reveal 
any pathological findings” (“Yes”, ”No”) assessed at screening will be presented. 
• Vital signs; systolic/diastolic blood pressure, respiratory rate, heart rate and body 
temperature at each time point and changes from baseline to each time point will be 
summarised by descriptive statistics by treatment group. The overall assessment of vital 
signs categorized as “normal”, “abnormal, not clinically significant” or “abnormal, 
clinically significant” (as judged by the investigator) will be summarised by time point using 
frequency tables and listings presented by treatment group. In addition, shift tables for the 
overall assessment of vital signs between baseline and each subsequent time point will be 
presented. 
• 12-lead ECG; will be listed for each subject and summarized as the vital signs parameters. 
• The overall assessment of continuous ECG monitoring will be summarised at Day 3 (EOT) 
by treatment group. 
• Safety laboratory analyses data (hematology, clinical chemistry incl. liver function test, 
urinalysis); 
The following analyses will be performed for quantitative parameters (hematology, 
clinical chemistry incl. liver function test) and for qualitative parameters (results from 
urine dipstick test): 
o Standard descriptive summary statistics and for quantitative parameters additionally 
geometric mean and geometric standard deviation will be calculated. 
o Standard descriptive summary statistics, geometric mean and geometric standard 
deviation will be calculated for the absolute changes in quantitative parameters. 
o Frequencies of normal, above normal, and below normal values will be computed for 
quantitative parameters with normal ranges. 
o Shift tables displaying changes with respect to the normal range over time will be 
provided for quantitative parameters with normal ranges. 
o All laboratory data will be listed. These listings will include flags so that all normal 
and all abnormal values can be found. 
o Overall assessment will be summarised for hematology, clinical chemistry incl. liver 
function test, and urinalysis by treatment group. In addition, shift tables for the overall 
assessment between baseline and each subsequent time point will be presented. 
• CrCl, calculated by site before IMP administrations 3-5 in mL/min will be summarised by 
time point. In addition, CrCl will be categorized as follows 
o CrCl ≥ 60 mL/min 
o 30 mL/min ≤ CrCl < 60 mL/min 
o CrCl <30 mL/min, 
and will be presented using absolute and relative frequencies. 
• Overall assessment of urinary output at Day 3 (EOT) will be summarised by treatment 
group. Further details on urinary output will be listed. 


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• Hemoglobin A1c (HbA1c) in blood at screening and Day 31 (EOS) will be listed. 
 
Quantitative longitudinal parameters will also be presented graphically as mean-by-visit plots 
and subject-profile-by-visit plots. 
 
4.3.2.2 ADA Evaluation 
Analysis of presence and titers of ADA will be performed on SAF. Summary tables will be 
provided, including a shift table for presence of ADA between Baseline and Visit 7 (EOS). 
ADA samples obtained beyond the protocol specified time window for Visit 7 will be accepted. 
For this evaluation, presence of ADA at a visit will be defined as follows: 
Presence of ADA at a visit is negative, if 
o initial result is reported as negative or 
o initial result is reported as positive and confirmatory result is reported as negative. 
Presence of ADA at a visit is positive, if 
o both, initial and confirmatory result is reported as positive. 
If the confirmatory result is missing, presence of ADA will be identical to the initial reported 
result. Otherwise presence of ADA will be not evaluable. 
The characteristics of ADA will be listed. 
 
4.3.2.3 PK Evaluation 
The PK analysis will be based on the PK set. 
Descriptive statistics will be presented for plasma concentrations by scheduled sample time. 
For scheduled sample time see CSP V1.0 Table 4. 
The PK parameters will be calculated by non-compartmental analysis (NCA) using software 
Phoenix WinNonlin® version 8.3 (Build 8.3.2.116) or higher. 
The following PK parameters for RMC-035 in plasma will be assessed for each of the 5 IMP 
administrations: 
• Cmax (maximum observed concentration after each IMP administration) 
• Ctrough (lowest concentration reached before next dose is administered) 
• tmax (time after each IMP administration when Cmax is observed) 
The following PK parameters for RMC-035 in plasma will be additionally assessed: 
• AUC0-24h ss (area under the curve from 0 to 24 hours after fourth dose administration, where 
0 is the pre-dose measurement of fourth dose and 24h is the pre-dose measurement of fifth 
dose) 
• Peak to trough ratio (PTR) (after fourth dose) 
• Rac (AUC) (Accumulation ratio calculated from AUC0-5h,ss and AUC0-5h after single dosing) 
with the following formula: 


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𝑅𝑅𝑎𝑎𝑎𝑎 (𝐴𝐴𝐴𝐴𝐴𝐴) = 
𝐴𝐴𝐴𝐴𝐴𝐴0−5h,ss 
 
𝐴𝐴𝐴𝐴𝐴𝐴0−5h,single dose 
where AUC0-5h,single dose is the AUC from 0 to 5 hours after first dose administration, where 
0 is the pre-dosemeasurement before first dose and 5 is the 5 hour measurement after first 
dose. AUC0-5h,ss will be calculated as the AUC from 0 to 5 hours after fourth dose 
administration, where 0 is the pre-dose measurement before fourth dose administration and 
5 is the 5 hour measurement after fourth dose. 
• t½ (terminal half-life after fourth dose) (Help parameters for calculation of t½ will be given: 
λz (LAMZ), Lambda z upper (LAMZUL), Lambda z lower (LAMZLL), Number of points 
used for λz (LAMZNPT), R2) 
• PK parameters (AUCτ and t½) will also be calculated or extrapolated after all other dose 
administrations, if possible. Since τ varies between the different dose administrations and 
therefore the values of AUCs cannot be compared, τ will be replaced by the respective time 
window as follows: 
 
o AUC0-6h, 1st dose: Using the pre-dose measurement of first dose to pre-dose 
measurement of second dose, which will be a time window of 6 hours. 
 
o AUC0-6h, 2nd dose: Using the pre-dose measurement of second dose to pre-dose 
measurement of third dose, which will be a time window of 6 hours. 
 
o AUC0-12h, 3rd dose: Using the pre-dose measurement of third dose to pre-dose 
measurement of fourth dose, which will be a time window of 12 hours. 
 
o AUC0-2h, 5th dose: Using the pre-dose measurement of fifth dose to 2 hours after fifth 
dose administration, which will be a time window of 2 hours. 
 
Additionally AUC0-2h will be calculated for all doses, if possible. 
An overview of the different time windows of the AUCs to be calculated will be presented in 
the following table: 
 
Dose 
No. 
Calculated AUCs 
0-2h 
0-5h 
0-6h 
0-12h 
0-24h 
1 
x 
x 
x* 
2 
x 
x* 
3 
x 
x* 
4 
x 
x 
x* 
5 
x* 
*AUCτ for the different administration occasions 
For the PK calculations the received concentration values will be used. Actual dose and 
actual blood sampling time point will be used in the NCA. 
The infusion length is 60 min for the first dose administration and 30 min for second to 
fifth dose administration. 


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The AUC method used will be the ‘lin up/log down’, and the plasma model (200-202). The 
λz will be estimated for each profile after each dose based on visual inspection of the 
terminal part of the log-concentration time plot including at least three data points. If the 
terminal phase regression based on R2 will be less than 0.85, then the following parameters 
could not be reported; t½, λz. 
Pre-treatment values (before first dose) below LLOQ will be set to zero in the NCA 
calculation. 
Concentration values below the lower limit of quantitation (LLOQ) that precede the first 
quantifiable concentration value will be set to zero for linear plots and for all calculations and 
summary statistics but will be excluded from semi-logarithmic plots. All other LLOQ values 
will be treated as missing for all analyses. Possible outlying concentration values excluded from 
the PK analysis will be reported and justified in the study report. 
Listings for the PK parameters will be presented over time by treatment group and age group 
(18-69 years of age and ≥70 years of age) and additionally by treatment group and renal function 
at baseline. Listings will also include dosing of the respective IMP administration. The 
parameters will also be summarized with number of patients with non-missing values, 
arithmetic mean, SD, CV, median, minimum, maximum, geometric mean, geometric CV% for 
each of the 5 IMP administrations. In addition, the individual and mean concentration-time 
profiles will be illustrated graphically with line charts. Dose proportionality will be evaluated 
for Cmax and AUCτ using descriptive statistics and graphs (i.e. scatter plots). Different IMP 
doses will be indicated by color. 
 
4.4 
Evaluation of exploratory endpoints 
The evaluation of exploratory variables, described in section 2.4, will be based on FAS. 
Exploratory efficacy/pharmacodynamics/biomarkers measured before database lock will be 
summarised using frequency tables and descriptive statistics for absolute and/or relative change 
from baseline by time point. 
For scheduled sample time points of biomarkers see CSP V1.0, Table 4. 
Evaluation of exploratory biomarkers and urine concentration of RMC-035 may be performed 
and reported separately. Cardiac biomarkers NT-proBNP and Troponin T will be reported as 
per this SAP. 
Presence of MAKE30 (yes/no) and combinations of categories met will be tabulated using 
absolute and relative frequencies. 
 
4.5 
Missing Values 
Baseline value will be the last available value pre-surgery. If the pre-surgery baseline value is 
missing at Visit 2, the screening value will be used, if applicable. 
Handling of technical failures and values reported as ‘< x’ or ‘> x in context of the safety 
laboratory is described in Section 2.1.3. 
Handling of missing start and/or end dates of concomitant therapies in described in 
Section 4.2.5. 
Handling of concentration values below the LLOQ in context of the PK analysis is described 
in Section 4.3.2.3. 


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5 INTERIM ANALYSIS 
No interim analysis is planned. 
 
6 CHANGES FROM PROTOCOL 
The analyses planned in this analysis plan are consistent with the provisions in the clinical study 
protocol, except with regard to the following: 
• Analysis sets SCR and RAN were added. This will guarantee complete data listings of all 
data documented in the eCRF. 
• Analysis set FAS was additionally defined to allow for exploratory SCr-based efficacy 
evaluations. 
• AEs will not be presented classified in PTs and investigator terms, but only presented 
classified in SOCs and PTs, which both are coded. However, the investigator term is part 
of the AE data listings. 
• The secondary endpoint ‘Clinically significant changes in vital signs (blood pressure, heart 
rate, respiratory rate)’ was changed to ‘Changes in vital signs (blood pressure, heart rate, 
respiratory rate)’ and the secondary endpoint ‘Clinically significant changes in 12- lead 
ECG was changed to ‘Changes in 12-lead ECG’. 
The reason for this is that the summary tables described in 4.3.2.1 will only make an overall 
statement about ‘clinical significant changes’ but not about clinical significant changes for 
a single parameter (e.g. heart rate). But as according to CSP Section 8.3 any abnormal 
laboratory test result (hematology, clinical chemistry or urinalysis) or other safety 
assessments (e.g. ECG, continuous ECG monitoring, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (i.e. not related to progression of underlying disease 
or medical procedure, i.e. cardiac surgery) has to be documented as an AE, details on 
clinically significant assessments are part of the AE data listings and AE summary tables 
described in Section 4.3.1. 
• Cardiac biomarker Troponin T will be evaluated instead of Troponin I, since this is the only 
value the safety laboratory can measure. 
 
7 SUMMARY TABLES AND DATA LISTINGS 
 
7.1 
Summary Tables 
The summary tables planned for this analysis are listed in Appendix A. 
Treatment groups will be labelled as RMC-035 and Placebo, respectively. 
In tables presenting baseline characteristics summary statistics will be provided for each 
treatment group and for the treatment groups pooled. 
General format for categorical variables (SAS output): 


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RMC-035 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
X-variable 
Category 1 
X (XX.X) 
X (XX.X) 
X (XX.X) 
Category 2 
X (XX.X) 
X (XX.X) 
X (XX.X) 
Numbers showing number of subjects and percentage of subjects in brackets 
with N as denominator 
 
More than one X-variable may be analysed within a table. Variables can have more than two 
categories. Percentages are displayed with 1 decimal. 
General format for continuous variables (SAS output): 
 
 
RMC-035 
(N=XX) 
Placebo 
(N=XX) 
Total 
(N=XX) 
X-variable 
N 
Mean 
SD 
Min 
Median 
Max 
Abbreviations: n = number of subjects with non-missing value, SD = Standard 
Deviation 
 
More than one x-variable may be analysed within a table. 
In tables presenting PK parameters summary statistics will be provided for each treatment group 
and for the treatment groups pooled. The different dose levels for verum patients will be pooled. 
Additionally, tables with summary statistics for each dose level of RMC-035 (i.e. 1.3 mg/kg, 
0.65 mg/kg, and 0.43 mg/kg) per time point will be provided. In these tables values for placebo 
and treatment groups pooled will not be repeated. 
The general format for tables of PK Analysis will look analogous to the summary statistics for 
baseline characteristics described above. 
The number of decimals used for minima and maxima depends on the scaling of the respective 
data. Mean (arithmetic and geometric), median, standard deviation, CV and geometric CV% 
will be displayed with one additional decimal. Frequencies will be displayed with no decimals. 
 
7.2 
Data Listings 
The data listings planned are listed in Appendix B. 
Data listings will include all randomised patients, the disposition listing will include all 
screened patients. Flags will be provided in the listings indicating which patients are included 
in the different analysis sets. RND analysis set will be used except of the disposition listing 
where SCR analysis set will be used. 


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In general, data listings will be presented by treatment group. Within each treatment group, 
patients will be sorted by the screening number. 
Listings for the PK parameters will be presented over time by treatment group and age group 
(18-69 years of age and ≥70 years of age) and additionally by treatment group and renal function 
at baseline. These listings will also include dosing of the respective IMP administration. 
 
7.3 
Figures 
Figures planned are listed in Appendix C. 


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8 SIGNATURE 
 
Sponsor 
 
 
Alberto Hernandez Garcia, Statistician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Signatures (continued) 
 
 
Biostatistician: 
 
 
Jana Neumann 
KLIFO GmbH, Germany 
 
 
 
 
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9 APPENDICES 
 
A 
List of Summary Tables 
B 
List of Data Listings 
C 
List of Figures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix A 
Page 1 of 9 
Statistical Analysis Plan for Final Analysis 
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Final Version 1.0 
 
 
List of Summary Tables 
 
Analysis Sets: 
SCR 
= All Patients Screened 
RND 
= All Patients Randomised 
FAS 
= Full Analysis Set 
SAF 
= Safety Analysis Set 
PK 
= PK Analysis Set 
 
No. 
Title/Content 
Analysis Sets 
1. Study Patients 
1 - 1.1 
Number of patients screened, randomised and included in each analysis 
set, proportion of patients screened but not randomised, frequency of 
reasons for non-randomisation, reasons for exclusion from PK analysis 
set 
SCR 
1 - 1.2 
Completion of full treatment period, follow-up period and full study, 
reasons for premature discontinuation 
Note: Reasons for premature discontinuation will be presented by all 
observed combinations. 
SAF 
1 - 1.3 
Study duration: Last visit of the study 
SAF 
1 - 2.1 
Inclusion and exclusion criteria 
SAF 
1 - 2.2 
Protocol deviations affecting the evaluation of the PK parameters 
SAF 
1 - 2.3 
Compliance with scheduled time windows - Difference between the dates 
of baseline and screening, and difference between the dates of basline 
visit and of each subsequent visit 
SAF 
1 - 2.4 
Compliance with scheduled IMP dose and overall compliance with 
scheduled IMP doses 
SAF 
1 - 3.1 
Demographic data 
Gender, age, age groups, ethnicity, race, height, weight, BMI 
SAF/PK 
1 - 3.2 
Medical history and disease charcteristics 
SAF/PK 
1 - 3.3 
Surgical history 
SAF/PK 
1 - 3.4 
Renal function at baseline - eGFR (based on serum creatinine with CKD- 
EPI equation) 
Note: including categorisation of eGFR 
SAF/PK 
1 - 3.5 
Physical examination at screening 
SAF/PK 
1 - 4.1 
Treatment compliance - IMP dose per IMP administration 
SAF 
1 - 4.2 
Treatment compliance - Total infusion volume [mL] 
SAF 
1 - 4.3 
Treatment compliance - Infusion rate [mL/min] per IMP administration 
SAF 
1 - 4.4 
Treatment compliance - Duration of administration per IMP 
administration 
SAF 
1 - 4.5 
Treatment compliance - Irregularities in IMP administration per IMP 
administration 
SAF 
1 - 4.6 
Treatment compliance - Number of infusions 
SAF 
1 - 4.7 
Treatment compliance - Any dose reduction due to creatinine clearance 
or eGFR <30 mL/min or 30 to <60 mL/min (yes/no) 
SAF 
1 - 4.8 
Treatment compliance - Any irregularities in any IMP administration 
SAF 


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No. 
Title/Content 
Analysis Sets 
1 - 5.1 
All documented therapies (prior or during the study) 
RND/SAF 
1 - 5.2 
Concomitant therapies administered during the treatment period 
SAF 
1 - 5.3 
Concomitant therapies administered during the follow-up period 
SAF 


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No. 
Title/Content 
Analysis Sets 
2. Safety and Tolerability Evaluation - Primary Endpoint 
2 - 1 
Number of subjects with different adverse event categories, overview 
SAF 
2 - 2 
Treatment-emergent adverse events by System Organ Class (SOC) and 
Preferred Term (PT) 
SAF 
2 - 3 
Treatment-emergent serious adverse events by System Organ Class 
(SOC) and Preferred Term (PT) 
SAF 
2 - 4 
Treatment-emergent non-serious adverse events by System Organ Class 
(SOC) and Preferred Term (PT) 
SAF 
2 - 5 
Treatment-emergent adverse events of Special Interest by System Organ 
Class (SOC) and Preferred Term (PT) 
SAF 
2 - 6 
Treatment-emergent adverse events reported as related 
(possible/probable) to IMP by System Organ Class (SOC) and Preferred 
Term (PT) 
SAF 
2 - 7 
Treatment-emergent adverse events leading to withdrawal of IMP by 
System Organ Class (SOC) and Preferred Term (PT) 
SAF 
2 - 8 
Treatment-emergent adverse events by seriousness, severity, causality, 
measures (AE treatment and action taken to IMP) and outcome, overview 
SAF 
2 - 9 
Treatment-emergent adverse events by seriousness, System Organ Class 
(SOC) and Preferred Term (PT) 
SAF 
2 - 10 
Treatment-emergent adverse events by severity, System Organ Class 
(SOC) and Preferred Term (PT) 
SAF 
2 - 11 
Treatment-emergent adverse events by causality, System Organ Class 
(SOC) and Preferred Term (PT) 
SAF 
2 - 12 
Treatment-emergent adverse events by measures (AE treatment and 
action concerning IMP), System Organ Class (SOC) and Preferred Term 
(PT) 
SAF 
2 - 13 
Treatment-emergent adverse events by outcome, System Organ Class 
(SOC) and Preferred Term (PT) 
SAF 
 
3. Safety and Pharmocokinetics Evaluation 
3 - 1 
Physical examination at Day 3 (EOT) and changes from screening to 
EOT. 
Note: Change from screening to EOT will be presented by shift table 
SAF 
3 - 2.1 
Vital signs by time point and absolute changes from baseline by time 
point 
- Systolic blood pressure 
- Diastolic blood pressure 
- Respiratory rate 
- Heart rate 
- Body temperature 
SAF 
3 - 2.2 
Overall assessment of vital signs by time point 
SAF 
3 - 2.3 
Overall assessment of vital signs: Change from baseline by time point 
Note: Shift tables 
SAF 


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No. 
Title/Content 
Analysis Sets 
3 - 3.1 
12-lead ECG parameter and absolute changes from baseline by time point 
- Heart rate 
- PR interval 
- QRS interval 
- QT interval 
- QTc interval 
SAF 
3 - 3.2 
Overall 12-lead ECG assessment by time point 
SAF 
3 - 3.3 
Overall 12-lead ECG assessment: change from baseline by time point 
visit 
Note: Shift tables 
SAF 
3 - 3.4 
Overall continuous ECG assessment at Day 3 (EOT) 
SAF 
3 - 4.1.1 
- 
3 - 4.1.13 
Hematology: Laboratory parameters by time point 
- Leukocytes 
- Erythrocytes 
- Hemoglobin 
- Erythocyte Volume Fraction (EVF) 
- Mean corpuscular volume (MCV) 
- Mean corpuscular hemoglobin (MCH) 
- Mean corpuscular hemoglobin concentration (MCHC) 
- Thrombocytes 
- Neutrophils abs. 
- Monocytes abs. 
- Lymphocytes abs. 
- Eosinophils abs. 
- Basophils abs. 
SAF 
3 - 4.2.1 
- 
3 - 4.2.13 
Hematology: Absolute changes in laboratory parameters from baseline by 
time point 
- Leukocytes 
- Erythrocytes 
- Hemoglobin 
- Erythocyte Volume Fraction (EVF) 
- Mean corpuscular volume (MCV) 
- Mean corpuscular hemoglobin (MCH) 
- Mean corpuscular hemoglobin concentration (MCHC) 
- Thrombocytes 
- Neutrophils abs. 
- Monocytes abs. 
- Lymphocytes abs. 
- Eosinophils abs. 
- Basophils abs. 
SAF 


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No. 
Title/Content 
Analysis Sets 
3 - 4.3.1 
- 
3 - 4.3.13 
Hematology: Normality of laboratory parameters by time point 
- Leukocytes 
- Erythrocytes 
- Hemoglobin 
- Erythocyte Volume Fraction (EVF) 
- Mean corpuscular volume (MCV) 
- Mean corpuscular hemoglobin (MCH) 
- Mean corpuscular hemoglobin concentration (MCHC) 
- Thrombocytes 
- Neutrophils abs. 
- Monocytes abs. 
- Lymphocytes abs. 
- Eosinophils abs. 
- Basophils abs. 
SAF 
3 - 4.4 
Hematology: Shift table for laboratory parameters from baseline to each 
subsequent time point 
Note: Changes from normal to abnormal and from abnormal to normal 
SAF 
3 - 4.5 
Hematology: Overall assessment by timepoint 
SAF 
3 - 4.6 
Hematology overall assessment: Change from baseline by time point visit 
Note: Shift tables 
SAF 
3 - 5.1.1 
- 
3 - 5.1.21 
Clinical chemistry incl. liver function: Laboratory parameters by time 
point 
- Sodium 
- Potassium 
- Phosphate 
- Urea nitrogen 
- Serum Creatinine 
- eGFR (based on serum creatinine) 
- C-reactive protein (CRP) 
- Albumin 
- Calcium 
- Chloride 
- Cystatin C 
- Magnesium 
- Urid acid 
- eGFR (based on serum creatinine and cystatin C) 
- Total bilirubin 
- Conjugated bilirubin 
- AST 
- ALT 
- Gamma-glutanyltransferase (GGT) 
- ALP 
- eGFR (based on cystatin C) 
SAF 


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No. 
Title/Content 
Analysis Sets 
3 - 5.2.1 
Clinical chemistry incl. liver function: Absolute changes in laboratory 
SAF 
- 
parameters from baseline by time point 
3 - 5.2.21 
- Sodium 
- Potassium 
- Phosphate 
- Urea nitrogen 
- Serum Creatinine 
- eGFR (based on serum creatinine) 
- C-reactive protein (CRP) 
- Albumin 
- Calcium 
- Chloride 
- Cystatin C 
- Magnesium 
- Urid acid 
- eGFR (based on serum creatinine and cystatin C) 
- Total bilirubin 
- Conjugated bilirubin 
- AST 
- ALT 
- Gamma-glutanyltransferase (GGT) 
- ALP 
- eGFR (based on cystatin C) 
3 - 5.3.1 
Clinical chemistry incl. liver function: Normality of laboratory 
SAF 
- 
parameters by time point 
3 - 5.3.21 
- Sodium 
- Potassium 
- Phosphate 
- Urea nitrogen 
- Serum Creatinine 
- eGFR (based on serum creatinine) 
- C-reactive protein (CRP) 
- Albumin 
- Calcium 
- Chloride 
- Cystatin C 
- Magnesium 
- Urid acid 
- eGFR (based on serum creatinine and cystatin C) 
- Total bilirubin 
- Conjugated bilirubin 
- AST 
- ALT 
- Gamma-glutanyltransferase (GGT) 
- ALP 
- eGFR (based on cystatin C) 


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No. 
Title/Content 
Analysis Sets 
3 - 5.4 
Clinical chemistry incl. liver function: Shift table for laboratory 
parameters from baseline to each subsequent time point 
Note: Changes from normal to abnormal and from abnormal to normal 
SAF 
3 - 5.5 
Clinical chemistry: Overall assessment by timepoint 
SAF 
3 - 5.6 
Clinical chemistry overall assessment: Change from baseline by time 
point visit 
Note: Shift tables 
SAF 
3 - 6.1.1 
Urinalysis: Laboratory parameters by time point 
SAF 
- 
- Specific gravity 
3 -6.1.10 
- pH 
- Leucocytes 
- Nitrite 
- Protein 
- Glucose 
- Ketones 
- Urobilinogen 
- Bilirubin 
- Erythrocytes 
3 - 6.2 
Urinalysis: Overall assessment by time point 
SAF 
3 - 6.3 
Urinalysis overall assessment: Change from baseline by time point visit 
Note: Shift tables 
SAF 
3 - 7.1 
Urinary output: Overall assessment at Day 3 (EOT) 
SAF 
3 - 7.2 
Urinary output: Creatinine clearance (urine) by time point 
SAF 
3 - 7.3 
Urinary output: Categorised creatinine clearence (urine) by time point 
SAF 
3 - 8.1 
Plasma concentration of RMC-035 by scheduled sample time 
Note: Summary statistics are provided for each treatment group (RMC- 
035; Placebo) and for the treatment groups pooled. Additionally, tables 
with summary statistics for each dose level of RMC-035 by time point are 
provided. 
PK 
3 - 8.2.1 
PK Parameters for RMC-035 in plasma after each of the 5 IMP infusions: PK 
- 
- Cmax 
3 - 8.2.5 
- Ctrough 
- tmax 
- AUCs* 
- t1/2 
Note: Summary statistics are provided for each treatment group 
(RMC-035; Placebo) and for the treatment groups pooled. 
Additionally, tables with summary statistics for each dose level of 
RMC-035 are provided. 
* For each IMP infusion all calculated AUCs will be tabulated 
separately (see AUC-table in SAP Section 4.3.2.3) 


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No. 
Title/Content 
Analysis Sets 
3 - 9.3.1 
PK Parameters for RMC-035 in plasma after fourth dose: 
PK 
- 
- PTR 
3 - 9.3.2 
- Rac(AUC) 
Note: Summary statistics are provided for each treatment group (RMC- 
035; Placebo) and for the treatment groups pooled. Additionally, tables 
with summary statistics for each dose level of RMC-035 by time point are 
provided. 
3 - 10.1 
Presence of ADA at Baseline and Visit 7 (EOS) 
Note: A shift table of presence of ADA between Baseline and Visit 7 
(EOS) will also be presented. 
SAF 
3 - 10.2 
Titers of ADA at Baseline and Visit 7 (EOS) 
SAF 
 
 
4. Exploratory Evaluation and Other Variables 
4 - 1.1.1 
- 
4 - 1.1.2 
Biomarkers: Cardiac biomarkers by time point 
- NT-proBNP 
- Troponin-T 
FAS 
4 - 1.2.1 
- 
4 - 1.2.2 
Biomarkers: Cardiac biomarkers - changes from baseline by time point 
- NT-proBNP 
- Troponin-T 
FAS 
4 - 1.3 
Cardiac biomarkers: Overall assessment by timepoint 
FAS 
4 - 2.1.1 
- 
4 - 2.1.6 
Hemodynamic assessments by time point: 
- Cardiac output (CO) 
- Mixed venous saturation (SvO2) 
- Central venous pressure (CVP): Right ventricular pressure systolic 
- Central venous pressure (CVP): Right ventricular pressure diastolic 
- Central venous pressure (CVP): Pulmonary artery pressure systolic 
- Central venous pressure (CVP): Pulmonary artery pressure diastolic 
FAS 
4 - 2.2.1 
- 
4 - 2.2.6 
Hemodynamic assessments: Changes from baseline by time point: 
- Cardiac output (CO) 
- Mixed venous saturation (SvO2) 
- Central venous pressure (CVP): Right ventricular pressure systolic 
- Central venous pressure (CVP): Right ventricular pressure diastolic 
- Central venous pressure (CVP): Pulmonary artery pressure systolic 
- Central venous pressure (CVP): Pulmonary artery pressure diastolic 
FAS 
4 - 3 
Presence of major adverse kidney event until Day 31 (FU, EOS) (MAKE) 
and combination of MAKE criteria met 
FAS 


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No. 
Title/Content 
Analysis Sets 
4 - 4.1.1 
- 
4 - 4.1.2 
Percent increase from baseline by time point in 
- Serum creatinine 
- Cystatin C 
FAS 
4 - 4.2.1 
- 
4 - 4.2.2 
Maximum increase from baseline during the study until Visit 6 in 
- Serum creatinine 
- Cystatin C 
FAS 
4 - 4.3.1 
- 
4 - 4.3.3 
Percent increase from baseline by time point in 
- eGFR (SCr) 
- eGFR (Cystatin C) 
- eCRF (SCr and Cystatin C) 
FAS 
4 - 4.4.1 
- 
4 - 4.4.3 
Maximum increase from baseline during the study until Visit 6 in 
- eGFR (SCr) 
- eGFR (Cystatin C) 
- eCRF (SCr and Cystatin C) 
FAS 
4 - 4.5 
Post-baseline AUC of Serum creatinine levels from baseline to 48 hours, 
72 hours and Visit Day 7 post-surgery 
FAS 
4 - 4.6 
Post-baseline AUC of Cystatin C levels from baseline to 48 hours, 72 
hours and Visit Day 7 post-surgery 
FAS 
4 - 4.7 
Post-baseline AUC of eGFR(SCr) levels from baseline to 48 hours, 72 
hours and Visit Day 7 post-surgery 
FAS 
4 - 4.8 
Post-baseline AUC of eGFR(Cystatin C) levels from baseline to 48 hours, 
72 hours and Visit Day 7 post-surgery 
FAS 
4 - 4.9 
Post-baseline AUC of eGFR(SCr and Cystatin C) levels from baseline to 
48 hours, 72 hours and Visit Day 7 post-surgery 
FAS 
4 - 5.1 
Severity of AKI 
FAS 
4 - 5.2 
Duration (days) and persistence of AKI 
FAS 
4 - 6.1 
Length of index Intensive Care Unit (ICU) stay and index hospital stay 
FAS 
4 - 6.2 
Nature of patient discharge facility 
FAS 


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Final Version 1.0 
 
 
 
List of Data Listings 
Analysis Sets: 
SCR = All Patients Screened 
RND = Randomized patients 
 
No. 
Title 
Set 
Variables to be included/Variables of 
the following form in the eCRF and 
corresponding derived variables 
Patient Disposition and Baseline Characteristics 
1 – 1.1 
Patient disposition - Allocation to 
analysis sets, reasons for exclusion 
from analysis sets, and treatment 
group in treatment period 
SCR 
Randomised; FAS; PK set; exclusion 
from PK set; treatment group 
1 – 1.2.1 
Randomisation - Not randomised 
patients 
SCR 
Month/year of birth; Screening date; 
Reason and specification for non- 
randomisation 
1 – 1.2.2 
Randomisation - Randomised 
patients 
RND 
Randomisation (incl. Date, Time, 
Randomisation Number); Reason and 
specification for non-randomisation 
1 – 1.3.1 
Completion of treatment period 
RND 
Completion of full treatment period; 
Reasons for premature discontinuation 
(EOT form) 
1 – 1.3.2 
Completion of follow-up period 
RND 
Completion of follow-up period; Reasons 
for subject withdrawal from study (EOS 
form) 
1 – 1.3.3 
Completion of full study 
RND 
Completion of full study; Reason for non- 
completion (combination of EOT and 
EOS form) 
1 – 1.4 
Study duration 
RND 
Last Visit during study; First dose of IMP; 
Last dose of IMP; Number of IMP 
administration; Withdrawal Date 
1 – 1.5.1 
Visit dates and differences between 
visit dates 
RND 
Visit; Visit Date; Date Difference; 
1 – 1.5.2 
Differences between visit dates 
(categorized) 
RND 
Visit; Visit Date; Date Difference 
(categorized) 
1 – 1.5.3 
Differences between start time of 
first IMP administration at baseline 
and start time of each subsequent 
IMP administration 
RND 
All related variables 
1 – 1.5.4 
PK sample times and differences 
between IMP infusion and 
corresponding PK samples 
RND 
Start date and time of IMP infusion, date 
of pre-dose PK sample, PK sample 
times, Difference between start IMP 
infusion and PK sample time; 
Irregularities in plasma PK sampling 
Note: Per IMP administration 


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No. 
Title 
Set 
Variables to be included/Variables of 
the following form in the eCRF and 
corresponding derived variables 
1 – 1.5.5 
Differences between IMP infusion 
and corresponding PK samples 
RND 
Difference between start IMP infusion 
and PK sample time 
Note: Per IMP administration 
Note: CSP V1.0 Table 4 serves as 
template for this listing 
1 – 2.1 
Protocol deviations affecting 
evaluation of PK parameters 
RND 
Type of deviation with specification and 
details; minor or major; reason if minor 
1 – 2.2 
Protocol deviations - overall 
RND 
Data from protocol deviations log 
1 - 2.2 
Inclusion and exclusion criteria 
SCR 
ELIG/RAND Form: Eligibility check 
variables 
1 – 2.3 
Compliance with scheduled IMP 
dose and overall compliance with 
scheduled IMP doses 
RND 
All related variables 
1 – 3.1 
Demographic data I 
RND 
Gender, age, age groups, ethnicity, race, 
height, weight, BMI 
1 – 3.2 
Demographic data II: Women 
related information 
RND 
Child-bearing potential; Pregnancy Test 
1 – 3.3 
Medical history and disease 
characteristics 
RND 
Any disease/symptom/findings; 
Disease/symptom/finding; Onset of 
disease; Ongoing at screening; Date of 
resolution; Relevant details; MedDRA 
coding 
1 – 3.4 
Surgical history 
RND 
Any surgeries; Surgery; Date; Relevant 
details on surgery; MedDRA coding 
1 – 3.5 
Renal function at baseline 
RND 
eGFR at baseline; eGFR categorized at 
baseline 
Note: eGFR at baseline based on serum 
creatinine 
1 – 3.6 
Physical examination at screening 
RND 
Performed; Systems assessed; 
Pathological findings 
1 – 4 
Treatment compliance 
RND 
Variables stated in section 4.2.4 of the 
SAP 
1 – 5 
IMP administration 
RND 
All variables from IMP ADMIN, PK 
SAMPL form if not listed above and 
except for variables regarding plasma 
sampling for pharmacokinetics 
1 – 6.1 
Concomitant medication (Part 1) 
RND 
ATC Levels 
1 – 6.2 
Concomitant medication (Part 2) 
RND 
Pharmaceutical formulation; Indication; 
Dose 
1 – 6.3 
Concomitant medication (Part 3) 
RND 
Frequency; CM Number; Generic Name; 
Frequency; Specification other 
frequency; Route of Administration; 
Specification other route of 
administration; Start and End of drug 
therapy; Therapy ongoing; Used pre- 
study; Used during treatment period; 
Used during FU period 


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No. 
Title 
Set 
Variables to be included/Variables of 
the following form in the eCRF and 
corresponding derived variables 
1 – 7 
Surgery 
RND 
All variables from SURGERY from 
1 – 8 
Pregnancy of female partner 
RND 
All related variables 
1 – 9 
Formal fields (several parts) 
SCR 
1 – 10 
Investigator’s comments (optional) 
SCR 


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No. 
Title 
Set 
Variables 
Safety and Tolerability 
2 – 1 
Adverse events 
RND 
Variables from AE form and 
corresponding derived variables 
2 – 2 
Serious adverse events and deaths 
RND 
see Listing 2 - 1 
2 – 3 
Adverse events of special interest 
(AESI) 
RND 
see Listing 2 - 1 
2 – 4 
AEs reported as related 
(possible/probable) to IMP 
RND 
see Listing 2 - 1 
2 - 5 
Adverse events leading to 
withdrawal of IMP 
RND 
see Listing 2 - 1 
2 - 6 
Pre-treatment adverse events of all 
patients included into the study 
SCR 
see Listing 2 - 1 


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No. 
Title 
Set 
Variables 
Safety and Pharmocokinetics 
3 – 1 
Physical examination at EOT 
RND 
Performed; Systems assessed; Any 
changes compared to the screening 
examination 
3 – 2.1 
Vital signs - Systolic and diastolic 
blood pressure and absolute 
changes 
RND 
Visit; Time point; Date; Time; Values; 
Absolute changes from Baseline 
3 – 2.2 
Vital signs - Respiratory rate, heart 
rate and body temperature and 
absolute changes 
RND 
see above; Temperature measurement 
method 
3 – 2.3 
Vital signs - Overall assessment 
RND 
Visit; Time point; Value 
3 – 3.1 
12-lead ECG - Heart rate, PR 
interval, QRS interval, QT interval, 
QTc interval and absolute changes 
RND 
Visit; Time point; Date; Time; Absolute 
changes from baseline 
3 – 3.2 
12-lead ECG - Overall assessment 
RND 
Visit; Time point; Overall ECG 
assessment; Reason for no assessment 
3 – 3.3 
Overall continuous ECG monitoring 
RND 
ECG monitoring initiated; Start date and 
time; Stop date and time; Reason for not 
done; Overall assessment at EOT 
3 – 4.1.1 
Safety laboratory: Formal fields, 
sampling dates and times 
RND 
For Hematology, Clinical chemistry, and 
Hba1c analysis 
3 – 4.1.2 
Safety laboratory: Irregularities 
RND 
For Hematology, Clinical chemistry, 
Urinalysis 
3 – 4.1.3 
Safety laboratory: Overall 
assessments 
RND 
For Hematology, Clinical chemistry, 
Urinalysis 
3 – 4.2.1 
- 
3 – 
4.2.13 
Hematology: Laboratory parameters 
and absolute changes 
- Leukocytes 
- Erythrocytes 
- Hemoglobin 
- Erythocyte Volume Fraction (EVF) 
- Mean corpuscular volume (MCV) 
- Mean corpuscular haemoglobin 
(MCH) 
- Mean corpuscular hemoglobin 
concentration (MCHC) 
- Thrombocytes 
- Neutrophils abs. 
- Monocytes abs. 
- Lymphocytes abs. 
- Eosinophils abs. 
- Basophils abs. 
RND 
Visit; Time point; Value; Unit; Lower and 
upper limit NR; NR Flag; Technical 
failure; Clinical assessment; Absolute 
change from baseline 


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3 – 4.3.1 
- 
3 – 
4.3.21 
Clinical chemistry incl. liver 
function: Laboratory parameters and 
absolute changes 
- Sodium 
- Potassium 
- Phosphate 
- Urea nitrogen 
- Serum Creatinine 
- eGFR (based on serum creatinine) 
- C-reactive protein (CRP) 
- Albumin 
- Calcium 
- Chloride 
- Cystatin C 
- Magnesium 
- Urid acid 
- eGFR (based on serum creatinine 
and cystatin C) 
- Total bilirubin 
- Conjugated bilirubin 
- AST 
- ALT 
- Gamma-glutanyltransferase (GGT) 
- ALP 
- eGFR (based on cystatin C) 
RND 
Visit; Time point; Value; Unit; Lower and 
upper limit NR; NR Flag; Technical 
failure; Clinical assessment; Absolute 
change from baseline 
3 – 4.4 
HbA1c analysis 
Visit; Value; Unit; Lower and upper limit 
NR; NR Flag; Technical failure; Clinical 
assessment; Irregularities 
3 – 5.1 - 
3 – 5.10 
Urinalysis: Laboratory parameters 
- Specific gravity 
- pH 
- Leucocytes 
- Nitrite 
- Protein 
- Glucose 
- Ketones 
- Urobilinogen 
- Bilirubin 
- Erythrocytes 
RND 
Visit; Value; if applicable: Lower and 
upper limit NR and NR Flag 
3 – 6.1 
Urinary output: Hourly recording 
RND 
All related variables 
3 – 6.2 
Urinary output: Overall assessment 
at EOT 
RND 
Visit; Value 
3 – 6.3 
Urinary output: Creatinine Clearance 
RND 
All related variables 
3 – 7.1 
Plasma concentration of RMC-035: 
Date and time of samples taken 
RND 
Visit; Time point; Date and time of pre- 
dose sample; Time of corresponding 
subsequent samples 


20-ROS-04 (RMC-035) 
EudraCT No: 2020-004107-14 
Statistical Analysis Plan for Final Analysis 
Appendix B 
Page 7 of 9 
Guard_SAP_App_B_List_of_Listings_v10_final_20210611 
Final Version 1.0 
 
 
3 – 7.2.1 
Plasma concentration of RMC-035 
by treatment group and age group 
RND 
Visit; Time point; Dosing of the 
respective IMP administration; Value 
Note: Age group: 18-69 years or ≥70 
years of age at baseline 
Note: Time point should also reflect the 
number of the planned IMP 
administration 
3 – 7.2.2 
Plasma concentration of RMC-035 
by treatment group and renal 
function at baseline 
RND 
Visit; Time point; Dosing of the 
respective IMP administration; Value 
Note: Renal function at baseline: 
Categorisation of eGFR 
Note: Time point should also reflect the 
number of the planned IMP 
administration 
3 – 7.3.1 
PK Parameters for RMC-035 in 
plasma after each of the 5 IMP 
infusions by treatment 
group and age group: 
- Cmax 
- Ctrough 
- tmax 
- AUCs* 
- t1/2 
RND 
Visit; Time point; Dosing of the 
respective IMP administration; PK values 
Note: Age group: 18-69 years or ≥70 
years of age at baseline 
Note: Time point should also reflect the 
number of the planned IMP 
administration 
* For each IMP infusion all calculated 
AUCs will be listed (see AUC-table in 
SAP Section 4.3.2.3) 
3 – 7.3.2 
PK Parameters for RMC-035 in 
plasma after each of the 5 IMP 
infusions by treatment 
group and renal function at baseline: 
- Cmax 
- Ctrough 
- tmax 
- AUCs* 
- t1/2 
RND 
Visit; Time point; Dosing of the 
respective IMP administration; PK values 
Note: Renal function at baseline: 
Categorisation of eGFR 
Note: Time point should also reflect the 
number of the planned IMP 
administration 
* For each IMP infusion all calculated 
AUCs will be listed (see AUC-table in 
SAP Section 4.3.2.3) 
3 – 7.4.1 
PK Parameters for RMC-035 in 
plasma after fourth dose by 
treatment group and age group: 
- PTR 
- Rac(AUC) 
RND 
Visit; Time point; Dosing of the 
respective IMP administration; PK values 
Note: Age group: 18-69 years or ≥70 
years of age at baseline 
Note: Time point should also reflect the 
number of the planned IMP 
administration 
3 – 7.4.2 
PK Parameters for RMC-035 in 
plasma after fourth dose by 
treatment group and renal 
function at baseline: 
- PTR 
- Rac(AUC) 
RND 
Visit; Time point; Dosing of the 
respective IMP administration; PK values 
Note: Renal function at baseline: 
Categorisation of eGFR 
Note: Time point should also reflect the 
number of the planned IMP 
administration 
3 – 8 
Presence and titers of 
ADA and characteristics of ADA 
RND 
All related variables 


20-ROS-04 (RMC-035) 
EudraCT No: 2020-004107-14 
Statistical Analysis Plan for Final Analysis 
Appendix B 
Page 8 of 9 
Guard_SAP_App_B_List_of_Listings_v10_final_20210611 
Final Version 1.0 
 
 
No. 
Title 
Set 
Variables 
Exploratory Evaluation and Other Variables 
4 – 1 
Biomarkers: Formal fields, sampling 
dates and times 
RND 
All related variables for plasma, serum, 
and urine 
4 – 2.1 
Cardiac biomarkers: Formal fields, 
sampling dates and times 
RND 
All related variables 
4 – 2.2.1 
- 
4 – 2.2.2 
Cardiac biomarkers: Laboratory 
parameters and absolute changes 
- NT-proBNP 
- Troponin-T 
RND 
Visit; Time point; Value; Absolute change 
from baseline; Irregularities in cardiac 
biomarker analysis 
4 – 2.3 
Cardiac biomarkers: Overall 
assessment 
RND 
Visit; Time point; Value 
4 – 3 
Concentration of RMC-035 in urine: 
Formal fields, sampling dates and 
times 
RND 
All related variables 
4 – 4.1 
Hemodynamic assessments: Formal 
fields, sampling dates and times 
RND 
All related variables 
4 – 4.2.1 
- 
4 – 4.2.6 
Hemodynamic assessments and 
changes from baseline 
- Cardiac output (CO) 
- Mixed venous saturation (SvO2) 
- Central venous pressure 
(CVP):Right ventricular pressure 
systolic 
- Central venous pressure (CVP): 
Right ventricular pressure 
diastolic 
- Central venous pressure (CVP): 
Pulmonary artery pressure 
systolic 
- Central venous pressure (CVP): 
Pulmonary artery pressure 
diastolic 
RND 
Visit; Time point; Value; Absolute change 
from baseline 
4 – 5.1 
Major adverse kidney event 
(MAKE30) during the trial 
RND 
MAKE during the trial (yes/no) 
4 – 5.2 
Major adverse kidney event 
(MAKE30) and components of 
MAKE30 by visit 
RND 
Visit; MAKE30 (yes/no); MAKE criteria 
4 – 5.3 
Dialysis information 
RND 
Visit; Variables regarding dialysis from 
the V-Start form 
4 – 6.1.1 
- 
4 – 6.1.5 
Percent increase from baseline in 
- Serum creatinine 
- Cystatin C 
- eGFR(SCr) 
- eGFR(Cystatin C) 
- eGFR(SCr and Cystatin C) 
RND 
Visit; Time point; Value; Absolute change 
from baseline; Relative change from 
baseline 
4 – 6.2 
Maximum percent increase from 
baseline until Visit 6 in Serum 
creatinine, Cystatin C, and in the 
corresponding eGRF values 
RND 
Maximum percent increase from baseline 
until Visit 6 for 
- Serum creatinine 
- Cystatin C 
- eGFR(SCr) 
- eGFR(Cystatin C) 
- eGFR(SCr and Cystatin C) 


20-ROS-04 (RMC-035) 
EudraCT No: 2020-004107-14 
Statistical Analysis Plan for Final Analysis 
Appendix B 
Page 9 of 9 
Guard_SAP_App_B_List_of_Listings_v10_final_20210611 
Final Version 1.0 
 
 
4 – 6.3.1 
- 
4 – 6.3.5 
Post-baseline AUC 48 hours, 72 
hours and at Visit Day 7 post- 
surgery for 
- Serum Creatinine (SCr) 
- Cystatin C levels 
- eGFR(SCr) 
- eGFR(Cystatin C) 
- eGFR(SCr and Cystatin C) 
RND 
All related variables 
4 – 7.1 
Severity, duration and persistence of 
AKI 
RND 
Maximum AKI stage until Visit 6; 
Duration of AKI, persistence of AKI 
(yes/no) 
Note: Maximum AKI stage: The highest 
stage per patient will be used 
4 – 7.2 
AKI Stage and its components by 
visit 
RND 
AKI stage by visit (until Visit 6); SCr 1.5 
to 1.9 times baseline value (yes/no), 
Increase in SCr ≥0.3 mg/dL (≥ 26.5 
µmol/L) within 48 hours (yes/no); Urine 
output <0.5 mL/min/h for 6 to <12 hours 
(yes/no); SCr 2.0-2.9 times baseline 
value (yes/no); urine output <0.5 
mL/min/h for ≥ 12 hours (yes/no); SCr 
3.0 times baseline value (yes/no); 
Increase in SCr 5.0 mg/dL (≥353.6 
µmol/L) (yes/no); initiation of renal 
replacement therapy (yes/no); Urine 
output <0.3 mL/min/h for ≥24 hours 
(yes/no); Anuria for ≥12 hours (yes/no) 
4 – 8.1 
Length of index Intensive Care Unit 
(ICU) stay 
RND 
Variables from ICU form and 
corresponding derived variables 
4 – 8.2 
Length of index hospital stay and 
discharge facility 
RND 
Variables from HOSP form and 
corresponding derived variables 
 
NOTE: The wording may be adapted in the final output, also some listings may be split into 
two or more parts if they do not fit on the page, and several listings may be combined where 
reasonable depending on size. 


20-ROS-04 (RMC-035) 
EudraCT No: 2020-004107-14 
Statistical Analysis Plan for Final Analysis 
Appendix C 
Page 1 of 3 
Guard_SAP_App_C_List_of_Figures_v10_final_20210611 
Final Version 1.0 
 
 
 
List of Figures 
Analysis Sets: 
SAF = Safety Analysis Set 
PK = PK Analysis Set 
 
No. 
Title 
Type 
Set 
Safety and Pharmocokinetics Evaluation 
3 – 1.1.1 
- 
3 – 1.1.5 
Vital signs – Mean-by-visit: 
- Systolic blood pressure 
- Diastolic blood pressure 
- Respiratory rate 
- Heart rate 
- Body temperature 
Box plots 
SAF 
3 – 1.2.1 
- 
3 – 1.2.5 
Vital signs – Subject-profile-by-visit: 
- Systolic blood pressure 
- Diastolic blood pressure 
- Respiratory rate 
- Heart rate 
- Body temperature 
Line charts 
SAF 
3 – 2.1.1 
- 
3 – 2.1.5 
12-lead ECG – Mean-by-visit: 
- Heart rate 
- PR interval 
- QRS interval 
- QT interval 
- QTc interval 
Box plots 
SAF 
3 – 2.2.1 
- 
3 – 2.2.5 
12-lead ECG - Subject-profile-by-visit: 
- Heart rate 
- PR interval 
- QRS interval 
- QT interval 
- QTc interval 
Line charts 
SAF 
3 – 3.1.1 
- 
3 – 3.1.13 
Hematology laboratory parameters - Mean-by-visit: 
- Leukocytes 
- Erythrocytes 
- Hemoglobin 
- Erythocyte Volume Fraction (EVF) 
- Mean corpuscular volume (MCV) 
- Mean corpuscular hemoglobin (MCH) 
- Mean corpuscular hemoglobin concentration (MCHC) 
- Thrombocytes 
- Neutrophils abs. 
- Monocytes abs. 
- Lymphocytes abs. 
- Eosinophils abs. 
- Basophils abs. 
Box plots 
SAF 


20-ROS-04 (RMC-035) 
EudraCT No: 2020-004107-14 
Statistical Analysis Plan for Final Analysis 
Appendix C 
Page 2 of 3 
Guard_SAP_App_C_List_of_Figures_v10_final_20210611 
Final Version 1.0 
 
 
No. 
Title 
Type 
Set 
Safety and Pharmocokinetics Evaluation 
3 – 3.2.1 
- 
3 – 3.2.13 
Hematology laboratory parameters - Subject-profile-by-visit: 
- Leukocytes 
- Erythrocytes 
- Hemoglobin 
- Erythocyte Volume Fraction (EVF) 
- Mean corpuscular volume (MCV) 
- Mean corpuscular hemoglobin (MCH) 
- Mean corpuscular hemoglobin concentration (MCHC) 
- Thrombocytes 
- Neutrophils abs. 
- Monocytes abs. 
- Lymphocytes abs. 
- Eosinophils abs. 
- Basophils abs. 
Line charts 
SAF 
3 – 4.1.1 
- 
3 – 4.1.21 
Clinical chemistry incl. liver function laboratory parameters – 
Mean-by-visit: 
- Sodium 
- Potassium 
- Phosphate 
- Urea nitrogen 
- Serum Creatinine 
- eGFR (based on serum creatinine) 
- C-reactive protein (CRP) 
- Albumin 
- Calcium 
- Chloride 
- Cystatin C 
- Magnesium 
- Urid acid 
- eGFR (based on serum creatinine and cystatin C) 
- Total bilirubin 
- Conjugated bilirubin 
- AST 
- ALT 
- Gamma-glutanyltransferase (GGT) 
- ALP 
- eGFR (based on cystatin C) 
Box plots 
SAF 


20-ROS-04 (RMC-035) 
EudraCT No: 2020-004107-14 
Statistical Analysis Plan for Final Analysis 
Appendix C 
Page 3 of 3 
Guard_SAP_App_C_List_of_Figures_v10_final_20210611 
Final Version 1.0 
 
 
No. 
Title 
Type 
Set 
Safety and Pharmocokinetics Evaluation 
3 – 4.2.1 
- 
3 – 4.2.21 
Clinical chemistry incl. liver function laboratory parameters – 
Subject-profile-by-visit: 
- Sodium 
- Potassium 
- Phosphate 
- Urea nitrogen 
- Serum Creatinine 
- eGFR (based on serum creatinine) 
- C-reactive protein (CRP) 
- Albumin 
- Calcium 
- Chloride 
- Cystatin C 
- Magnesium 
- Urid acid 
- eGFR (based on serum creatinine and cystatin C) 
- Total bilirubin 
- Conjugated bilirubin 
- AST 
- ALT 
- Gamma-glutanyltransferase (GGT) 
- ALP 
- eGFR (based on cystatin C) 
Line charts 
SAF 
3 – 5.1 
PK Analysis - Individual concentration-time profiles 
Line chart 
PK 
3 – 5.2 
PK Analysis - Mean concentration-time profile 
Line chart 
PK 
3 – 6.1 
PK Analysis - Dose proportionality for Cmax 
Scatter plots 
PK 
3 – 6.2 
PK Analysis - Dose proportionality for AUCτ 
Note: Since τ varies between the different dose administrations, 
the following AUCs will be used: AUC0-6h, 1st dose, AUC0-6h, 2nd dose, 
AUC0-12h, 3rd dose, AUC0-24h, 4th dose, AUC0-2h, 5th dose (see SAP 
Section 4.3.2.3) 
Scatter plots 
PK 
 
NOTE: Some figures may be combined in one output file where reasonable. 

Prot_003.pdf: 
Guard Therapeutics International AB  
RMC-035 
                                                                        20-ROS-04 
 
Confidential 
 
Page 1 of 67 
Version 2.0, 22 Dec 2020 
CLINICAL STUDY PROTOCOL 
Protocol Title:  
A Phase 1b, Randomised, Double-Blind, Parallel Treatment Group Clinical Study to Evaluate 
the Safety, Tolerability and Pharmacokinetics of RMC-035 in Subjects Undergoing Non-
Emergent On-Pump Coronary Artery Bypass Graft and/or Valve Surgery 
Protocol Number: 20-ROS-04 
Compound: RMC-035 
Amendment Number: N/A 
Study Phase: Phase 1b 
 
Short Title:  
A Phase 1b study of RMC-035 in subjects undergoing Cardiac Surgery 
Sponsor Name:  
Guard Therapeutics International AB  
Tobias Agervald, MD, PhD  
E-mail: tobias.agervald@guardtherapeutics.com 
Legal Registered Address:  
Guard Therapeutics International AB  
Scheelevägen 22, SE-223 63 Lund, Sweden  
Phone: +46 46 286 50 30  
Regulatory Agency Identifier Number(s) 
EudraCT No.:  2020-004107-14 
Approval Date:  
22-DEC-2020 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by applicable 
laws and regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential. 
 
 
 
 


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                                                                        20-ROS-04 
 
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Version 2.0, 22 Dec 2020 
 
Sponsor Signatory: 
 
 
 
 
 
Tobias Agervald 
Chief Medical Officer 
 
Date 
 
 
 
 
 
 
Principal Investigator Signatory: 
 
 
 
 
 
Prof. Dr. Med. Alexander Zarbock 
Principal Investigator 
 
Date 
 
 
 
 
 
 


Guard Therapeutics International AB  
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                                                                        20-ROS-04 
 
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Version 2.0, 22 Dec 2020 
RESPONSIBLE PERSONNEL 
 
Sponsor/Emergency Contact -  
Medically Responsible Person 
and Coordinating Office 
 
 
 
Tobias Agervald, MD, PhD  
Guard Therapeutics International AB  
Scheelevägen 22,  
SE-223 63 Lund, Sweden  
E-mail address: tobias.agervald@guardtherapeutics.com 
Phone number: +46 768 70 93 98 
 
Coordinating Investigator 
 
 
Prof. Dr. Med. Alexander Zarbock 
Münster University Hospital  
Dep. of Anesthesiology and Critical Care Medicine 
Albert-Schweitzer-Strasse 33, Campus 1, Building A1 
DE-481 49 Münster, Germany 
E-mail: zarbock@uni-muenster.de 
Phone number: +49 251 83-44017 
 
Contract Research 
Organisation (CRO) -   
trial management and clinical 
monitoring 
 
KLIFO A/S 
Smedeland 36,  
DK-2600 Glostrup, Denmark 
E-mail address: sara.hedman@klifo.com 
Phone number: +45 44 22 29 00 
 
Pharmacovigilance 
 
KLIFO A/S 
Smedeland 36,  
DK-2600 Glostrup, Denmark 
E-mail: Pharmacovigilance@klifo.com  
Fax number: +45 39 20 90 45 
 
Pharmacy  
 
University Hospital Münster, 
DE- Münster, Germany 
Dr. rer. Nat. C. Klaas  
E-mail: cristoph.klaas@ukmuenster.de 
Phone number: +49-251-8348843 
 
Local Laboratory  
(safety, biomarkers)  
 
University Hospital Münster, Germany  
Dr. rer. Nat. Manfred Fobker 
E-mail: Manfred.Fobker@ukmuenster.de 
Phone number: +49-251-8348701  
 
Analysis Laboratory 
(pharmacokinetics) 
 
 
Mercodia AB 
Sylveniusgatan 8A,  
SE- 754 50 Uppsala, Sweden 
Phone number: +46 18 57 00 70 
 
 
 


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                                                                        20-ROS-04 
 
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Version 2.0, 22 Dec 2020 
RESPONSIBLE PERSONNEL 
 
Analysis Laboratory  
(ADA samples) 
 
Wieslab AB 
Lundavägen 151 
SE- 212 24 Malmö, Sweden 
Phone number: +46 40 53 76 00 
 
Calculation of 
Pharmacokinetics parameters 
 
PKxpert AB 
Karolinska Institutet Science Park 
Fogdevreten 2 
SE-171 65 Solna, Sweden 
Phone number: +46 8 765 698 175  
 
 
 


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                                                                        20-ROS-04 
 
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Version 2.0, 22 Dec 2020 
TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ........................................................................................ 8 
1.1 
Synopsis ....................................................................................................................... 8 
1.2 
Schedule of Assessments ........................................................................................... 11 
2 
INTRODUCTION ................................................................................................... 16 
2.1 
Study Rationale ......................................................................................................... 16 
2.2 
Background................................................................................................................ 16 
2.2.1 
Pharmacology ............................................................................................................... 16 
2.2.2 
Summary of Toxicology Studies .................................................................................. 16 
2.2.3 
Summary of Clinical Studies ........................................................................................ 17 
2.2.3.1 
Single Ascending Dose Study (17-ROS-01) ............................................................... 17 
2.2.3.2 
Multiple Ascending Dose Study (19-ROS-02) ........................................................... 17 
2.2.3.3 
Renal Impairment Study (19-ROS-03)....................................................................... 18 
2.2.3.4 
Anti-Drug-Antibodies (ADA) ..................................................................................... 18 
2.3 
Benefit/Risk Assessment ........................................................................................... 19 
2.3.1 
Key Safety Information ................................................................................................ 19 
2.3.1.1 
Risks associated with the Patient Population and Study Assessments ...................... 20 
2.3.1.2 
General and Standard Precautions in the study ........................................................ 20 
2.3.2 
Benefit Assessment ...................................................................................................... 20 
2.3.3 
Overall Benefit: Risk Assessment ................................................................................ 20 
3 
OBJECTIVES AND ENDPOINTS ........................................................................ 21 
3.1 
Primary, secondary and exploratory objectives ......................................................... 21 
3.1.1 
Primary objective: ........................................................................................................ 21 
3.1.2 
Secondary objective: .................................................................................................... 21 
3.1.3 
Exploratory objectives: ................................................................................................. 21 
3.2 
Primary, secondary and exploratory endpoints ......................................................... 21 
3.2.1 
Primary endpoint .......................................................................................................... 21 
3.2.2 
Secondary endpoint ...................................................................................................... 21 
3.2.3 
Exploratory endpoint(s) ................................................................................................ 22 
4 
STUDY DESIGN ..................................................................................................... 23 
4.1 
Overall Design ........................................................................................................... 23 
4.2 
Scientific Rationale for Study Design ....................................................................... 24 
4.3 
Dose and Dose regimen ............................................................................................. 24 
4.3.1 
Dose Adjustment for Renal Function at baseline ......................................................... 25 
4.4 
End of Study Definition............................................................................................. 25 
5 
STUDY POPULATION .......................................................................................... 26 
5.1 
Inclusion Criteria ....................................................................................................... 26 
5.2 
Exclusion Criteria ...................................................................................................... 27 
5.3 
Screen Failures .......................................................................................................... 28 
6 
TREATMENTS ....................................................................................................... 29 
6.1 
Treatments(s) administered ....................................................................................... 29 
6.2 
Preparation/Handling/Storage/Accountability .......................................................... 30 
6.2.1 
Packaging and labelling of IMP ................................................................................... 30 
6.2.2 
Storage of IMP ............................................................................................................. 30 
6.2.3 
Preparation of IMP ....................................................................................................... 30 
6.2.4 
Administration of IMP ................................................................................................. 30 


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6.2.5 
Accountability of IMP .................................................................................................. 31 
6.2.6 
Return and Destruction of IMP .................................................................................... 31 
6.3 
Measures to Minimize Bias; Randomization and Blinding ....................................... 31 
6.4 
Treatment Compliance .............................................................................................. 32 
6.5 
Concomitant Therapy ................................................................................................ 32 
6.5.1 
Restricted concomitant medications: ............................................................................ 32 
6.6 
Dose Modification ..................................................................................................... 33 
6.7 
Treatment after the End of the Study ........................................................................ 33 
7 
TEMPORARY STUDY HALT, DISCONTINUATION OF IMP AND 
SUBJECT DISCONTINUATION/WITHDRAWAL ........................................... 34 
7.1 
Temporary Study Halt ............................................................................................... 34 
7.2 
Discontinuation of IMP ............................................................................................. 34 
7.3 
Subject Discontinuation/Withdrawal from the Study................................................ 35 
7.3.1 
Replacement of subjects ............................................................................................... 35 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................. 36 
8.1 
Recording of Data...................................................................................................... 36 
8.2 
Demographics and other baseline characteristics ...................................................... 36 
8.2.1 
Informed Consent ......................................................................................................... 36 
8.2.2 
Demography ................................................................................................................. 36 
8.2.3 
Height and weight......................................................................................................... 36 
8.2.4 
Medical/surgical history ............................................................................................... 36 
8.2.5 
Prior and concomitant medication ................................................................................ 37 
8.2.6 
Pregnancy test ............................................................................................................... 37 
8.3 
Safety Assessments ................................................................................................... 37 
8.3.1 
Physical Examinations.................................................................................................. 37 
8.3.2 
Assessments before, during and after Surgery ............................................................. 38 
8.3.3 
Vital Signs .................................................................................................................... 38 
8.3.4 
Electrocardiograms ....................................................................................................... 38 
8.3.5 
ECG monitoring ........................................................................................................... 38 
8.3.6 
Clinical Safety Laboratory Assessments ...................................................................... 38 
8.3.7 
Urinary output .............................................................................................................. 39 
8.4 
Adverse Events and Serious Adverse Events ............................................................ 39 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ........................ 40 
8.4.2 
Method of Detecting AEs and SAEs ............................................................................ 40 
8.4.3 
AEs and SAEs excluded from recording and reporting ............................................... 40 
8.4.4 
Follow-up of AEs and SAEs ........................................................................................ 40 
8.4.5 
Regulatory Reporting Requirements for SAEs ............................................................ 40 
8.4.6 
Pregnancy ..................................................................................................................... 41 
8.4.7 
Adverse Events of Special Interest ............................................................................... 41 
8.5 
Treatment of Overdose .............................................................................................. 41 
8.6 
Efficacy Assessments ................................................................................................ 42 
8.7 
Pharmacokinetics Assessments ................................................................................. 43 
8.8 
Pharmacodynamics and Biomarkers ......................................................................... 44 
8.9 
Immunogenicity Assessments ................................................................................... 45 
8.10 
Medical Resource Utilization and Health Economics ............................................... 46 
9 
STATISTICAL CONSIDERATIONS ................................................................... 47 
9.1 
Statistical Hypotheses ................................................................................................ 47 


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9.2 
Sample Size Determination ....................................................................................... 47 
9.3 
Population for Analyses ............................................................................................ 47 
9.4 
Statistical Analyses .................................................................................................... 47 
9.4.1 
General Considerations ................................................................................................ 47 
9.4.2 
Demographic and Baseline Characteristics .................................................................. 47 
9.4.3 
Treatment compliance .................................................................................................. 48 
9.4.4 
Primary endpoint(s) ...................................................................................................... 48 
9.4.5 
Secondary endpoint(s) .................................................................................................. 48 
9.4.6 
Exploratory endpoint(s) ................................................................................................ 49 
9.5 
Interim Analyses ........................................................................................................ 49 
9.6 
Data Monitoring Committee (DMC) ......................................................................... 49 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 50 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................... 50 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 50 
10.1.2 
Financial Disclosure ..................................................................................................... 50 
10.1.3 
Informed Consent Process ............................................................................................ 50 
10.1.4 
Data Protection ............................................................................................................. 51 
10.1.5 
Insurance....................................................................................................................... 51 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 51 
10.1.7 
Data Quality Assurance ................................................................................................ 52 
10.1.8 
Source Documents ........................................................................................................ 53 
10.1.9 
Study and Site Start and Closure .................................................................................. 53 
10.2 
Appendix 2: Clinical Laboratory Tests ..................................................................... 55 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 56 
10.3.1 
Definition of AE ........................................................................................................... 56 
10.3.2 
Definition of SAE ......................................................................................................... 57 
10.3.3 
Recording and Follow-Up of AE and/or SAE .............................................................. 58 
10.3.4 
Reporting of SAEs ........................................................................................................ 61 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 62 
10.5 
Appendix 5: List of Abbreviations and Definitions of Terms ................................... 64 
11 
REFERENCES ........................................................................................................ 67 
 
TABLE OF TABLES 
Table 1  Schedule of Assessment – Complete Study Period ................................................. 11 
Table 2  Schedule of Assessment – Treatment Period ........................................................... 14 
Table 3  IMP characteristics .................................................................................................... 29 
Table 4  Plasma PK: Sampling time point’s incl. allowed sampling windows .................... 43 
Table 5  Biomarkers: sample, assay and time points’ incl. allowed sampling windows .... 45 
Table 6  Defined Populations ................................................................................................... 47 
Table 7  Protocol Required Safety Laboratory Assessments ............................................... 55 
 
TABLE OF FIGURES 
Figure 1   Study Flowchart ......................................................................................................... 24 


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Rationale: 
This is the first clinical study in cardiac surgery patients and is being conducted to guide further 
clinical development in this patient population. Based on an integrated assessment of available 
nonclinical and clinical data, the number of doses and infusion time are considered to be safe and 
to provide targeted protection against oxidative stress and heme toxicity in this patient 
population, with the aim to prevent or ameliorate post-surgery renal injury.  
Key Objectives and Key Endpoints: 
Primary Objective: 
• 
To evaluate the safety and tolerability of RMC-035 in subjects undergoing non-emergent,  
on-pump Coronary Artery Bypass Graft (CABG) and/or valve surgery 
 
Secondary Objective: 
• To evaluate the pharmacokinetics of RMC-035 in this patient population 
• 
Identification and characterization of Anti-Drug-Antibodies (ADA) developed after 
multiple intravenous administrations of RMC-035 
 
Primary Endpoint: 
• Nature, frequency and severity of AEs  
 
Secondary Endpoint: 
• Clinically significant changes in safety laboratory tests (hematology, biochemistry, 
urinalysis)  
• Clinically significant changes in vital signs (blood pressure, heart rate, respiratory rate)  
• Clinically significant changes in 12-lead ECG  
• Pharmacokinetics of RMC-035 in plasma: Cmax, Ctrough  
• Pharmacokinetics of RMC-035 in plasma after fourth dose: AUCτ, Cmax, Ctrough, PTR, 
Rac(AUC), t1/2  
• 
Presence and titers of ADA 30 days after surgery  
• Characteristics of ADA developed 30 days after surgery with regards to isotype, 
neutralizing capacity and cross-reactivity with endogenous alpha-1-microglobulin 
 
 
 
 
 
 
 
 
 
 
 
 


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Overall Design: 
This is a study with two parallel treatment groups where subjects are randomised to receive  
RMC-035 or a matching placebo in a double-blind fashion.  
Randomization will be performed on Day -1 where consented subjects, who are found eligible for 
study participation, will be randomised to receive intravenous dosing of either RMC-035 treatment 
or matching placebo in a 2:1 ratio.  
Subjects must comply with the following key inclusion and exclusion criteria:  
Key Inclusion Criteria: 
• Female and male subjects with an age ≥18 years  
• Subject is scheduled for non-emergent (elective) CABG and/or valve surgery (single or 
multiple valves) with use of cardiopulmonary bypass (CPB) 
• Subject has at least ONE of the following risk factors for AKI at screening: 
o History of LVEF <35% for at least 3 months prior to screening assessed by either 
echocardiography, cardiac MRI or nuclear scan.  
o History of previous open chest cavity cardiac surgery with or without CPB 
o Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months prior to 
screening AND ongoing treatment with an approved anti-diabetic drug 
o Age ≥70 years 
o Documented history of heart failure NYHA class II or higher for at least 3 months 
or longer at screening 
o Documented history of previous AKI before date of screening independent of the 
etiology of AKI 
o Documented history of anemia with hemoglobin ≤ 11 g/dL (≤6.8 mmol/L) for at 
least 3 months prior to screening 
o Documented history of albuminuria, defined as UACR >30 mg/g or > 30 mg/24 
hour in a 24-hour urine collection. 
o eGFR is ≤ 60 mL/min/1.73 m2 using the Chronic Kidney Disease – Epidemiology 
Collaboration (CKD-EPI) equation 
 
Key Exclusion Criteria: 
• Estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m2 using the Chronic 
Kidney Disease – Epidemiology Collaboration (CKD-EPI) equation at screening or at 
baseline 
• Subject has surgery scheduled to be performed without CPB (“off-pump”) 
• Subject has surgery scheduled for aortic dissection  
• Subject is scheduled for CABG and/or valve surgery combined with additional non-
emergent cardiac surgeries, e.g. for atrial fibrillation ablation 
• Subject is scheduled to undergo trans catheter aortic valve implantation (TAVI) or  
trans catheter aortic valve replacement (TAVR), or single vessel off-pump surgeries or 
left ventricular device (LVAD) implantation 
• Subject has a requirement for any of the following within one week prior to surgery: 
defibrillator or permanent pacemaker, mechanical ventilation, IABP, LVAD, other forms 
of mechanical circulatory support (MCS) (Note: The prophylactic insertion of an IABP 
preoperatively for reasons not related to existing LV pump function is not exclusionary) 
 


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Disclosure Statement:  
This is a randomised, parallel group treatment study with two (2) arms where subject and 
investigator are blinded. 
Number of Subjects: 
Twelve subjects undergoing elective on-pump CABG and/or valve surgery at high risk to 
develop peri- and post-surgery AKI will be enrolled in the study.  
Two additional subjects may be enrolled at the Sponsor’s discretion in case of early treatment 
discontinuations, which are not due to formal stopping criteria. 
 
Treatment Groups and Duration: 
The study will consist of three study periods:  
• Screening: Day -1  
• Treatment period: Day 1-3  
• Safety follow-up period: Day 4-31.  
The follow-up period will consist of three visits (Day 4, Day 7 and Day 31).  
A total of five doses of RMC-035 or placebo will be administered as IV infusions during the 
treatment period:  
• First dose of RMC-035 is 1.3 mg/kg or placebo and will be administered over 60 
minutes. Dose administration should start during surgery, 10 minutes before the expected 
start of cardiopulmonary bypass (CPB).  
• Second, third, fourth and fifth doses of RMC-035 are 1.3 mg/kg per dose or placebo 
administration and will be administered over 30 minutes. Dose administrations start at  
6, 12, 24 and 48 hours after the start of the first dose administration. 
• Dose of RMC-035 will be reduced by 50% (i.e. 0.65 mg/kg per dose administration) in 
patients with eGFR 30 to <60 mL/min/1.73 m2 at baseline. 
• The dose of RMC-035 may be reduced for the 3rd, 4th and 5th IMP administration, 
depending on the renal function. 
 
Data Monitoring Committee:  
No data monitoring committee will be established and used in this clinical study. 
 


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1.2 
Schedule of Assessments  
Table 1  Schedule of Assessment – Complete Study Period 
 
 
Assessments 
Screening Period 
Treatment Period 
Follow-Up Period 
 
1 day 
IMP Administration 
Up to 30 days after surgery 
Visit Number 
1 
2 
3 
4 (EOT) 
5 
6 
7 (EOS)  e 
Visit Day 
-1 
1 
2 
3 
4 
7 
31 
Allowed visit window (days) 
-5 
±0 
±0 
±0 
±0 
±1 
±3 
Informed consent 
x 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
In/Exclusion criteria 
x 
x 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
Weight and height a 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
x 
 
 
 
Prior and concomitant medication  
x 
 
 
 
 
 
 
Serum pregnancy test (HCG) (WOCBP only) 
x 
 
 
 
 
 
x 
Hematology lab 
x 
x 
x 
x 
x 
x 
x 
Clinical chemistry lab 
x 
x 
x 
x 
x 
x 
x 
Cardiac biomarkers (NT-proBNP, Troponin I) 
 
x 
x 
x 
x 
x 
x 
Liver function lab 
x 
x 
x 
x 
x 
x 
x 
Serum Creatinine (SCr) and Cystatin C 
x 
x 
x 
x 
x 
x 
x 


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Assessments 
Screening Period 
Treatment Period 
Follow-Up Period 
 
1 day 
IMP Administration 
Up to 30 days after surgery 
Visit Number 
1 
2 
3 
4 (EOT) 
5 
6 
7 (EOS)  e 
Visit Day 
-1 
1 
2 
3 
4 
7 
31 
Allowed visit window (days) 
-5 
±0 
±0 
±0 
±0 
±1 
±3 
HbA1c 
x 
 
 
 
 
 
x 
Urinalysis 
 
x 
 
x 
 
 
 
Randomization 
x 
 
 
 
 
 
 
IMP administration 
 
x 
x 
x 
 
 
 
Plasma PK sampling  
 
x 
x 
x 
 
 
 
12-lead electrocardiogram 
x 
x 
x 
x 
 
x 
 
Continuous ECG monitoring b 
 
 
 
 
 
 
 
Vital signs (BP, heart rate, respiratory rate) 
x 
x 
x 
x 
x 
x 
 
Surgery Assessments c 
 
x 
 
 
 
 
 
Discharge from ICU d 
 
 
 
 
 
 
 
Hemodynamic Assessments  (CO, SvO2, CVP) 
 
x 
 
 
 
 
 
Urine output 
 
 
 
 
 
 
 
Sampling for biomarkers (plasma, serum and urine)  
 
x 
x 
x 
x 
 
 
Sampling for RMC-035 (urine) 
 
x 
x 
x 
x 
 
 
ADA assessment  
 
x 
 
 
 
 
x 
AE and concomitant medication recording  
 
 
 
 
 
 
 


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a Height only measured at screening (visit 1) 
b Cardiac surveillance from start of first infusion until 6 hours after start of last infusion 
c Data being collected before, during and after surgery: time on CPB, duration of surgery, volume blood loss, administration of fluids (e.g. transfusion of red blood cells and osmotic agents) and 
time of admission to the ICU 
d Time of discharge from ICU to hospital ward, another treatment facility or home 
e Visit can take place either at the investigational site or at the patient’s general practitioner 
 
 
 


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Table 2  Schedule of Assessment – Treatment Period 
Visit Day  
Day 1 
Day 2 
Day 3 
Hours 
Pre-surgery a 
0 b 
0.25 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
48 
Visit Number 
2 
3 
4 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication c 
X 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Cardiac Surgery Assessments d   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 x e 
 
 
 
 
 
 
 
x f 
 
x f 
x f 
x f 
Plasma PK sampling 
X 
 
x 
x 
x 
x 
x 
x 
x 
x g 
 
x g 
x g 
x g 
12-lead electrocardiogram  
X 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Continuous ECG monitoring h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, heart rate, respiratory 
rate) 
X 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Hematology lab 
X 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Clinical chemistry lab 
X 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Cardiac biomarkers  
(NT-proBNP, Troponin I) 
X 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Liver function tests 
X 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Serum Creatinine (SCr) and Cystatin C 
X 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
Urinanalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Hemodynamic Assessments (CO, CVP) l 
X 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Hemodynamic Assessments (SvO2) 
X 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
Sampling for biomarkers (plasma, 
serum and urine) i 
X 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Sampling for RMC-035 (urine) 
X 
 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
Urinary output k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit Day  
Day 1 
Day 2 
Day 3 
Hours 
Pre-surgery a 
0 b 
0.25 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 
24 
48 
Visit Number 
2 
3 
4 
Creatinine Clearance (CrCl) (urine) m 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
ADA assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Pre-surgery assessments will be performed within 60 minutes before surgery   
b Time point 0 is defined as 10 minutes before expected onset of cardiopulmonary bypass (CPB) 
c Including medications and anesthesia administered during surgery  
d Collection before, during and after surgery: time on CPB, duration of surgery, volume blood loss, administration of fluids (e.g. transfusion of red blood cells and osmotic agents) and time of 
admission to the ICU.  
e IV infusion over 60 minutes, first infusion should start 10 minutes before expected onset of CPB 
f IV infusion over 30 minutes at 6 h, 12 h, 24 h and 48 h after the start of first infusion 
g PK sampling will be performed at the following time points:   
Day 1 (Infusion at 6 h): 6, 6.5, 7, 8 h  
Day 1 (Infusion at 12 h): 12, 12.5, 13 (optional sample), 14 (optional sample) h 
Day 2 (infusion at 24 h): 24, 24.5, 25, 26. 27, 28, 29 h  
Day 3 (infusion at 48 h ): 48, 48.5, 49, 50 h.  
h Cardiac surveillance from start of first infusion until 6 hours after start of last infusion  
i Detailed description on analytes at each specific time point is described in Table 5 
k Urinary output will be measured at an hourly basis for 48 h according to site standard procedure   
l Cardiac output (CO) will be measured pre-surgery, immediately after surgery and at 24 h via TTE (transthoracic echocardiography) or TEE (transesophageal echocardiography).  
Central venous pressure (CVP) will also be measured pre-surgery, immediately after surgery as well as at 24 h.  
m  CrCl will be calculated in collected urine between IMP administrations, starting before the 3rd IMP administration. 
Day 1 (IMP infusion at 12 h): urine collection interval 6-10 h 
Day 2 (IMP infusion at 24 h): urine collection interval 18-22 h 
Day 3 (IMP infusion at 48 h): urine collection interval 42-46 h (OR eGFR will be calculated using SCr (CKD-EPI), if the urine collection via urine catheter has been stopped at this time point) 
 
 


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2 
INTRODUCTION 
 
The investigational medicinal product (IMP), RMC-035, contains the pharmacologically active 
protein RMC-035, a recombinant variant of endogenous human alpha-1-microglobulin (A1M).  
RMC-035 is being developed for the prevention and treatment of AKI in patients undergoing 
cardiac surgery. This is an area of large unmet medical need, where patients who develop  
post-surgery AKI are at risk for additional severe complications, including need for renal 
replacement therapy, progression to chronic kidney disease (CKD) and mortality. Thus, a 
single AKI episode after cardiac surgery can lead to a significant burden of comorbidities, 
prolonged hospital stays, poor quality of life and high long-term costs. 
RMC-035 has been evaluated in three phase 1 clinical studies: 17-ROS-01 (single ascending 
dose study); 19-ROS-02 (multiple ascending dose study); and 19-ROS-03 (renal impairment 
study). Based on available clinical and non-clinical data, RMC-035 is assessed as safe and 
generally well tolerated both in healthy subjects and in subject with renal impairment. 
 
2.1 
Study Rationale 
This is a phase 1b, randomised, double-blind, parallel treatment group clinical study, to assess 
safety, tolerability and pharmacokinetics of RMC-035 in subjects undergoing non-emergent 
on-pump coronary artery bypass graft and/or valve surgery. This is the first clinical study in 
cardiac surgery patients and is being conducted to guide further clinical development in this 
patient population. Based on an integrated assessment of available non-clinical and clinical 
data, the number of doses and infusion time are considered to be safe and to provide targeted 
protection against oxidative stress and heme toxicity in this patient population, with the aim to 
prevent or ameliorate post-surgery renal injury.  
 
2.2 
Background 
2.2.1 
Pharmacology 
The investigational medicinal product (IMP) RMC-035 is a recombinant variant of the 
endogenous human protein alpha-1-microglobulin (A1M). RMC-035 is a potent antioxidant, 
harbouring multiple physiological functions including reductase activity and radical 
scavenging, heme binding and protection of mitochondria during cellular stress. The key non-
clinical data supporting the pharmacological utility of RMC-035 1 derives from animal 
models of ischemic AKI. In addition, a number of other animal models related to renal 
injuries, e.g. due to heme- or radiation exposure, has provided further support for the use of 
RMC-035 as a renal protector. Although experimentally diverse, the targeted 
pathophysiological mechanism in these models is to a certain extent similar, where oxidative 
stress is considered to be a central disease mechanism.  
 
2.2.2 
Summary of Toxicology Studies 
Good laboratory practice (GLP) repeated dose toxicity studies of intravenous (IV) administered 
RMC-035 have been conducted in rat (14 and 28 days of repeated dosing), marmoset (28 days 
repeated dosing) and cynomolgus monkey (3 days repeated dosing). In addition, exploratory 
non-GLP single and multiple dose toxicity studies have been conducted in rat, marmoset and 
cynomolgus monkey. 


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In marmoset and cynomolgus monkey GLP-studies, RMC-035 related histopathological 
changes in kidneys with tubular degenerative changes and casts have been observed. 
Furthermore, in the cynomolgus monkey study, a transient increase in plasma creatinine and 
urea was observed. All changes appeared dose-dependent and were reversible after 4 weeks of 
recovery. Immunohistochemical staining confirmed RMC-035 presence in casts, suggesting 
that pathological changes were the result of excessive protein filtration by the tubules at high 
RMC-035 doses leading to renal protein overload. In rat studies, no specific test-item related 
pathophysiological changes were recorded, and treatment related effects were limited to 
transient clinical signs (discomfort and piloerection). 
No observed adverse effect levels (NOAEL) were established in all GLP-studies and have been 
set at 25/20 mg/kg/day in rats, 10 mg/kg/day in marmoset and 10 mg/kg/day in the cynomolgus 
monkey. Target organ toxicity considered for NOAEL and dose setting is kidney tubular injury 
due to protein overload, the result of a high Cmax (protein concentration) rather than cumulative 
exposure (AUC).  
More recent GLP studies, 14-day repeated dosing in rat and 3-day repeated dosing in 
cynomolgus monkey, provided NOAELs at higher exposure levels (269 and 161 µg/mL 
respectively) indicating that higher exposure levels would be safe. A conservative approach 
has been adopted that has used the 28-day study exposure levels to define the maximum 
exposure levels in humans.  
2.2.3 
Summary of Clinical Studies 
2.2.3.1 
Single Ascending Dose Study (17-ROS-01) 
In study 17-ROS-01 (SAD), five dose levels were evaluated in the dose range of 0.08 to 
2.6 mg/kg. Briefly, six subjects were included in the first three cohorts (dose levels: 0.08, 
0.24 and 0.72 mg/kg) to receive either RMC-035 or placebo (4:2 randomization) as a single  
IV infusion over 30 minutes. In cohort 4 and 5 (dose levels: 1.3 and 2.6 mg/kg), 8 subjects  
(6 on active and 2 on placebo) were included. 
RMC-035 administered as single ascending doses (0.08 to 2.6 mg/kg) to healthy subjects was 
safe and well tolerated as assessed by AEs, vital signs, ECGs, physical examinations and 
safety laboratory parameters. There were no deaths or other serious adverse events (SAEs) or 
AEs leading to discontinuation reported as related to RMC-035 during the study. One SAE of 
Syncope following standing up from the bed was reported by one subject dosed with RMC-
035 2.6 mg/kg, which was not considered as related to IMP in a subject known to have a 
history of syncope. 
There were no clinically significant abnormalities in any of the laboratory, vital signs or 
ECG, except a transient increase of white blood cell count at 12 h after dosing in the highest 
dose group. For more details, please refer to the Investigator’s Brochure (IB). 
2.2.3.2 
Multiple Ascending Dose Study (19-ROS-02) 
In study 19-ROS-02 (MAD), three dose levels were evaluated, 0.43, 0.86 and 1.3 mg/kg per 
dose, respectively. Six subjects were included per dose group to receive either RMC-035 or 
placebo (4:2 randomization) as multiple doses over 48 h. The first dose was administered as 
an IV infusion over 60 minutes (infusion start at t=0). Subsequent doses were administered at 
t=6, 12, 24, 36 and 48 h as IV infusions over 30 minutes.  
RMC-035 was considered safe and well tolerated as assessed by AEs, vital signs, physical 
examinations and safety laboratory parameters. There were no deaths or SAEs reported in 
this study. The most frequently reported event was local Infusion Site Reactions (ISRs) 
reported by the majority of subjects. ISRs were characterized by varying symptomatology 


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including localized redness, tenderness, pain and swelling. In one subject an ISR led to early 
discontinuation after the 5th administration. Symptoms were generally mild in severity (only 
two subjects had ISRs of moderate severity) and lasted mostly for several days to 3 weeks in 
individual subjects. In this study the use of an anti-coagulant ointment resulted in a shorter 
duration of symptoms.  
Other events reported more frequently than in the placebo group were nausea and vomiting. 
All events were mild to moderate in severity and resolved spontaneously.  
There were no clinically significant changes reported in clinical laboratory, vital signs and 
ECG assessments. A transient increase in Leucocyte count was observed in higher dose 
groups at the 12-hour time point, which was considered not clinically significant by the 
investigator. Furthermore, apparent reductions in serum creatinine, urea nitrogen and uric 
acid (mainly in the 1.3 mg/kg group) were observed during the treatment period and at 
follow-up visits, which were all considered not clinically significant by the investigator. 
 
2.2.3.3 
Renal Impairment Study (19-ROS-03) 
Study 19-ROS-03 is an ongoing open-label phase 1 study to investigate the effect of renal 
function on the pharmacokinetics, safety and tolerability of RMC-035.  
In total eight subjects with eGFR ≥15 and < 90 mL/min/1.73 m2 not on dialysis is planned to 
be included and allocated into one of five estimated GFR (eGFR) strata based on their renal 
function. Distribution of subjects were as follows: 1 subject in stratum 1 (≥75-<90), 1 subject 
in stratum 2 (≥60-<75) and 2 subjects per stratum in strata 3 to 5, i.e. ≥45-<60, ≥30-<45 and 
≥15-<30, respectively.  
Complete safety data and pharmacokinetic results are available for subjects in strata 1 to 4 
who received a single IV infusion of RMC-035 over 30 minutes at a dose of 0.43 mg/kg. 
Results are to be considered preliminary since database lock did not yet occur.  
RMC-035 was safe and well tolerated based on AEs, vital signs, ECGs, physical 
examinations and safety laboratory parameters. There were no deaths or other serious adverse 
events (SAEs) or AEs leading to discontinuation during the study. There were no clinically 
significant abnormalities in any of the laboratory, vital signs or ECGs. Only one AE was 
reported in one subject (reported term feeling cold). The event was of mild severity, possibly 
related to study drug and resolved spontaneously approximately 2 hours after onset.  
The plasma clearance of RMC-035 correlated to renal function across the spectrum of eGFR. 
AUC increased in subjects with renal impairment as compared to healthy subjects, whereas 
the Cmax remained essentially unaltered.  
 
2.2.3.4 
Anti-Drug-Antibodies (ADA) 
Three subjects in the SAD study (17-ROS-01) and ten subjects in the MAD study (19-ROS-
02) developed confirmatory titers of ADA during follow-up at 20-22 days after dosing.  
In the renal impairment study (19-ROS-03), one of eight subjects had confirmatory titers of 
ADA at follow-up. 
For a more detailed overview of the safety and pharmacology of RMC-035, please refer to the 
Investigator’s Brochure (IB) 1. 


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2.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of RMC-035 may be found in the Investigator’s Brochure 1. 
2.3.1 
Key Safety Information 
Preclinical experience includes an extensive safety toxicology program with Good Laboratory 
Practice (GLP)-studies with up to 28 days once daily IV dosing in rats and marmosets as well 
as once daily dosing for three days in cynomolgus monkeys. The only identified target organ 
is the kidneys, the principal toxicity findings were renal tubular histopathology and associated 
changes to renal function biomarkers related to higher exposures and short infusion times that 
resulted in high plasma RMC-035 concentrations (Cmax). These studies confirm that potential 
renal toxicity is primarily related to the maximum exposure (Cmax) and not cumulative exposure 
(AUC). The maximum Cmax levels in the SAD study cohort with 2.6 mg/kg was 38.8 µg/mL 
whilst the highest Cmax levels in the MAD study cohort with 1.3 mg/kg administered 6 times 
over 48 hours was 19.5 µg/mL. These levels are still below the NOAEL levels of 60 µg/mL 
(marmoset 28-day study) and 161 µg/mL (cyno 3-day study) in the relevant toxicology studies. 
RMC-035 is rapidly distributed to the kidney, with a terminal half-life (t1/2) of around 4 h in 
marmoset, 5 h in cynomolgus monkey and a human t1/2 of 16 h in the MAD study. 
RMC-035 was evaluated in 42 subjects in three clinical studies in healthy subjects and 
subjects with varying degrees of renal function. The most reported adverse events were ISRs, 
headache, nausea and vomiting. Anti-Drug Antibodies were confirmed in the majority of 
subjects who received multiple doses of RMC-035. 
The following risk mitigation factors are applied for this study: 
ISRs:  
• IMP will be administered in a central venous line whenever possible (use of 
central venous catheters is considered standard of care in cardiac surgery) 
• IMP will be diluted in a sodium chloride infusion buffer prior to administration 
and will be administered with higher infusion rate to minimize local irritancy 
• The infusion site will be carefully monitored, however should local irritancy still 
arise, it should be managed by standard of care treatment when clinically 
indicated, e.g. with topical anti-coagulants and cooling.  
Renal protein overload attributable to high RMC-035 Cmax: 
• Maximum clinical dose is set to 1.3 mg/kg per dose administration. The risk for 
renal protein overload with this dose is considered small. No signs of renal tubular 
injury, tubular stress or changes in renal function were observed so far in clinical 
studies at higher exposure levels, and no relevant accumulation (i.e. increase in 
Cmax) is expected based on the short treatment duration and rapid initial 
elimination of RMC-035 from plasma (approximately 70-80% of RMC-035 is 
eliminated from plasma within one hour after end-of-infusion).  
• As a precautionary measure for this first clinical study in cardiac surgery patients, 
subjects with eGFR<60 mL/min/1.73 m2 will have the administered dose reduced 
0.65 mg/mg as modeling of PK data in renally impaired subjects demonstrated an 
approximately doubling of RMC-035 exposure (AUC) at this eGFR level. 
• Exclusion of subjects with baseline eGFR<30 mL/min/1.73 m2 


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• Due to possible changes in renal function during the study the dose for the 3rd, 4th 
and 5th IMP administration will be adjusted based on actual renal function as 
defined in section 6.6. 
• Development of AKI stage 3 as per KDIGO criteria including requirement for 
renal replacement therapy (i.e. dialysis) is a formal stopping criterion (see Section 
7.2).  
 
Development of ADAs:  
• The potential risks associated with ADAs are limited given the short treatment 
duration (<3 days) and rapid initial plasma clearance of RMC-035. Thus, potential 
formation of ADAs are not expected to have impact on the PK or pharmacological 
properties of RMC-035. The risk for unforeseen cross-reactions due to re-
exposure of RMC-035 is mitigated by exclusion of subjects who were previously 
exposed to RMC-035.  
2.3.1.1 
Risks associated with the Patient Population and Study Assessments 
 
• Subjects undergoing cardiac surgery represent a high-risk population for developing 
cardiovascular events, e.g. cardiac ischemia and arrhythmias. Subjects are also 
expected to be at increased risk to develop a post-operative decline in renal function 
due to the surgical procedure.  
2.3.1.2 
General and Standard Precautions in the study 
• Close monitoring of Subjects during and after IMP administration. Subjects will 
remain at the Investigational site (i.e. ICU or post-operative ward) immediately 
following cardiac surgery and will be closely monitored by medical staff during the 
full treatment period.  
• The Investigational Site will ascertain that adequate facilities and procedures are 
available to handle emergency situations should they occur during the study.  
• Each subject will be provided with a subject information card with information about 
the study, the IMP, subject study ID, name of the Investigator and an emergency 
number.  
2.3.2 
Benefit Assessment 
• This is the first study of RMC-035 in cardiac surgery, and the benefit of RMC-035 for 
prevention and treatment of AKI is currently unknown.  
• For subjects allocated to receive placebo, no benefit can be expected. 
2.3.3 
Overall Benefit: Risk Assessment 
Overall, a careful risk mitigation strategy as outlined above has been implemented based on  
non-clinical and clinical experience with RMC-035.  
Taking this into account, the potential risks identified in association with RMC-035 are 
justified and well-balanced given the study objectives and information gain to guide further 
clinical development. 


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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Primary, secondary and exploratory objectives 
3.1.1 
Primary objective: 
• To evaluate the safety and tolerability of RMC-035 in subjects undergoing non-
emergent, on-pump Coronary Artery Bypass Graft (CABG) and/or valve surgery 
 
3.1.2 
Secondary objective: 
• To evaluate the pharmacokinetics of RMC-035 in this patient population 
• 
Identification and characterization of ADA developed after multiple intravenous 
administrations of RMC-035 
 
3.1.3 
Exploratory objectives: 
• To evaluate post-baseline changes in biomarkers of renal function and tubular 
damage/stress  
• To evaluate post-baseline changes in biomarkers of oxidative stress and inflammatory 
cytokines 
• To evaluate post-baseline changes in markers of cardiovascular and hemodynamic 
function  
 
3.2 
Primary, secondary and exploratory endpoints 
3.2.1 
Primary endpoint 
• Nature, frequency and severity of AEs  
3.2.2 
Secondary endpoint 
• Clinically significant changes in safety laboratory tests (hematology, biochemistry, 
urinalysis)  
• Clinically significant changes in vital signs (blood pressure, heart rate, respiratory 
rate)  
• Clinically significant changes in 12-lead ECG  
• Pharmacokinetics of RMC-035 in plasma: Cmax, Ctrough  
• Pharmacokinetics of RMC-035 in plasma after fourth dose: AUCτ, Cmax, Ctrough, 
PTR, Rac(AUC), t1/2 
• 
Presence and titers of ADA 30 days after surgery  
• Characteristics of ADA developed 30 days after surgery with regards to isotype, 
neutralizing capacity and cross-reactivity with endogenous alpha-1-microglobulin 
 
 
 
 
 
 
 


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3.2.3 
Exploratory endpoint(s) 
• Post-baseline changes in specific categories of biomarkers: 
• renal tubular damage and stress markers, e.g.   
KIM-1, TIMP2, IGFBP7, IL-18, L-FAPB, NGAL (urine)  
KIM-1, NGAL and A1M (plasma) 
• oxidative stress markers e.g. 8OH-dG (serum and urine) 
• inflammatory cytokines e.g. IL-6 and IL-8 (plasma) 
• cardiac biomarkers, e.g. NT-proBNP and Troponin I 
• Concentration of RMC-035 in urine  
• Post-baseline changes in hemodynamic assessments, including cardiac output (CO),  
mixed venous saturation (SvO2) and central venous pressure (CVP). 
• Presence of major adverse kidney event at 30 days (MAKE30), defined as a 
composite  
of death, dialysis or ≥ 25% eGFR reduction based on either CKD-EPI or modified 
CKD-EPI equations, respectively. 
• Percent increase and maximum percent increase in SCr and Cystatin C (and 
corresponding estimated GFR values based on CKD-EPI and modified CKD-EPI 
equations, respectively) from baseline  
• Post-baseline AUC of Serum Creatinine (SCr) and Cystatin C levels (and 
corresponding eGFR values) from baseline to 48 hours, 72 hours and 7 days post-
surgery 
• Severity of AKI defined as the following:  
o Stage 1: SCr 1.5 to 1.9 times baselinewithin 7 days, OR ≥0.3 mg/dL (≥ 26.5 
µmol/L) within 48 hours OR urine output <0.5 mL/min/h for 6 to <12 hours 
o Stage 2: SCr 2.0-2.9 times baseline within 7 days OR urine output <0.5 
mL/min/h for ≥ 12 hours 
o Stage 3: SCr 3.0 times baseline within 7 days, OR increase in SCr 5.0 mg/dL 
(≥353.6 µmol/L), OR initiation of renal replacement therapy OR urine output 
<0.3 mL/min/h for ≥24 hours OR anuria for ≥12 hours 
• Duration and persistence of AKI defined as either the following  
o The number of days from start of AKI (KDIGO definition) 5 where either SCr 
increase ≥ 0.3 mg/dL above pre-AKI reference point (first comparison is 
versus pre-surgery baseline, or a reference value after baseline if AKI occurs 
after 48 hours post-surgery) or if SCr increase is ≥ 1.5 times baseline or 
dialysis in the first 7 days, or up to discharge if prior to 7 days 
o Persistent AKI defined as AKI (KDIGO definition) for >48 hours 
• Length of index Intensive Care Unit (ICU) stay and index ICU stay 
o Index ICU stay (in Days) defined as the duration of stay in the ICU 
immediately following surgery or recovery room post-surgery until ICU 
discharge  
o Index hospital stay (in Days) is defined as the duration of stay in the hospital 
from admission to hospital discharge for the index surgery  
• Nature of patient discharge facility (e.g. home, skilled nursing facility, rehabilitation 
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4 
STUDY DESIGN 
4.1 
Overall Design 
• This is a phase 1b, randomised, double-blind, parallel treatment group clinical study, 
to assess safety, tolerability and pharmacokinetics of RMC-035 in subjects 
undergoing non-emergent on-pump coronary artery bypass graft and/or valve surgery.  
• Twelve (12) subjects will be enrolled at a single investigational site and randomised 
to receive either RMC-35 or matching placebo in a 2:1 ratio. Two (2) additional 
subjects may be enrolled at the Sponsor’s discretion in case of early treatment 
discontinuations, which are not due to formal stopping criteria. The study will consist 
of three study periods:  
o Screening (Visit 1 on Day -1(-5 days)),  
o 3-days treatment period (Visit 2-4 on Day 1-3)  
o Up to 30 days safety follow-up period (Day 4-31).  
The follow-up period will consist of three visits (Visit 5-7) at Day 4,  
Day 7 (±1day) and Day 31 (±3 days). Visit 7 can take place either at the 
investigational site or if not possible at the subjects general practitioner after 
agreement with the Investigator.  
• Randomization will be performed on Day -1 where consented subjects, who are found 
eligible for study participation, will be randomised to receive IV dosing of either 
RMC-035 treatment or matching placebo:  
• In total five (5) doses of RMC-035 will be administered as follows:  
- 
First dose is 1.3 mg/kg and administered over 60 minutes. Dose administration 
should start during surgery, 10 minutes before the expected start of 
cardiopulmonary bypass (CPB).  
- 
Second, third, fourth and fifth dose is 1.3 mg/kg per dose administration and 
administered over 30 minutes. Dose administrations start at 6, 12, 24 and 48 hours 
after the start of the first dose administration. 
- 
Placebo will be dosed at identical time points and infusion rates as RMC-035.  
• Assessment (type and time points) during screening, treatment period and safety 
follow-up period are detailed in the Schedule of Assessment (Section 1.2). 
 
 
 
 
 
 
 
 
 
 


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Figure 1   Study Flowchart 
 
 
 
4.2 
Scientific Rationale for Study Design 
RMC-035 is under clinical development for the prevention and treatment of AKI in patients 
undergoing cardiac surgery (CABG and/or valve replacement) with the use of CPB. This is 
the first study of RMC-035 in cardiac surgery patients and will provide an initial assessment 
of the safety, tolerability and pharmacokinetic properties in the target population for future 
clinical development. An early exploratory assessment of efficacy will be performed by 
analysing panels of biomarkers and post-operative changes in renal function.  
 
A placebo control will be used to establish the frequency and magnitude of changes in 
endpoints that may occur in the absence of active treatment. Treatment allocation is 
randomised to minimize bias in the assignment of subjects to treatments. Blinded treatment 
allocation will reduce potential bias during data collection and evaluation of endpoints.  
 
4.3 
Dose and Dose regimen 
The clinically established safe dosing regimen of RMC-035 as assessed in healthy subjects is 
2.6 mg/kg as single dose (SAD study) and 1.3 mg/kg administered 6 times in 48 hours  
(MAD study). In this Phase 1b safety and tolerability study in cardiac surgery patients the 
following dosing regimen is applied:  
• RMC-035 will be administered 5 times in 48 hours 
• The first dose is 1.3 mg/kg administered over a one hour infusion  
• RMC-035 will then be administered in a dose of 1.3 mg/kg during 30 minutes at  
6, 12, 24 and 48 hours after the start of the first administration  
• For subjects with an eGFR at baseline of < 60mL/min/1.73m2 the dose will be 
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• The dose of RMC-035 for the 3rd, 4th and 5th administration may be reduced 
depending on the renal function (see Section 6.6). RMC-035 will be diluted and 
administered in a fixed volume IMP should preferably be administered through a 
Central Venous Catheter (CVC) in a lumen which is reserved for the IMP. If the CVC 
is removed after surgery, IMP may be administered via a catheter in a peripheral vein. 
This catheter should preferably be reserved for IMP administration only. 
This dosing regimen is considered to provide intra- and post-operative renal protection of 
RMC-035 considering the PK and non-clinical pharmacology data.  
 
4.3.1 
Dose Adjustment for Renal Function at baseline 
Preliminary results of the study in subjects with renal dysfunction (19-ROS-03) show that 
elimination of RMC-035 is dependent on renal function. As a precautionary measure for the 
first clinical study in cardiac surgery patients, subjects with a GFR<60 mL/min/1.73 m2 will 
have the administered dose reduced to 0.65 mg/kg as modeling of the 19-ROS-03 renal 
impaired subjects demonstrated a doubling of RMC-035 exposure (AUC).  
 
4.4 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed the full study 
period including end of study visit 7 on Day 31 ±3 days. All randomised subjects will be 
followed up to Day 31 for AEs and attainment of predefined study endpoints.  
The end of the study is defined as the date when the last visit of the last subject in the study at 
the Investigational site has occurred. 


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5 
STUDY POPULATION 
Twelve (12) subjects undergoing elective on-pump CABG and/or valve surgery with risk 
factors to develop peri- and post-surgery AKI will be enrolled in the study. 
Two additional subjects may be enrolled at the Sponsor’s discretion in case of early treatment 
discontinuations which are not due to formal stopping criteria.Prospective approval of protocol 
deviations to enrollment criteria, also known as protocol waivers or exemptions, will NOT be 
allowed. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Independent Ethics Committee (IEC)-approved written Informed Consent and privacy 
language as per national regulations has been obtained from the subject prior to any 
study-related procedures 
2. Subject has the ability to understand and comply with the study requirements and has 
provided written informed consent  
3. Subject age is ≥18 years  
4. Subject is scheduled for non-emergent (elective) CABG and/or valve surgery (single 
or multiple valves) with use of cardiopulmonary bypass (CPB) 
5. Subject has at least ONE of the following risk factors for AKI at screening: 
a. History of LVEF <35% for at least 3 months prior to screening assessed by 
either echocardiography, cardiac MRI or nuclear scan.  
b. History of previous open chest cavity cardiac surgery with or without CPB 
c. Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months prior to 
screening AND ongoing treatment with an approved anti-diabetic drug 
d. Age ≥70 years 
e. Documented history of heart failure NYHA class II or higher for at least 3 
months or longer at screening 
f. Documented history of previous AKI before date of screening independent of 
the etiology of AKI 
g. Documented history of anemia with hemoglobin ≤ 11 g/dL (≤6.8 mmol/L) for 
at least 3 months prior to screening 
h. Documented history of albuminuria, defined as UACR >30 mg/g or > 30 
mg/24 hour in a 24-hour urine collection. 
i. eGFR is ≤ 60 mL/min/1.73 m2 using the Chronic Kidney Disease – 
Epidemiology Collaboration (CKD-EPI) equation 
6. Female subject is either:  
       Of non-childbearing potential 
• postmenopausal (defined as at least 1 year without any menses) prior 
to screening OR 
• documented surgically sterile or status post hysterectomy (at least 1 
month prior to screening) 
       Or if of childbearing potential 
• agree not to try to become pregnant during the study and for 28 days 
after the final study drug administration  
• must have a negative serum pregnancy text at screening and 
• if heterosexually active, agree to consistently use a highly effective 
form of birth control* starting at screening and throughout the study 
period, and continue to do so for 28 days after final study treatment 
administration. If using hormonal contraception this method must be 
supplemented with a barrier method, preferably male condom. 
7. Female subject must not be breastfeeding at screening or throughout the study period 
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8. Female subject must not donate ova/egg starting at screening and throughout the 
study period and for 28 days after final study drug administration 
9. Male subject and their female spouse/partner(s) who are of childbearing potential 
must be using a highly effective form of birth control starting at screening and 
continue to do so throughout the study period and for 12 weeks after final study 
treatment administration.  
10. Male subjects must not donate sperm starting from screening, throughout the study 
period and up to 12 weeks after final study drug administration  
11. Subject agrees not to participate in another interventional study from the time of 
signing the informed consent until the End of Study visit (EOS) 
 
*Highly effective forms of birth control include 3:  
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
• Intrauterine device (IUD)  
• Intrauterine hormone-releasing system (IUS)  
• Bilateral tubal occlusion  
• Vasectomised partner  
• True sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.   
 
5.2 
Exclusion Criteria 
Subjects will be excluded from participation in the study if any of the following criteria apply: 
1. Subject has any medical condition that in the opinion of the investigator makes the 
subject unsuitable for study participation 
2. Estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m2 using the Chronic 
Kidney Disease – Epidemiology Collaboration (CKD-EPI) equation at screening or at 
baseline 
3. Subject has surgery scheduled to be performed without CPB (“off-pump”) 
4. Subject has surgery scheduled for aortic dissection  
5. Subject has surgery to correct any major congenital heart defect    
6. Subject is scheduled for a condition that is immediately life-threatening 
7. Subject is scheduled for CABG and/or valve surgery combined with additional non-
emergent cardiac surgeries, e.g. for atrial fibrillation ablation 
8. Subject is scheduled to undergo trans catheter aortic valve implantation (TAVI) or  
trans catheter aortic valve replacement (TAVR), or single vessel off-pump surgeries 
or left ventricular device (LVAD) implantation 
9. Subject experiences a cardiogenic chock or hemodynamic instability which require 
inotropes or vasopressors or other mechanical devices such as intra-aortic balloon 
counter-pulsation (IABP) within 24 hours prior to surgery or anticipated to be 
required during surgery 
10. Subject has a requirement for any of the following within one week prior to surgery: 


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defibrillator or permanent pacemaker, mechanical ventilation, IABP, LVAD, other 
forms of mechanical circulatory support (MCS) (Note: The prophylactic insertion of 
an IABP preoperatively for reasons not related to existing LV pump function is not 
exclusionary) 
11. Required cardiopulmonary resuscitation within 14 days prior to cardiac surgery 
12. Ongoing sepsis (as defined by SEPSIS-3, the Third International Consensus 
Definitions for Sepsis and Septic Shock) or history of sepsis within the past 2 weeks 
or untreated diagnosed infection prior to or at screening and before randomization.  
13. Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST)≥ 2 times the upper limit of normal (ULN) at screening 
14. Subject has a history of kidney transplantation 
15. Subject has received an investigational medicinal product in the last 90 days (or after 
5 half-lives of the investigational drug, whichever is longer 
16.  Subject has a known allergy to, RMC-035 or one if its excipients, or has previously 
received, RMC-035 
 
5.3 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not eligible for participation according to inclusion/exclusion criteria. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
subjects to meet the Consolidated Standards of Reporting Studies (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  
Minimal information includes informed consent date, demography, reason for screen failure 
details and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be re-screened. If the subject has failed one of the inclusion criteria or fulfilled one of the 
exclusion criteria related to laboratory parameters, re-sampling is not allowed.  
However, in case of technical issues (e.g. haemolysed or lost), re-sampling is allowed for the 
affected parameters but this is not regarded as re-screening.  
 
 


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6 
TREATMENTS 
Study treatment is defined as investigational medicinal product (IMP) including placebo 
intended to be administered to a study subject according to the study protocol. 
6.1 
Treatments(s) administered 
The IMPs in this study are RMC-035 and its corresponding Placebo.  
RMC-035 contains a pharmacological active protein RMC-035 which is a recombinant 
version of the endogenous human protein alpha-1-microglobulin.  
RMC-035 and Placebo are manufactured according to Good Manufacturing Practice (GMP) 
standards for this study on behalf of the sponsor. Instructions for safe receipt, handling and 
storage of RMC-035 are described in the IMP Manual. 
Table 3  IMP characteristics  
IMP 1 
 
Compound Name 
RMC-035 
Pharmaceutical form 
Solution for injection 
Strength 
4.0 mg/mL (10 mL vial containing 40 mg in total) 
Route of administration 
Intravenous infusion 
Dose 
First dose 1.30 mg/kg – infusion over 60 minutes.  
Remaining dose administrations at 6, 12, 24 and 48 hours after 
the start of the first dose – infusion over 30 minutes 
Physical characteristics 
Sterile, clear, particle free and colourless or slightly yellow 
liquid 
Excipients 
Sodium phosphate 10 mM pH 7,4, NaCl 0.15 M,  
L-Histidine 2 mg/mL 
Packaging 
10 mL glass vials sealed with 20 mm serum stoppers,  
crimped with caps 
Storage 
≤ ˗ 70°C 
IMP 2 
 
Compound Name 
Placebo for RMC-035 
Pharmaceutical form 
Solution for injection 
Strength 
N/A 
Route of administration 
Intravenous infusion 
Dose 
Placebo with identical infusion times and duration as RMC-035 
Physical characteristics 
Sterile, clear, particle free and colourless or slightly yellow 
liquid 
Excipients 
Sodium phosphate 10 mM pH 7,4, NaCl 0.15 M,  
L-Histidine 2 mg/mL 
Packaging 
10 mL glass vials sealed with 20 mm serum stoppers, 
crimped with caps 
Storage 
˗20 ±5°C 


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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and labelling of IMP 
Packaging and labelling will be performed in accordance with GMP and national regulatory 
requirements 2. 
RMC-035 solution for injection and its corresponding Placebo are filled in glass vials each 
containing an extractable volume of 10 mL solution. The vials will be packaged in a suitable 
carton box, each containing 8 vials. 
RMC-035 solution for injection and placebo are visually identical. Vials of each kind will be 
labelled and packaged separated from each other in a non-blinded way. Blinding will be 
assured at the time of labelling of the infusion syringe. 
6.2.2 
Storage of IMP 
Vials with RMC-035 must be stored at ≤ ˗ 70°C and vials with Placebo at ˗20 ±5°C in a 
secure location with controlled access.  
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IMPs received and that any discrepancies are reported and 
resolved before use of the study product. 
The storage temperature must be monitored by a calibrated, stationary and continuously 
recording system. Minimum requirement is a calibrated min/max thermometer. 
A temperature log must be kept to document the storage within the right temperature interval. 
Centralized monitoring and alerting system should be used or the temperature should be 
checked at least every working day. Any deviations in storage temperature must be reported 
immediately to sponsor and the IMP must not be used until acceptance from the sponsor is 
received. 
6.2.3 
Preparation of IMP  
Preparation of the IMP will be done by trained staff at the investigational site in a dedicated 
area. There will be two unblinded persons working together, one performing the preparation 
and one supervising the process. 
The IMP will be diluted with 0.9% sodium chloride to a volume of 50 mL prior to 
administration. The drug concentration of the prepared solution for IV infusion will depend 
on the body weight-adjusted dose for each patient. 
The diluted product may be stored in a prefilled infusion syringe in a refrigerator (+2-8°C) 
for a maximum of 72 hours. Administration to the subject shall be completed within 2 hours 
after the syringe has been taken out of the refrigerator. 
Detailed guidance for preparation of the IMP including which auxiliary supplies to use during 
preparation will be described in a separate IMP Manual or equivalent. 
6.2.4 
Administration of IMP 
Only subjects enrolled in the study may receive IMP and only trained and authorized site 
staff may prepare or administer it.  
RMC-035/Placebo will be administered five (5) times as an IV infusion with a syringe 
infusion pump. Syringes with 50 mL of solution, specifically diluted and labelled in a blinded 
manner for the specific subject, will be delivered to the staff at investigational site. 
The IMP should be administered via a central venous catheter (CVC) whenever possible. One 
lumen of the CVC should be reserved for IMP administration in order to avoid potential 


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interactions. If a CVC is not available, IMP may also be delivered in a peripheral venous line, 
specifically reserved for IMP infusion.  
First IMP administration will start during surgery, around 10 minutes before the anticipated 
initiation of CPB. The first infusion (1.3 mg/kg or 0.65 mg/kg) will be administered IV at an 
infusion rate of 0.8 mL/min. Start time of the first dose administration will serve as reference 
point for further dose administrations and protocol-mandated assessments. 
Four additional doses will be given as IV infusions (1.3 mg/kg/dose or 0.65 mg/kg/dose), at 
an infusion rate of 1.6 mL/min, 6, 12, 24 and 48 hours respectively after start of the first 
infusion. The volume to be infused over 30 minutes will be 33 mL and the infusion rate  
1.1 mL/min in case the dose is reduced to 0.43 mg/kg/dose in any of the IMP administrations 
3-5, as described in section 6.6.  
In case the subject is discharged from the ICU to a non-ICU ward, prior to last 
administration, the remaining dose(s) will be administered either by trained non-ICU staff, or 
preferably, by trained ICU staff at the non-ICU ward.    
All administrations will be done under medical supervision. 
Detailed guidance for administration of the IMP including which syringe pump and auxiliary 
supplies to use will be described in a separate IMP Manual or equivalent. 
6.2.5 
Accountability of IMP 
The pharmacy and the investigational site will maintain appropriate Storage and 
Accountability logs as well as a Subject Dispensing Log or equivalent detailing dates and 
quantities of IMP received, prepared for and used by each subject. 
6.2.6 
Return and Destruction of IMP 
All used, partly used, expired or damaged IMP must be stored separately from non-allocated 
study products. No temperature monitoring is required 
Destruction of used and partly used IMP in vials and infusion syringes can be performed on 
an ongoing basis and will be done according to local procedures after accountability is 
finalised by the site and reconciled by the monitor. Documentation on destruction will be 
forwarded to the sponsor.  
Any unused IMP will be returned for destruction to the sponsor or sponsor representative 
after drug accountability has been performed and verified by the monitor. 
6.3 
Measures to Minimize Bias; Randomization and Blinding 
This is a double-blind study and the allocation of treatments will not be disclosed until after 
declaration of clean file and the database has been locked. 
Eligible patients will on Day -1 subjects be assigned a unique number (randomization 
number) in ascending numerical order at the investigational site. The randomization number 
encodes the subject’s assignment to one of two arms of the study, according to the 
randomization schedule generated prior to the study by the Statistics Department at KLIFO.  
Each subject will be dispensed blinded IMP, at the same dose, labelled with his/her unique 
randomization number, throughout the study. 
A sealed envelope that contains the treatment allocation for each subject will be provided to 
the investigator. The sealed envelope will be retained by the investigator (or representative) 
in a secured area with restricted access. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a subjects’ IMP dose is warranted. Subject 
safety must always be the first consideration in making such a determination. If the 


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investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a subject’s IMP dose unless this could delay 
emergency treatment of the subject. If a subject’s IMP dose is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. Once the study is complete, all envelopes 
(sealed and opened) must be accounted for and returned to the sponsor. 
A similar set of decoding envelopes will be maintained at KLIFO PV, in a secured area with 
restricted access. 
6.4 
Treatment Compliance 
When subjects are dosed at the investigational site, they will receive IMP directly from the 
investigator or designee, under medical supervision to guarantee treatment compliance. The 
date and start and stop time of each infusion as well as the volume administered will be 
recorded in the source documents and transcribed to the eCRF.  
The dose of IMP and study subject identification will be confirmed at the time of dosing by a 
member of the investigational site staff other than the person administering the study product. 
6.5 
Concomitant Therapy 
Any prescription and non-prescription medications (e.g. over-the-counter drugs and herbal 
supplements) that the subject is receiving at the time of screening or receives during the study 
must be recorded along with: 
• Trade name or generic name 
• Indication/reason for use  
• Dates of administration including start and stop dates 
• Dosage information including dose and frequency 
Concomitant medication refers to all drugs and therapies used from the time the Informed 
Consent Form (ICF) was signed through the end of study participation incl. medications used 
during surgery (for instance anaesthesia).  
Changes, additions, or discontinuations to medications will be assessed and recorded in the 
eCRF during each study visit. If a change is due to an AE, then this must be reported 
according to Appendix 3. The Sponsor should be contacted if there are any questions 
regarding concomitant or prior therapy. 
6.5.1 
Restricted concomitant medications: 
• Antioxidant supplementation (e.g. vitamin C and E) should be discontinued before 
randomization and up to patient discharge 
• Nephrotoxins (e.g. metformin, NSAIDs) should be discontinued before randomization 
and up to patient discharge 
• Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers 
(ARB) should be discontinued on the day of hospital admission and preferably 
avoided until 72 hours after start of surgery. ACEi/ARB may be used within 72 hours 
after surgery if clinically indicated.  
 


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6.6 
Dose Modification 
 The dose of RMC-035 may be reduced for IMP administrations 3, 4 and 5 based on renal 
function. Creatinine Clearance (CrCl as mL/min) will be measured before the 3rd, 4th and 5th 
IMP administration to decide on possible dose reduction. If the urine catheter is removed after 
24 hours the dose for the 5th IMP administration at 48 hours will be based on the eGFR (as 
mL/min/1.73m2) based on serum creatinine as per the CKD-EPI equation. 
• For the 3rd and 4th IMP administration CrCl will be used to estimate renal function 
• For the 5th IMP administration CrCl OR eGFR will be used to assess renal function 
The renal function will determine the dose:  
• Patients with a CrCl/eGFR <60 mL/min will receive 0.65 mg/kg per dose 
administration 
• Patients with a CrCl/eGFR <30 mL/min will receive 0.43 mg/kg per dose 
administration 
The dose of IMP will not be increased once a decrease has been made. 
 
6.7 
Treatment after the End of the Study 
When discontinuing the IMP, the subject should be transferred to local standard of care if 
needed at the discretion of the investigator or treating physician. 


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7 
TEMPORARY STUDY HALT, DISCONTINUATION OF IMP AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Temporary Study Halt 
• If one grade 4 Adverse Event is reported, which is an Injection Site Reaction (ISR) or 
Infusion Related Reaction (IRR) and which is considered to be an immune mediated 
reaction and possibly related to IMP, recruitment of new subjects into the study will be 
halted temporarily. Dosing of ongoing subjects will also be discontinued. All subjects 
will remain in the study and continue follow up until scheduled end of study.  
• If a grade 3 Adverse Event is reported in ≥2 subjects, which is an ISR or IRR which are 
considered immune mediated reactions and possibly related to IMP, further recruitment 
will be stopped.  Subjects who are ongoing will continue dosing of IMP unless any ISR or 
IRR related event of any grade is reported in these subjects. All subjects will remain in 
the study and continue follow up until scheduled end of study.   
If a Temporary Study Halt criterion is met as described above, the Sponsors Medical 
Representative and the Principal Investigator will assess the individual case(s) and report the 
assessment to the competent authority and Ethics Committee. 
The study will only continue recruitment after consultation with and approval from the CA. 
7.2 
Discontinuation of IMP 
• Subjects who receive or require any of the following interventions during treatment 
period will be discontinued from study treatment: 
o Renal replacement therapy (RRT) i.e. dialysis 
o Intra-operative and/or post-operative intra-aortic balloon pump (IAPB) 
o Percutaneous or surgical mechanical circulatory support (MCS) or extra-corporeal 
membrane or oxygenator (ECMO) 
• Study treatment will also be stopped if any of the following liver chemistry stopping 
criteria, defined in the FDA Guidance on Drug-Induced Liver Injury31 is met:  
o ALT ≥ 3 x Upper Limit of Normal (ULN) combined with total bilirubin  
≥ 2 x ULN (>35% direct bilirubin).  
NOTE: serum bilirubin fractionation should be performed if testing is available. If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury).  
o ALT ≥ 3 x ULN combined with International Normalized Ratio (INR) > 1.5  
o ALT ≥ 5 x ULN.  
o ALT ≥ 3 x ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia).  
• In rare instances, it may be necessary for a subject to prematurely discontinue (definitive 
discontinuation) study treatment. If study treatment is definitively discontinued, the 
subject will remain in the study to be evaluated until visit 7 (if possible) or complete visit 
7 as an early termination visit as a minimum.  
• Subjects who develop a grade 3 or higher Adverse Event as per CTCAE v5.0 Nov 2017 4, 
which is an Injection Site Reaction or Infusion Related Reaction and which is considered 
to be an immune mediated reaction, will discontinue IMP. 
• Subjects who develop stage 3 (see section 8.6) AKI, according to KDIGO definition 5 


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7.3 
Subject Discontinuation/Withdrawal from the Study 
• 
A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.  
• 
If a subject withdraws consent or is withdrawn by the investigator, the investigator 
must ask the subject if he/she is willing, as soon as possible, to have assessments 
performed according to visit 7 (e.g. the end of study visit).  
See the Schedule of Assessments (Section 1.2) for data to be collected and 
transcribed to the eCRF. Any ongoing SAE at the time of withdrawal will be 
followed as described in Section 8.4. 
• 
If the subject withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a subject withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully 
respecting the subject's rights. Where the reasons are obtained, the primary reason 
for withdrawal must be specified in the end of treatment/study form in the eCRF. 
• 
Discontinuation of the study as its whole is handled as part of Appendix 1. 
 
7.3.1 
Replacement of subjects 
• 
Up to two (2) additional subjects may be randomised in case of early 
discontinuations for other reasons than formal stopping criteria before visit 4. This is 
to ensure 12 subjects completing visit 4 in the study. Subjects replacing a 
discontinued subject should be randomised to the same treatment arm to maintain a 
balanced randomisation.   


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8 
STUDY ASSESSMENTS AND PROCEDURES 
• 
The study assessments and procedures are described below and the timing of the 
same are summarized in the Schedule of Assessments (Section 1.2).  
• 
Adherence to the study design requirements, including those specified in the 
Schedule of Assessments, is essential and required for study conduct and protocol 
waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
the study. 
• 
All subjects screened will be assigned a screening number and the investigator will 
maintain a screening log to record details of all subjects screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  
• 
Subjects found eligible will be randomised to receive one of the two treatment arms 
according to a computer-generated randomization list provided by KLIFO A/S. 
• 
The planned maximum amount of blood collected from each subject over the 
duration of the study, will not exceed approximately 400 mL. Repeat or unscheduled 
samples may be taken in addition for safety reasons or for technical issues with the 
samples. 
8.1 
Recording of Data 
The Principal Investigator will provide the Sponsor with all data produced during the study 
from the scheduled assessments and ensure the accuracy, completeness, legibility and 
timeliness (within 7 days) of the data reported to the Sponsor in the eCRF and in all required 
reports.  
8.2 
Demographics and other baseline characteristics 
8.2.1 
Informed Consent 
Signed Informed Consent must be obtained before any screening procedures are initiated.  
For further instruction on the procedure, see Section 10.1.3. 
8.2.2 
Demography 
The following demography data will be collected and recorded: gender, age (years), ethnicity 
(Hispanic or Latino, non-Hispanic or Latino) and race (American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White). 
8.2.3 
Height and weight 
Height (cm) and weight (kg with one decimal) will also be measured and recorded.  
The weight recorded at the screening visit will be used for calculation of IMP dose.  
8.2.4 
Medical/surgical history 
Medical/surgical history and disease characteristics, a listing of relevant past and current 
diseases, and the details of active diseases will be obtained from medical records. 


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8.2.5 
Prior and concomitant medication 
Prior prescription and non-prescription medications (e.g. over-the-counter drugs and herbal 
supplements) taken within 28 days prior to screening will be obtained by the Principal 
Investigator by interview and/or medical history. 
Medications are classified as prior if the stop date is before or on the day for obtaining 
Informed Consent.  
Concomitant medication refers to all drugs and therapies used from the time the ICF was 
signed through the end of study participation and is described in Section 6.5.  
Medications (incl. anaesthesia) given before and during surgery will be recorded and 
transferred to the eCRF.  
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
8.2.6 
Pregnancy test  
All female subjects of child-bearing potential will have a serum pregnancy test performed at 
screening as pregnant subjects will be excluded to participate in the study. In addition, serum 
pregnancy tests must be performed at the end of study visit (Visit 7).  
For specific tests, see Appendix 2. 
8.3 
Safety Assessments 
Timing and frequency of all safety assessments are outlined in the Schedule of Assessments 
(Section 1.2). 
Any abnormalities in the safety assessment will be specified and documented as clinically 
significant or not clinically significant. Abnormal post-dose findings assessed by the 
Investigator as clinically significant will be reported as AEs. 
Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or other 
safety assessments (e.g. ECG, continuous ECG monitoring, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e. not related to progression of underlying 
disease or medical procedure, i.e. cardiac surgery) is an Adverse Event (Section 10.3.1).  
8.3.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the following 
systems: 
• Cardiovascular 
• Neurological 
• Head (including ears, nose, throat [ENT], and eyes) 
• Lymphatic system 
• Endocrine system 
• Peripheral vascular system 
• Lungs and respiratory tract 
• Gastrointestinal, liver, spleen 
• Urogenital system 
• Muscular and skeletal system 


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• Skin and connective tissue 
8.3.2 
Assessments before, during and after Surgery 
Specific surgery assessments performed before, during and after surgery will be collected as 
per the standard hospital care and transferred to the eCRF on Visit 2.  
Data points to collect are time on CPB, duration of surgery, blood loss volume, 
administration of fluids (red blood cells, crystalloids, colloids and other) and time of 
admission to the ICU, see Section 1.2.  
8.3.3 
Vital Signs 
• 
Vital signs will include body temperature (˚C (one decimal)), systolic and diastolic 
blood pressure (BP) (mmHg), heart rate (bpm) and respiratory rate (breaths per 
min). 
• 
Vital signs will be measured in a supine position for the subject preceded by at least 
5 minutes rest in a quiet setting without distractions (e.g. television, cell phones). 
• 
BP, heart rate and respiratory rate measurements will be assessed by three 
consecutive readings recorded at intervals of at least 1 minute. The average of the 
three readings will be recorded in the CRF.  
8.3.4 
Electrocardiograms 
• 
Single 12-lead ECG will be obtained in supine position after 10 minutes of rest 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  
• 
12-lead ECGs will be reviewed on-site by the Investigator. 
8.3.5 
ECG monitoring 
• 
Continuous ECG monitoring will be used for cardiac surveillance from start of first 
infusion until 6 hours after start of last IMP administration and will be monitored 
on-site by the Investigator. 
• 
Data will be monitored but not recorded in the eCRF. 
8.3.6 
Clinical Safety Laboratory Assessments 
Clinical chemistry, cardiac biomarkers and hematology  
• 
Blood samples for analysis of clinical chemistry (including Creatinine, cystatin C 
and liver function tests), cardiac biomarkers and hematology parameters will be 
collected through venipuncture or an indwelling venous catheter.  
• 
See Appendix 2 for the list of clinical laboratory tests to be performed and the 
Schedule of Assessments (Section 1.2) for the timing and frequency. 
• 
Actual sampling times will be recorded. 
• 
The analysis of the samples will be performed by the certified clinical chemistry 
laboratory at the University Hospital in Münster according to routine analytical 
methods.   
• 
The investigator must review the laboratory report, document the result of the 
review (i.e. clinical assessment for values out of range) on the laboratory report, and 
record any clinically relevant changes occurring during the study in the AE section 


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of the eCRF. The laboratory reports must be filed with the source documents.  
Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the subject's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or 
medical monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
o If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator (e.g. SAE 
or AE), then the results must be recorded in the eCRF. 
Urinalysis 
• 
Urinalysis by means of a regular dipstick test will be performed at the 
investigational site.  
• 
See Appendix 2 for the list of clinical laboratory tests to be performed and the 
Schedule of Assessments (Section 1.2) for the timing and frequency of sampling. 
• 
Actual sampling times and results for each parameter will be recorded in the eCRF. 
8.3.7 
Urinary output 
Collection of urine according to site standard procedures will start before surgery via a urine 
catheter and continue until 48 hours after start of first IMP administration. The urinary 
output (mL per hour) will be recorded, as stated in the Schedule of Assessments (Section 
1.2). Urine will be collected from spontaneous voids in case the catheter is removed before 
the collection ends. Total volume (mL) of urinary output during each collection period will 
be measured, recorded and transferred to the eCRF.  
Urine volume collected before IMP administrations 3-5 will be used together with a urine 
Creatinine value to calculate the CrCl (i.e. renal function), as specified in Schedule of 
Assessment (Section 1.2). The CrCl will decide if the dose for the coming IMP 
administration should be reduced. 
8.4 
Adverse Events and Serious Adverse Events 
See further guidance in Section 10.3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
AEs will be reported by the subject (or, when appropriate, by a caregiver or surrogate). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the subject to discontinue the study (Section 7.2) 


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8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
end of study-visit at the time points specified in the Schedule of Assessments (Section 1.2). 
All SAEs will be recorded and reported to KLIFO Pharmacovigilance (PV) and sponsor 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to KLIFO within 24 hours of 
it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.4.3 
AEs and SAEs excluded from recording and reporting 
A pre-existing condition (i.e., a disorder present before the AE reporting period started/ signing 
the Informed Consent Form (ICF) recorded on the medical history/physical examination form) 
should not be recorded as an AE unless the condition worsens or episodes increase in frequency 
during the AE reporting period. 
Signs and symptoms which, according to the investigator are expected and well established 
and known consequences of the indication or the surgical procedure, both in intensity and 
frequency, should not be recorded as AEs or SAEs except for events with a fatal outcome. Any 
unexpected change in the intensity or frequency must be recorded and reported as an AE or 
SAE as applicable. 
8.4.4 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAEs including AEs of Special Interest (as defined in 
Section 8.4.7),  must be followed on a regular basis, according to the investigator’s clinical 
judgment, until the event has resolved or until the investigator assesses it as chronic or stable. 
This implies follow up may continue after EOT and that additional investigations may be 
requested by Sponsor. Further information on follow-up procedures is provided in Appendix 
3.  
8.4.5 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the KLIFO PV of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects and 
the safety of a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory 


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requirements relating to safety reporting to the regulatory authority, Independent 
Ethics Committees (IEC), and investigators. 
• 
For all studies investigator safety reports must be prepared for suspected unexpected 
serious adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to the regulatory authority, Independent Ethics 
Committees (IEC), and investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure. 
8.4.6 
Pregnancy 
• 
Details of all pregnancies in female subjects and, if indicated, female partners of 
male subjects will be collected after the start of treatment period and until end of 
study visit. 
• 
If a pregnancy is reported, the investigator should inform the sponsor within  
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.  
• 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4.7 
Adverse Events of Special Interest 
The following events are to be regarded Adverse Events of Special Interest (AESI), should 
they occur: 
• Injection Site Reaction (ISR) or Infusion Related Reaction (IRR) adverse events. 
All AESIs will be recorded and reported  
• as diagnosis with description of all localized and generalized symptoms 
• according to SAE timelines, regardless of whether the event is non-serious or serious 
(see section 8.4.1). 
The CTCAE ISR and IRR definitions and grading classifications are included in Section 10.3.3. 
 
8.5 
Treatment of Overdose 
An overdose is a dose higher than the dose specified in the protocol. 
Overdosing is not likely to occur in this study as all IMP will be administered at the 
Investigational site under medical surveillance. 
Sponsor does not recommend specific treatment for accidental overdoses, supportive measures 
as per standard of investigational site should take place (see Section 2.3). No known antidote 
is available. 
In the event of an overdose, the investigator should: 
1. Contact the sponsor immediately. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities until the 
IMP can no longer be detected systemically. 


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3. Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor based on the clinical evaluation of the subject. 
8.6 
Efficacy Assessments 
Parameters from efficacy (and safety) assessments will be based on post-baseline changes in 
following parameters: 
 
Efficacy parameters 
Definition 
Biomarkers of tubular stress/damage, 
oxidative stress, inflammatory 
cytokines, cardiac stress/function  
(see Section 8.8) 
Post-baseline changes 
 
Hemodynamic assessments (cardiac 
output (CO) (using echocardiography), 
mixed venous saturation (SvO2) and 
central venous pressure (CVP) 
(measured in central venous line).  
 
Post-baseline changes 
 
SCr and Cystatin C 
• 
Post-baseline changes in actual values 
• 
Percent increase and maximum percent increase in SCr 
and cystatin C (and corresponding estimated GFR values 
based on CKD-EPI and modified CKD-EPI equations, 
respectively) from baseline  
• 
Post-baseline AUC of SCr and Cystatin C levels (and 
corresponding eGFR values) from baseline to 48 hours, 
72 hours and 7 days post-surgery 
Major Adverse Kidney Event 
Present at visit 7 (MAKE30), assessed as developed if any of 
the following have occurred: 
• 
Death  
• 
Dialysis  
• 
Relative reduction of eGFR ≥25%  
Assessment is based on either CKD-EPI or modified CKD-EPI 
equations. 
Severity of AKI  
(using biochemistry result of SCr and 
urinary output measurements) 
Grade based on KDIGO definition 5: 
• 
Stage 1: SCr 1.5 to 1.9 times baseline within 7 days, OR 
≥0.3 mg/dL (≥ 26.5 µmol/L) within 48 hours OR  
urine output <0.5 mL/min/h for 6 to<12 hours 
• 
Stage 2: SCr 2.0-2.9 times baseline within 7 days OR 
urine output <0.5 mL/min/h for ≥ 12 hours 
• 
Stage 3: SCr 3.0 times baseline within 7 days, OR 
increase in SCr 5.0 mg/dL (≥353.6 µmol/L), OR 
initiation of renal replacement therapy OR  
urine output <0.3 mL/min/h for ≥24 hours OR  
anuria for ≥12 hours 
Duration of AKI   
(using biochemistry result of SCr and 
urinary output measurements) 
Duration based on KDIGO definition: 
The number of days from start of AKI (KDIGO definition) 
where either SCr increase ≥ 0.3 mg/dL above pre-AKI 
reference point (first comparison is versus pre-surgery 


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baseline, or a reference value after baseline if AKI occurs 
after 48 hours post-surgery) OR if SCr increase is ≥ 1.5 times 
baseline or dialysis in the first 7 days, OR up to discharge if 
prior to 7 days.  
Persistent AKI defined as AKI (KDIGO definition) for >48 
hours 
Length of Index ICU stay (days) 
Duration of stay (number of days) in the ICU immediately 
following surgery or recovery room post-surgery until 
discharge  
Length of Index Hospital stay (days) 
Duration of stay in the hospital from admission to hospital 
discharge for the index surgery  
Nature of patient discharge facility 
I.e. home, skilled nursing facility, rehabilitation center, other 
The assessments will be performed at the Investigational Site.  
8.7 
Pharmacokinetics Assessments 
Blood samples for the determination of plasma concentrations of RMC-035 after 
administration of the IMP, will be collected through a central or peripheral venous line.  
The actual date and time (24-hour clock time) of each sample will be recorded and 
transferred to the eCRF. 
Samples will be taken at the pre-specified time points in Table 4 and in  
Schedule of Assessments (Section 1.2):  
 
Table 4  Plasma PK: Sampling time point’s incl. allowed sampling windows  
Plasma PK 
sampling 
time window 
Predose 
≤30min 
15 min 
±5min 
30 min 
±5min 
1 h 
±5min 
2 h 
±15min 
3 h 
±15min 
4 h 
±15min 
5 h 
±15min 
Start of 
Infusion 1 
(t = 0 h) 
X 
X 
X 
X 
X 
X 
X 
X 
Start of 
Infusion 2 
(t = 6 h) 
X 
 
X 
X 
X 
 
 
 
Start of 
Infusion 3 
(t = 12 h) 
X 
 
X 
X* 
X* 
 
 
 
Start of 
Infusion 4 
(t = 24 h) 
X 
 
X 
X 
X 
X 
X 
X 
Start of 
Infusion 5 
(t = 48 h) 
X 
 
X 
X 
X 
 
 
 
* Optional PK sampling times 
 
Urine samples for the determination of urine concentrations of RMC-035 after 
administration of the IMP, will be collected as part of sampling of exploratory biomarkers at 
predefined time points as the urine biomarkers (see Table 5).  


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Drug concentration information that may unblind the study will not be reported to 
investigational site or blinded personnel until the study has been unblinded and both the 
bioanalytical laboratory and the pharmacokineticist will be blinded to treatment. 
Plasma samples for determination of concentrations of RMC-035 will be analysed by 
Mercodia AB by means of a validated enzyme linked immunosorbent assay (ELISA). Urine 
samples for determination of RMC-035 concentration will be analysed by Mercodia AB or by 
the Sponsor.  
The PK parameters in plasma and urine to be evaluated are listed in Section 9.4.5.  
 
Samples may be stored at the analytical laboratory until the database lock have been 
performed. 
8.8 
Pharmacodynamics and Biomarkers 
Collection of blood and urine samples for biomarker research is also part of this study.  
• Blood samples will be collected through an arterial line or an indwelling catheter.  
• Spot samples of urine where urine is drawn directly from the bladder while the 
subject is being catheterized and from normal voids once the catheter is removed. 
 
Samples for the following biomarker categories will be collected from all subjects in this 
study as specified in the Schedule of Assessments  
(see Section 1.2) and Table 5: 
o Tubular injury and stress markers e.g. 
 KIM-1, TIMP2, IGFBP7, IL-18, L-FABP, NGAL (urine) 
 KIM-1, NGAL and A1M (plasma)  
 
o Oxidative stress markers e.g. 
 8OH-dG (serum and urine)  
 
o Inflammatory cytokines e.g. 
 IL-8 and IL-6 (plasma) 
Additional biomarkers within these categories may be measured from already collected 
samples.  
 
 


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Table 5  Biomarkers: sample, assay and time points’ incl. allowed sampling windows  
Biomarker 
Sample 
Assay 
Predose 
≤60min 
4 h 
±15min 
12 h 
±15min 
24 h 
±30min 
48 h 
±30min 
72 h 
±60min 
A1M 
Serum 
ELISA 
x 
x 
x 
x 
x 
x 
KIM-1 
Serum 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
NGAL 
Plasma 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
8OH-dG 
Serum 
ELISA 
x 
x 
x 
x 
x 
x 
Inflammatory 
cytokines  
(eg. IL-8, IL-6) 
Plasma 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
KIM-1 
Urine 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
NGAL 
Urine 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
8OH-dG 
Urine 
ELISA 
x 
x 
x 
x 
x 
x 
TIMP2 / 
IGFBP7 
Urine 
Nephro-
check 
x 
x 
x 
x 
x 
x 
IL-18 
Urine 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
L-FAPB 
Urine 
ELISA, 
multiplex 
x 
x 
x 
x 
x 
x 
RMC-035 
Urine 
ELISA 
x 
x 
x 
x 
x 
x 
 
Samples will be analysed, stored and destroyed at the investigational site according to the 
normal procedures at the site.  
8.9 
Immunogenicity Assessments 
Blood samples for the determination of anti-drug antibodies (ADA) after administration of 
IMP will be collected through an indwelling venous catheter or venipuncture as detailed in 
the Schedule of Assessments (see Section 1.2). 
Instruction on the sample collection and handling will be detailed in the laboratory manual or 
equivalent. 
Initial screening of ADA will be performed using a standard bridging assay. Positive results 
in the screening assay will be confirmed by elimination of false positive results taking into 
account the limitations of the screening assay.  
Additionally, serum samples should also be collected at the final visit from subjects who 
discontinued study intervention or were withdrawn from the study. 
Samples will be analysed by Wieslab AB. 
 
Samples may be stored for a maximum of 2 years (or according to local regulations) 
following the last subject’s last visit for the study at a facility selected by the sponsor to 
enable further analysis of immune responses to the IMP.  
Potential ADAs may be further characterized beyond the scope of the study. 


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8.10 
Medical Resource Utilization and Health Economics 
This section is not relevant for this study as medical resource utilization and health 
economics will not be studied. 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
No statistical hypotheses are planned to be tested in this study. 
9.2 
Sample Size Determination 
No formal sample size calculation has been performed for this study. The number of subjects 
is based on precedent set by other clinical studies of similar nature.  
The proposed sample size of 12 evaluable subjects (8 subjects on active treatment and 4 on 
placebo) is considered sufficient to achieve the clinical study objectives. 
9.3 
Population for Analyses 
The following populations are defined: 
 
Table 6  Defined Populations 
Population 
Description 
Randomised 
All subjects who have been randomised at Day -1 
Full Analysis Set (FAS) 
The Full Analysis Set will consist of all randomised subjects 
who have received at least 1 dose of IMP.  
FAS will be used for efficacy and safety endpoints. 
PK Analysis Set (PK) 
PK Analysis Set will be used for the PK evaluation and will 
consist of all randomised subjects with no relevant protocol 
violations affecting the evaluation of the PK parameters. 
 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be signed and approved prior to database lock (DBL) 
and it will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints. 
9.4.1 
General Considerations 
All statistical analyses will be descriptive. Details of the data summaries will be presented in 
the SAP. 
Statistical analyses will be conducted after the end of the study (last patient end of study visit) 
once the database has been locked and data is unblinded. The results will be included in the 
clinical study report (CSR).  
Changes from the statistical analysis planned in this protocol will be described and justified in 
a protocol amendment, in the SAP, and/or in the CSR, as applicable, dependent on the type of 
deviation. 
 
All statistical analysis will be performed using SAS®. 
9.4.2 
Demographic and Baseline Characteristics 
• Demography data, medical/surgical history and all other relevant background data 
will be summarized in terms of descriptive statistics. 


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9.4.3 
Treatment compliance 
• The number of subjects treated in each treatment group will be presented by treatment 
in listings. 
9.4.4 
Primary endpoint(s) 
Safety analyses will be made on FAS. 
• Adverse Events; frequency (number and percentage) of subjects with TEAEs and AEs 
per treatment group will be fully listed by Investigator terms and MedDRA Preferred 
Term (PT). They will furthermore be summarized by System Organ Class (SOC) and 
PT. 
9.4.5 
Secondary endpoint(s) 
All safety analyses will be made on FAS. 
• Physical examination; abnormal findings will be specified and presented by subject 
and summarized by treatment group 
• Vital signs; systolic/diastolic blood pressure, respiratory rate, heart rate and body 
temperature will be summarized by descriptive statistics by visit and as changes from 
baseline to each visit split by treatment group  
• 12-lead ECG; will be listed for each subject and summarized as the vital signs 
parameters. ECGs will be categorized as “normal”, “abnormal, not clinically 
significant” or “abnormal, clinically significant” (as judged by the Investigator) and 
summarized by treatment group using frequency tables and listings 
• Safety laboratory analyses data (hematology, clinical chemistry incl. liver function 
test, urinalysis); will be presented with descriptive statistics by individual time 
courses and as change from baseline for each parameter and summarized by treatment 
group using listings. 
 
Descriptive statistics will be presented for plasma concentrations by scheduled sample time. 
Calculation of pharmacokinetic variables: 
The PK analysis will be based on the PK set.  
The PK parameters will be calculated by non-compartmental analysis (NCA) using software 
Phoenix WinNonlin®.  
The following PK parameters in plasma will be assessed: 
• Cmax (maximum observed concentration) 
• Ctrough (lowest concentration reached before next dose is administered) 
• AUCτ (area under the curve from 0 to t, where t is the last measurable sample after 
fourth dose) 
• Peak to trough ratio (PTR) (after fourth dose) 
• Rac (AUC) (Accumulation ratio calculated from AUCτ,ss and AUCτ after single dosing) 
• t½ ( terminal half-life after fourth dose) 
• PK parameters will also be calculated or extrapolated after all other dose 
administrations 
Listings for the PK parameters will be presented separately by treatment group, age group 
(18-69 years of age and ≥70 years of age) and renal function at baseline. The parameters will 
also be summarized with number of measurements, arithmetic mean, SD, CV, median, 


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minimum, maximum, geometric mean, geometric CV%. In addition, the individual and mean 
concentration-time profiles will be illustrated graphically. Dose proportionality will be 
evaluated for Cmax and AUCτ. 
Concentration values below the lower limit of quantitation (LLOQ) that precede the first 
quantifiable concentration value will be set to zero for linear plots and for all calculations and 
summary statistics but will be excluded from semi-logarithmic plots. All other LLOQ values 
will be treated as missing for all analyses. Possible outlying concentration values excluded 
from the PK analysis will be reported and justified in the study report. 
Analysis of presence and titers of ADA will be performed on FAS. 
Based on the relatively small sample size no formal hypothesis testing will be conducted. 
9.4.6 
Exploratory endpoint(s) 
Efficacy/pharmacodynamics/biomarkers as well as urine concentration of RMC-035 
(normalized for urine creatinine) assessments are part of exploratory endpoints only and will 
be performed on FAS and summarized using frequency tables and descriptive statistics for 
absolute and/or relative change from baseline. 
 
9.5 
Interim Analyses 
No interim analyses will be performed.  
9.6 
Data Monitoring Committee (DMC) 
No data monitoring committee will be established and used in this clinical study. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the 
following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• 
The protocol, ICF, Investigator Brochure, and other relevant documents (e.g. 
advertisements) must be submitted to an IEC and as applicable to the Competent 
Authority (CA) and reviewed and approved by the IEC and CA before the study is 
initiated. 
• 
Any amendments to the protocol will require IEC and CA approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study subjects. 
• 
KLIFO will be responsible for the following: 
o Notifying the IEC and CA of SUSARs or other significant safety findings as 
required by local law. 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IEC, European Directive 2001/20/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
• The Sponsor has delegated the responsibility for submission of study documents to 
IEC and CA to KLIFO. 
10.1.2 
Financial Disclosure 
Principal Investigator and all physicians of the study team will provide the sponsor with 
sufficient, accurate financial information as requested to allow the sponsor to submit complete 
and accurate financial certification or disclosure statements to the appropriate regulatory 
authorities.  
10.1.3 
Informed Consent Process 
• 
The investigator will explain the nature of the study to the subject and answer all 
questions regarding the study. 
• 
Subjects must be informed that their participation is voluntary and they may 
withdraw from the study at any time.  
• 
Subjects will be required to sign and personally date a statement of informed 
consent that meets the requirements of ICH-GCP requirements, where applicable, 
and the IEC or investigational site after the subject has had sufficient amount of time 
to consider participation. 


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• 
The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the subject. 
10.1.4 
Data Protection 
• 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only, i.e. data 
will be transferred in a pseudonymized manner. Subject names or any information 
which would make the subject identifiable will not be disclosed. A Subject 
Identification List or equivalent will be kept at the investigational site and no one 
outside of the investigational site will be able to identify the participating subjects. 
• 
The subject must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the subject who will be required to give consent for their 
data to be used as described in the informed consent.  
• 
The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance (QA) auditors or other authorized personnel appointed 
by the sponsor and by inspectors from regulatory authorities. 
• 
All data will be handled in accordance with the EU’s current Data Protection Law 
Enforcement Directive, The General Data Protection Regulation (GDPR) and the 
local data protection regulations. 
• 
For this study, the Sponsor and Investigational Site are the data controller of all data 
processed during the study and KLIFO and other sub-contractors used are data 
processors. 
10.1.5 
Insurance 
The Sponsor will ensure that subjects are covered by relevant insurances covering subjects 
participating in the study. Liability for study induced injury will be covered according to 
local requirements. 
10.1.6 
Dissemination of Clinical Study Data 
Basic information about this study will be registered in the global data registry 
www.clinicaltrials.gov before the first patient enters into the trial. 
 
A clinical study report describing the conduct of the study, the statistical analysis performed 
and the results obtained, will be prepared by the sponsor or delegate. The report will be 
reviewed and approved by, as a minimum, the investigators, the statistician and the sponsor.  
The study results will be reported in the European Clinical Trials Database (EudraCT) 
database per applicable regulations within 12 months after completion of the trial. 
 
A summarising report will be submitted to the applicable CA and IEC within 12 months after 
completion of the trial. 


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10.1.7 
Data Quality Assurance 
• 
All subject data relating to the study will be recorded in an electronic eCRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
Study monitors will perform ongoing source data verification (SDV) to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• 
The investigator must permit study-related monitoring and provide direct access to 
source data documents. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g. 
Contract Research Organizations (CRO)). 
• 
The sponsor and CRO have the right to perform an audit of the investigational site 
and the sponsor may also audit the CRO. Such audits will be conducted according to 
a specific audit plan. 
• 
The regulatory (competent) authorities, both national and foreign, may inspect the 
investigational site at any time. The investigator is responsible for notifying the 
sponsor of such an inspection immediately after gaining knowledge of it. 
• 
During the audit or inspection, the investigator will permit the auditor, and 
regulatory inspector(s) direct access to all relevant medical records and other source 
data, study-related files and eCRFs. 
• 
Records and essential documents, including signed ICFs, pertaining to the conduct 
of this study must be retained by the investigator for a minimum of 15 years after 
completion or discontinuation of the trial, if no further instructions are given by the 
sponsor. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location 
or party without written notification to the sponsor. 
 


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10.1.8 
Source Documents 
• 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s 
site. 
• 
Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• 
After data entry, the AEs will be coded according to MedDRA.  
Prior and Concomitant Medication will be coded according to WHO Drug 
Reference List and Anatomical Therapeutic Chemical Classification System 
(ATC). Medical History will be coded according to MedDRA. 
• 
Definition of what constitutes source data and where source data is located can be 
found in a Source Data Agreement Form or equivalent. 
10.1.9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects at the investigational site and the study will be closed after the last subject has 
commenced last visit. 
Planned trial period:  
First Subject First Visit: Q4 2020 
Last Subject Last Visit: Q3 2021 
The sponsor or designee reserves the right to close the investigational site or terminate the 
study at any time for any reason at the sole discretion of the sponsor. The Investigational site 
will be closed upon study completion. An investigational site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of an investigational site by the sponsor or investigator may 
include but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further development of the IMP 
• 
If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the Investigators, the IECs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The Investigator 
shall promptly inform the subject and should assure appropriate subject therapy 
and/or follow-up.Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 


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sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of studies with many investigational sites only in their entirety 
and not as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
• 
External CRO or laboratory involved in the conduct of the study has no publication 
rights regarding this study. 


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10.2 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed below will be performed by the local laboratory at the University 
Hospital in Münster. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator. 
• 
Pregnancy Testing at screening and at Visit 7 only apply for WOCBP. 
Table 7  Protocol Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Erythocyte Volume 
Fraction (EVF) 
Mean corpuscular 
volume (MCV) 
Monocytes 
Hemoglobin (Hb) 
Mean corpuscular 
hemoglobin (MCH) 
Lymphocytes 
Thrombocytes 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
Eosinophils 
Erythocytes 
Leucocytes 
Basophils 
 
Neutrophils 
 
Clinical Chemistry  
(excl. liver function 
labs) 
Albumin 
Cystatine C 
Sodium 
Calcium 
Estimated glomerular 
filtration rate (based 
on creatinine and 
cystatin C) 
Urea nitrogen 
Chloride 
Magnesium 
Uric acid 
Serum Creatinine 
Phosphate 
 
C-reactive protein (CRP) 
Potassium 
Liver function lab 
Alanine Aminotransferase 
(ALT) 
Aspartate 
Aminotransferase 
(AST) 
Gamma 
glutamyltransferase 
(GGT) 
Alkaline phosphatase 
(ALP) 
Bilirubin (total and 
conjugated) 
 
Cardiac biomarkers 
NT-proBNP 
Troponin-I 
 
Urinalysis 
Specific gravity 
pH 
Leucocytes 
Erythrocytes 
Protein 
Glucose 
Nitrite 
Urobilinogen 
Bilirubin 
Ketones 
Microscopic 
examination  
(if blood or protein is 
abnormal) 
 
Urine test 
Creatinine 
Other Screening 
Tests 
• 
Highly sensitive serum human chorionic gonadotropin (hCG) serum 
pregnancy test (as needed for WOCBP) 
• 
Hemoglobin A1c (HbA1c) in blood 


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10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study subject, 
temporally associated with the use of medicinal product, whether or not considered 
related to this IMP 
NOTE: An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of medicinal product. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results or other safety assessments including those 
that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after IMP administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE 
unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease or the surgical 
procedure, unless judged by the investigator to be more severe than expected for 
the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 
• Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 


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10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g. hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
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 subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, 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. 


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10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to KLIFO PV in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested 
by KLIFO PV. In this case, all subject identifiers, with the exception of the subject 
number, will be redacted on the copies of the medical records before submission to 
KLIFO PV. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of severity (CTCAE grade) 
The investigator will make an assessment of severity for each AE and SAE reported during 
the study and assign it to grades 1 through 5 according to the CTCAE classification version 
5.0. 4 
Grade refers to the severity of the AE. The CTCAE displays grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental 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. 
A Semi-colon indicates ‘or’ within the description of the grade. 
Activities of Daily Living (ADL) 
*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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Injection Site Reaction (ISR) or Infusion Related Reaction (IRR) of grade 3 or higher are 
considered Adverse Events of Special Interest and must be reported within 24 hours following 
the SAE deadline described in section 8.4.1. The CTCAE grading for ISR and IRR are 
provided in the table below. For unique clinical descriptions of severity for each AE, refer to 
the CTCAE classification guideline. 
CTCAE 
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Definition 
Injection site 
reaction 
(ISR) 
 
MedDRA 
SOC: General 
disorders and 
administration 
site 
conditions 
Tenderness 
with or 
without 
associated 
symptoms 
(e.g., 
warmth, 
erythema, 
itching) 
Pain; 
lipodystrophy; 
edema; 
phlebitis 
Ulceration or 
necrosis; 
severe tissue 
damage; 
operative 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
A disorder 
characterized by 
an intense 
adverse reaction 
(usually 
immunologic) 
developing at 
the site of an 
injection. 
Infusion 
related 
reaction 
(IRR) 
 
MedDRA 
SOC: Injury, 
poisoning and 
procedural 
complications 
Mild 
transient 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention 
not 
indicated 
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
<=24 hrs 
Prolonged 
(e.g., not 
rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for 
clinical 
sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
A disorder 
characterized by 
adverse reaction 
to the infusion 
of 
pharmacological 
or biological 
substances. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• The investigator is obligated to assess and record the relationship between the IMP 
and each occurrence of each AE/SAE according to the following definitions: 
o Not related (unlikely) 
 Does not follow a reasonable temporal sequence from drug 
administration 
 Is readily explained by the patient’s clinical state or by other modes 
of IMP administered to the patient 
o Related (possible/probable) 
 Follows a reasonable temporal sequence from IMP administration 
 Cannot be reasonably explained by the known characteristics of the 
patient’s clinical state 


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• Alternative etiology should be provided for all AEs assessed as possible related to 
IMP. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) version 6 and 
any updates in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to KLIFO PV. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to KLIFO PV. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Assessment of Outcome 
The investigator must judge outcome of the AE by the following terms: 
• Recovered 
o fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first trial related activity after the 
subject signed the informed consent. 
• Recovering 
o the condition is improving and the subject is expected to recover from the 
event. This term should only be used when the subject has completed the 
trial. 
• Recovered with sequelae 
o as a result of the AE the subject suffered persistent and significant 
disability/incapacity (e.g. became blind, deaf, paralysed). If the sequelae 
meet seriousness criteria, the AE must be reported as an SAE. 
• Not recovered 
• Fatal 
• Unknown 
o should only be used in cases where the subject is lost to follow-up. 
 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 


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• If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide KLIFO PV with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The investigator will submit any updated SAE data to KLIFO PV within 24 hours 
of receipt of the information. 
 
10.3.4 
Reporting of SAEs 
SAE Reporting to KLIFO PV via the eCRF 
• The primary mechanism for reporting an SAE to KLIFO PV will be the eCRF.  
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the eCRF as soon as it becomes available. 
• After the study is completed at a given site, the eCRF will be taken off-line to 
prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the eCRF has been taken off-line, then the 
site can report this information on a paper SAE form (see next section). 
 
SAE Reporting to KLIFO PV via Paper SAE form (in case of eCRF unavailability) 
• E-mail or fax transmission of the SAE via a paper form is the preferred method to 
transmit this information to KLIFO PV. 
• Initial notification via e-mail or fax does not replace the need for the investigator to 
enter the SAE data into the eCRF as soon as it becomes available. 
• Contacts for e-mail or fax SAE reporting: 
o Email: pharmacovigilance@klifo.com  
o Fax: +45 39 209 045 
 


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10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g. mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance3:  
Highly effective forms of birth control include:  
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable  
• Intrauterine device (IUD)  


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• Intrauterine hormone-releasing system (IUS)  
• Bilateral tubal occlusion  
• Vasectomised partner  
• True sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.    
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This 
applies only to male subjects who receive IMP. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female Subjects who become pregnant 
 
• 
The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a subject's pregnancy.  
• 
The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• 
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.4.5. While the investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting. 
• 
Any female subject who becomes pregnant while participating in the study will 
discontinue IMP administration. 


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10.5 
Appendix 5: List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
8OH-dG 
8 hydroxy 2 deoxyguanosine 
A1M 
Alpha-1-microglobulin 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration time curve  
AUCτ 
Area under the curve from 0 to t, where t is the last measurable sample 
BP 
Blood pressure 
CA 
Competent Authority 
CKD 
Chronic kidney disease 
CL 
Total systemic clearance 
Cmax 
Maximum (peak) concentration observed 
CO 
Cardiac output 
CPB 
Cardiopulmonary by-pass 
Ctrough 
Lowest concentration reached by a drug before the next dose is administered 
CrCl 
Creatinine clearance 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CVC 
Central venous catheter 
CVP 
Central venous pressure 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ELISA 
Enzyme linked immunosorbent assay 
FAS 
Full Analysis Set 
FDA 
U.S. Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration 
GLP 
Good Laboratory Practice 


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Abbreviation 
Definition 
GMP 
Good Manufacturing Practice 
h 
hour(s) 
Hb  
Hemoglobin  
IB  
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
ICU  
Intensive care unit  
IEC  
Independent ethics committee  
IGFBP7 
 Insulin like growth factor binding protein 7 
IL 
Interleukin 
IMP  
Investigational Medicinal Product  
INR 
International normalised ratio 
IRR 
Infusion related reaction (Injury poisoning and procedural complications) 
ISR 
Infusion site reactions (General disorders and administration site conditions) 
IV 
Intravenous 
KDIGO 
a global nonprofit organization developing and implementing evidence-based 
clinical practice guidelines in kidney disease 
KIM 
Kidney injury marker 
L-FAPB 
Fatty acid-binding protein 
LLOQ 
Lower limit of quantification 
MAD 
Multiple ascending dose 
MedDRA 
Medical dictionary for regulatory activities 
NCA 
Non-compartmental analysis 
NGAL 
Neutrophil gelatinase associated lipocalin 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
PA 
Pulmonary artery 
PK 
Pharmacokinetic 
PT 
Preferred term 
PTR 
Peak to trough ratio  
PV 
Pharmacovigilance 
QA 
Quality assurance 
Rac (AUC) 
Accumulation ratio calculated from AUCτ,ss and AUCτ 
after single dosing 
ROS 
Reactive oxygen species 
RRT 
Renal replacement therapy 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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Abbreviation 
Definition 
SCr 
Serum Creatinine 
SD 
Standard deviation 
SDV 
Source data verification 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SvO2 
mixed venous saturation 
TEAE 
Treatment emergent adverse event 
TIMP2 
Tissue inhibitor of metalloproteinases 2 
t½ 
Elimination half-life 
ULN 
Upper limit of normal 
WHO 
World Health Organisation 


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11 
REFERENCES 
 
1. Investigator’s Brochure for RMC-035 (4.0 mg/mL RMC-035 Solution for Injection), 
Version 6, Guard Therapeutics AB, 21 Sep 2020    
2. EU GMP Guidelines, Medicinal Products for Human and Veterinary Use,  
Annex 13, Investigational Medicinal Products and the German Ordinance on the 
implementation of Good Clinical Practice in the conduct of clinical trials on medicinal 
products for use in humans (GCP Ordinance - GCP-V), Section 5.  
3. Clinical Trial Facilitation Group (CTFG): Recommendations related to contraception 
and pregnancy testing in clinical trials 
4. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, 27 Nov 2017 
5. Kidney Disease Improving Global Outcome (KDIGO), Clinical Practice Guideline for 
Acute Kidney Injury, Volume 2, Issue 1, Mar 2012