Clinical trial NCT05126303
Conditions: Acute Kidney Injury
Sponsor: Guard Therapeutics AB
Start date: 2022-03-31; Completion date: 2023-07-12
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates RMC-035 compared to placebo for the prevention of acute kidney injury (AKI) in subjects who are at high risk for AKI following cardiac surgery. Half of the subjects will receive RMC-035 and the other half will receive placebo.

Detailed description:
This is a Phase 2, randomized, double-blind, adaptive, parallel group clinical study that will evaluate RMC-035 compared to placebo in subjects at high risk for acute kidney injury (AKI) following cardiac surgery. Subjects are randomized in a 1:1 ratio.

Arms: arm 1: RMC-035 is a concentrate (6.0 mg/mL) for solution for infusion for IV administration.

Dosing will be based on renal function at Day -1: Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth and fifth dose, while subjects with eGFR \>30 and \<60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for all five doses Dosing occurs at time 0 and then after 6, 12, 24 and 48 hours. arm 2: Identical to RMC-035 arm except that the placebo contains no active ingredient.
Interventions: intervention 1: RMC-035 intervention 2: Placebo
Intervention descriptions: intervention 1: Concentrate for Solution for Infusion intervention 2: Concentrate for Solution for Infusion

Protocol documents:
Prot_002.pdf: 
 
 TITLE PAGE 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
A Phase 2, Randomized, Placebo-Controlled, Double-Blind, 
Adaptive, Parallel Group Clinical Study to Evaluate the 
Efficacy and Safety of RMC-035 in Subjects at High Risk for 
Acute Kidney Injury Following Open-Chest Cardiac Surgery  
Study Name 
AKITA 
Protocol Number: 
21-ROS-05 
Investigational Product: 
RMC-035 or Placebo 
EudraCT Number:  
2021-004040-19 
Clinical Study Sponsor: 
Guard Therapeutics International AB 
Nybrogatan 34, 
SE-114 39 Stockholm, Sweden 
Version: 
3.1 
Protocol Amendment Date 
08 October 2022 
 
 
CONFIDENTIALITY NOTICE 
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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SIGNATURE PAGE 
 
Sponsor’s Approval 
The protocol has been approved by Guard Therapeutics International AB. 
 
Sponsor Signatories: 
 
 
 
 
 
 
 
 
Dr. med. Michael Reusch 
Medical Lead / Chief Medical Officer 
 
Sara Thuresson, MSc 
Head of Clinical Operations  
 
 
 
 
 
 
 
 
 
 
Alberto Garcia Hernandez, MSc 
Biostatistician  
 
Lead Investigator Signatory: 
 
 
 
 
 
 
 
 
Prof. Dr. med. Alexander Zarbock 
Lead Investigator 


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INVESTIGATOR’S AGREEMENT 
 
I have read the attached protocol 21-ROS-05 Version 3.1 (amendment 3.0) titled: A Phase 2, 
Randomized, Placebo-Controlled, Double-Blind, Adaptive, Parallel Group Clinical Study to 
Evaluate the Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury 
Following Open-Chest Cardiac Surgery, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice and applicable national or regional regulations and guidelines. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the conduct of the clinical investigation without prior written consent 
from Guard Therapeutics International AB. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature   
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name 
 


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EMERGENCY PERSONNEL 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor / 
24-Hour Emergency 
Contact  
Robert Gaston, MD 
Sr. Medical Director 
CTI Clinical Trial & Consulting 
Services 
100 E. RiverCenter Blvd 
Covington, KY 41011 
Email: rgaston@ctifacts.com 
 
Phone: 
USA/Canada: 1 800 936 1593 
Spain: 900 876 257 
Germany: 0800 1806593 
Czech Republic: 800 144 262 
SAE Reporting 
CTI Clinical Trial & Consulting 
Services 
100 E. RiverCenter Blvd 
Covington, KY 41011 
 
SAE eFax number: 
USA: 1 800 695 3418 
Canada: 1 877 349 5952 
Spain: 900 807 339  
Germany: 7319 7929001 
Czech Republic: 227 204 969 
 
Toll Free SAE Phone Hotline: 
USA: 1-877-755-0742 
Canada: 1 877 832 6358 
Spain: 900 1817513 
Germany: 0800 1817513 
Czech Republic: 800 144 513 
 


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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
EMERGENCY PERSONNEL ........................................................................................................4 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ....................................5 
LIST OF ABBREVIATIONS ........................................................................................................10 
1. 
SYNOPSIS .................................................................................................................14 
2. 
INTRODUCTION ......................................................................................................31 
2.1. 
Background .................................................................................................................33 
2.1.1. 
Pharmacology .............................................................................................................33 
2.1.2. 
Summary of Toxicology Studies ................................................................................34 
2.1.3. 
Summary of Completed Clinical Studies ...................................................................34 
2.1.3.1. 
Single Ascending Dose Study (17-ROS-01) ..............................................................34 
2.1.3.2. 
Multiple Ascending Dose Study (19-ROS-02) ...........................................................35 
2.1.3.3. 
Renal Impairment Study (19-ROS-03) .......................................................................35 
2.1.3.4. 
Exploratory Safety Study in Cardiac Surgery Subjects (20-ROS-04) ........................36 
2.1.4. 
Key Safety Information ..............................................................................................37 
2.1.4.1. 
Risk Mitigation Measures ...........................................................................................38 
2.1.5. 
Risk / Benefit Assessment ..........................................................................................39 
3. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................41 
3.1. 
Primary, Secondary, and Exploratory Objectives .......................................................41 
3.1.1. 
Primary Objectives .....................................................................................................41 
3.1.2. 
Secondary Objectives .................................................................................................41 
3.1.3. 
Exploratory Objectives ...............................................................................................41 
3.2. 
Primary, Secondary, and Exploratory Endpoints .......................................................42 
3.2.1. 
Primary Efficacy Endpoint .........................................................................................42 
3.2.2. 
Primary Safety Endpoint .............................................................................................42 
3.2.3. 
Secondary Endpoints ..................................................................................................42 
3.2.4. 
Exploratory Endpoints ................................................................................................43 


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4. 
INVESTIGATIONAL PLAN .....................................................................................45 
4.1. 
Overall Study Design ..................................................................................................45 
4.2. 
Participating Sites .......................................................................................................48 
4.3. 
Number of Subjects ....................................................................................................48 
4.4. 
Replacement of Subjects .............................................................................................48 
4.5. 
Completion of Study ...................................................................................................48 
4.6. 
Early Study Termination .............................................................................................48 
4.6.1. 
Discontinuation of a Site ............................................................................................48 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................50 
5.1. 
Subject Inclusion Criteria ...........................................................................................50 
5.2. 
Subject Exclusion Criteria ..........................................................................................51 
5.3. 
Subject Withdrawal Criteria .......................................................................................52 
5.3.1. 
Discontinuation of Investigational Medicinal Product ...............................................53 
5.3.1.1. 
Permanent discontinuation of IMP .............................................................................53 
5.3.1.2. 
Temporary discontinuation IMP .................................................................................53 
5.3.2. 
Lost to Follow-Up.......................................................................................................54 
6. 
TREATMENT OF SUBJECTS ..................................................................................55 
6.1. 
Investigational Medicinal Product ..............................................................................55 
6.1.1. 
RMC-035 ....................................................................................................................55 
6.1.2. 
Placebo ........................................................................................................................55 
6.1.3. 
Concomitant Medications ...........................................................................................55 
6.1.3.1. 
Restricted Concomitant Medications ..........................................................................56 
6.2. 
Investigational Medicinal Product Administration .....................................................56 
6.2.1. 
Rationale for RMC-035 Dosing ..................................................................................57 
6.3. 
Dose Adjustment Criteria ...........................................................................................57 
6.4. 
Treatment Compliance ................................................................................................57 
6.5. 
Randomization and Blinding ......................................................................................57 
6.5.1. 
Breaking the Blind ......................................................................................................58 
7. 
INVESTIGATIONAL MEDICINAL PRODUCT MATERIALS AND 
MANAGEMENT .......................................................................................................59 
7.1. 
Investigational Medicinal Product ..............................................................................59 
7.2. 
Investigational Medicinal Product Packaging and Labelling .....................................59 
7.3. 
Investigational Medicinal Product Storage .................................................................59 


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7.4. 
Investigational Medicinal Product Preparation ..........................................................59 
7.5. 
Administration ............................................................................................................60 
7.6. 
Investigational Medicinal Product Accountability .....................................................60 
7.7. 
Investigational Medicinal Product Handling and Disposal ........................................60 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................62 
8.1. 
Informed Consent .......................................................................................................62 
8.2. 
Demographic Data ......................................................................................................62 
8.3. 
Medical and Surgical History .....................................................................................62 
8.4. 
Prior and Concomitant Medications ...........................................................................62 
8.5. 
Weight and Height ......................................................................................................62 
8.6. 
Safety Assessments .....................................................................................................62 
8.6.1. 
Assessments Before, During and After Surgery .........................................................63 
8.6.2. 
Physical Examination .................................................................................................63 
8.6.3. 
Vital Signs ..................................................................................................................63 
8.6.4. 
Electrocardiograms .....................................................................................................64 
8.7. 
Laboratory Assessments .............................................................................................64 
8.7.1. 
Urine Albumin Creatinine Ratio and Urine Protein Creatinine Ratio ........................66 
8.7.2. 
Urinalysis ....................................................................................................................66 
8.7.3. 
Pregnancy Testing ......................................................................................................66 
8.8. 
Urine Output ...............................................................................................................66 
8.9. 
Major Adverse Kidney Events ....................................................................................67 
8.10. 
Pharmacokinetic Assessments ....................................................................................67 
8.11. 
Immunogenicity Assessments ....................................................................................67 
8.12. 
Health-Related Quality of Life Assessments ..............................................................68 
8.13. 
Exploratory Biomarkers ..............................................................................................69 
8.13.1. 
Kidney and Cardiac Biomarkers .................................................................................69 
8.13.2. 
Immunologic Biomarkers ...........................................................................................69 
9. 
SAFETY MONITORING AND REPORTING .........................................................70 
9.1. 
Definition of an Adverse Event ..................................................................................70 
9.2. 
Definition of a Serious Adverse Event .......................................................................71 
9.2.1. 
Suspected Unexpected Serious Adverse Reactions ....................................................71 
9.3. 
Adverse Events of Special Interest .............................................................................72 


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9.4. 
Relationship to Investigational Medicinal Product .....................................................72 
9.5. 
Assessment of Intensity ..............................................................................................73 
9.6. 
Recording Adverse Events .........................................................................................74 
9.7. 
Reporting Adverse Events ..........................................................................................74 
9.8. 
Pregnancy and Lactation .............................................................................................75 
9.9. 
Data Monitoring Committee .......................................................................................76 
10. 
STATISTICAL CONSIDERATIONS .......................................................................77 
10.1. 
Analysis Sets ...............................................................................................................77 
10.2. 
Sample Size Determination ........................................................................................77 
10.3. 
Stratification and Randomization ...............................................................................77 
10.4. 
Interim Analyses .........................................................................................................77 
10.4.1. 
Primary Endpoint ........................................................................................................77 
10.4.2. 
Exploratory Kidney and Cardiac Biomarkers .............................................................78 
10.5. 
Planned Method of Data Presentation and Analysis ...................................................78 
10.5.1. 
Demographic and Baseline Characteristics ................................................................78 
10.5.2. 
Efficacy .......................................................................................................................78 
10.5.3. 
Subgroup Analyses .....................................................................................................79 
10.5.4. 
Safety ..........................................................................................................................79 
10.5.5. 
Pharmacokinetics ........................................................................................................79 
10.5.6. 
Exploratory Biomarkers ..............................................................................................80 
10.5.6.1. 
Kidney and Cardiac Biomarkers .................................................................................80 
10.5.6.2. 
Immunologic Biomarkers ...........................................................................................80 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................81 
11.1. 
Study Documents ........................................................................................................81 
11.2. 
Study Monitoring ........................................................................................................81 
11.3. 
Audits and Inspections ................................................................................................82 
11.4. 
Institutional Review Board and Independent Ethics Committee ................................82 
12. 
DATA QUALITY ASSURANCE ..............................................................................83 
12.1. 
Inspection of Records .................................................................................................83 
12.2. 
Retention of Records ..................................................................................................83 
12.3. 
Data Protection ...........................................................................................................83 
13. 
ETHICS ......................................................................................................................84 


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13.1. 
Ethics Review .............................................................................................................84 
13.2. 
Ethical Conduct of the Study ......................................................................................84 
13.3. 
Written Informed Consent ..........................................................................................84 
13.4. 
Financial Disclosure ...................................................................................................85 
13.5. 
Insurance .....................................................................................................................85 
14. 
REPORT AND PUBLICATION ................................................................................86 
15. 
LIST OF REFERENCES ............................................................................................87 
16. 
APPENDICES ............................................................................................................90 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Terms ............................................................................................10 
Table 3: 
Schedule of Assessments – Complete Study Period ...................................................26 
Table 4: 
RMC-035 Characteristics ...........................................................................................55 
Table 5: 
Protocol Required Laboratory Assessments – Local Laboratory ...............................64 
Table 6: 
Protocol Required Laboratory Assessments – Central Laboratory ............................65 
Table 7: 
Plasma Pharmacokinetic Sampling Timepoints .........................................................67 
Table 8:  
Grading For Injection Site Reactions (ISR) and Infusion Related Reactions 
(IRR) ...........................................................................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Chart ........................................................................................................30 
Figure 2: 
Pathophysiological Pathways in CS-AKI ...................................................................31 
 
 


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LIST OF ABBREVIATIONS  
 
Table 2: 
Abbreviations and Terms  
Abbreviation or 
Specialist Term 
Explanation 
8-OHdG 
8-hydroxy-2'-deoxyguanosine 
A1M 
Alpha-1-microglobulin 
ACEi 
Angiotensin-converting enzyme inhibitor 
ADA 
Anti-drug antibodies 
ADL 
Activities of daily living 
AE 
Adverse event 
AKI 
Acute kidney injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BPM 
Beats per minute 
CABG 
Coronary artery bypass grafting 
CCL-14 
Chemokine ligand 14 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum (peak) concentration observed 
CP 
Conditional power 
CPB 
Cardiopulmonary bypass 
CRF 
Case report form 
CRO 
Contract research organization 
CS-AKI 
Cardiac surgery associated acute kidney injury 
CSR 
Clinical study report 
DMC 
Data monitoring committee 
cTnI 
Cardiac troponin I 
cTnT 
Cardiac troponin T 


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Abbreviation or 
Specialist Term 
Explanation 
CVC 
Central venous catheter 
ECG 
Electrocardiogram  
ECMO 
Extra-corporeal membrane oxygenator  
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-study 
EOT 
End-of-treatment 
EQ-5D-5L 
European quality of life 5 domain 5-level score 
FDA 
Food and Drug Administration 
FMV 
First morning void 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
h 
Hour(s) 
HRQoL 
Health related quality of life 
HRT 
Hormone replacement therapy 
IA 
Interim analysis 
IABP 
Intra-aortic balloon counter-pulsation 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
Ig 
Immunoglobulin 
IGFBP7 
Insulin-like growth binding factor 7 
IL-18 
Interleukin-18 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRR 
Infusion related reaction 
ISR 
Infusion site reaction 
ITT 
Intent to treat 


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Abbreviation or 
Specialist Term 
Explanation 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone releasing system 
IV 
Intravenous 
KIM-1 
Kidney injury molecule 1 
LFABP 
Liver fatty acid binding protein 
LVAD 
Left ventricular assist device 
LVEF 
Left ventricular ejection fraction 
MAD 
Multiple ascending dose 
MAKE 
Major adverse kidney events 
MCS 
Mechanical circulatory support 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent to treat 
MMRM 
Mixed model for repeated measurements  
MRI 
Magnetic resonance imaging 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NOAEL 
No observed adverse effect levels 
NSAID 
Non-steroidal anti-inflammatory drugs 
NT-pro-BNP 
N-terminal-pro-b-type natriuretic peptide 
NYHA 
New York Heart Association 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PRO 
Patient reported outcome 
PT 
Preferred term 
RRT 
Renal replacement therapy 
RAAS 
Renin-angiotensin-aldosterone system 
ROS 
Reactive oxygen species 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 


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Abbreviation or 
Specialist Term 
Explanation 
SCr 
Serum creatinine 
SD 
Standard deviation 
SF-36 
Medical outcomes study 36-item short form survey instrument 
SOA 
Schedule of assessments 
SOC 
System organ class 
SOP 
Standard operating procedure 
SpO2 
Oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
T2DM 
Type 2 diabetes 
TAVI 
Transcatheter aortic valve implantation 
TAVR 
Transcatheter valve replacement 
TEAE 
Treatment emergent adverse event 
TIMP2 
Tissue inhibitor of metalloproteinase 2 
TMF 
Trial master file 
UACR 
Urine albumin-to-creatinine ratio 
UPCR 
Urine protein-to-creatinine ratio 
ULN 
Upper limit of normal 
UO 
Urine output 
VAS 
Visual analogue scale 
WOCBP 
Woman of childbearing potential 
 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Guard Therapeutics International AB 
Name of Investigational Product: 
RMC-035 
Indication: Cardiac Surgery Associated Acute Kidney Injury (CS-AKI) 
Protocol Number: 21-ROS-05 
Phase: 2 
Regions: North America, 
Europe 
Title of Study:  
A Phase 2, Randomized, Placebo-Controlled, Double-Blind, Adaptive, Parallel Group Clinical Study 
to Evaluate the Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury 
Following Open-Chest Cardiac Surgery 
Studied period (years):  
Estimated date first subject enrolled: Quarter 4 2021 
Estimated date last subject completed: Quarter 2 2023 
Objectives:  
Primary Objectives: 
• 
To evaluate the efficacy of RMC-035 for prevention of AKI (Kidney Disease Improving Global 
Outcomes [KDIGO] definition) in subjects undergoing coronary artery by-pass graft (CABG) 
and/or valve surgery and/or aorta surgery with additional risk factors for developing cardiac 
surgery associated AKI 
• 
To evaluate the safety and tolerability of RMC-035  
 
Key Secondary Objectives: 
• 
To evaluate RMC-035 for the prevention of post-operative decline (within 72 hours) in renal 
function  
• 
To evaluate RMC-035 for the reduction of post-operative AKI duration  
 
Other Secondary Objectives: 
• 
To evaluate RMC-035 for preserving post-surgery renal function up to Day 90 
• 
To evaluate RMC-035 for the prevention of post-operative dialysis up to Day 90 
• 
To evaluate RMC-035 for the prevention of major adverse kidney events (MAKE) at Days 30 and 
90, respectively 
• 
To further evaluate RMC-035 for the  
o Prevention of AKI within 72 hours (based on cystatin C and/or Urine Output [UO]) 
o Persistence and severity of AKI within 72 hours (based on serum creatinine [SCr] and/or 
UO or cystatin C and/or UO) 
o Prevention, persistence, and severity of AKI within 7 days (based on SCr and/or UO or 
cystatin C and/or UO) 
• 
To evaluate RMC-035 for reducing post-operative albuminuria and proteinuria up to Day 90 


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• 
To evaluate the pharmacokinetics of RMC-035  
• 
Identification and characterization of anti-drug-antibodies (ADA) developed after intravenous 
administration of RMC-035 
 
Exploratory Objectives: 
• 
To evaluate post-baseline changes in kidney and cardiac biomarkers 
• 
To evaluate changes in immunologic biomarkers  
• 
To evaluate the length of post-operative stay in Intensive Care Unit (ICU) and overall 
hospitalization time 
• 
To evaluate health-related Quality of Life 
Primary Efficacy Endpoint: 
• 
AKI within 72 hours after first dose of IMP based on SCr and/or UO (AKI of any stage/severity 
according to KDIGO definition, ie, SCr ≥1.5 times baseline, or increase of SCr of ≥0.3 mg/dL 
[≥26.5 µmol/L], or UO <0.5 mL/kg/h for ≥6 hours) 
 
Primary Safety Endpoint: 
• 
Nature, frequency and severity of treatment-emergent adverse events (TEAEs) 
 
Key Secondary Endpoints: 
• 
Time-corrected area under the curve (AUC) of SCr for Day 1 to Day 4 (72 hours after first dose 
of IMP) 
• 
Duration of AKI defined as the number of days meeting the definition of AKI (KDIGO 
definition) starting within 72 hours after first dose of IMP until resolution  
 
Other Secondary Endpoints: 
• 
Post-baseline changes in renal function  
o SCr and cystatin C (and corresponding eGFR values) at 12, 24, 48, and 72 hours, 
respectively, and at Day 7/discharge, Day 30 and Day 90 
o Change from baseline, up to Day 7/discharge, of peak SCr and cystatin C 
o Time-corrected AUC of Cystatin C for Day 1 to Day 4 (72 hours after first dose of IMP) 
• 
Need for renal replacement therapy 
o Dialysis treatment (for any reason) within 72 hours and within 7 days after end of surgery 
o Dialysis-free days from end of surgery to Day 30 and Day 90, respectively  
• 
MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of estimated 
glomerular filtration rate (eGFR) compared to baseline using the Chronic Kidney Disease-
Epidemiology Collaboration (CKD-EPI) equations (with either SCr, cystatin C, or both) 
• 
AKI Characteristics 
o AKI within 72 hours after first dose of IMP based on cystatin C and/or UO (AKI of any 
stage/severity defined as cystatin C ≥1.5 baseline, OR UO <0.5 mL/kg/h for ≥6 hours) 


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o AKI within 7 days after first dose of IMP (based on SCr and/or UO criteria, or cystatin C 
and/or UO criteria)  
o AKI persistence, defined as an AKI (KDIGO definition) developing within 72 hours after 
first dose of IMP and with a duration of ≥72 hours. Persistence will also be assessed per 
AKI severity stage*   
o AKI severity stage* within 72 hours and within 7 days after first dose of IMP  
 
*Severity of AKI defined as the following:  
• 
Stage 1: SCr 1.5 to 1.9 times baseline within 7 days, OR ≥0.3 mg/dL 
(≥26.5 µmol/L) OR urine output <0.5 mL/kg/h for 6 to <12 hours 
• 
Stage 2: SCr 2.0-2.9 times baseline within 7 days OR urine output 
<0.5 mL/kg/h for ≥12 hours 
• 
Stage 3: SCr 3.0 times baseline within 7 days, OR increase in SCr 
4.0 mg/dL (≥353.6 µmol/L), OR initiation of renal replacement therapy 
OR urine output <0.3 mL/kg/h for ≥24 hours OR anuria for ≥12 hours 
• 
Post-baseline changes in urine albumin to creatinine ratio (UACR) and urine protein to creatinine 
ratio (UPCR) at Day 4, Day 30, and Day 90 
• 
Pharmacokinetics of RMC-035 in plasma (AUC and Cmax) 
• 
Presence and titers of ADA at Day 1 (pre-surgery), Day 30, and Day 90 
• 
Characteristics of ADA developed at Day 30 and Day 90 with regards to isotype, neutralizing 
capacity, and cross-reactivity with endogenous alpha-1-microglobulin (A1M) 
 
Exploratory Endpoints: 
Post-baseline changes in kidney and cardiac biomarkers: 
• 
Kidney Biomarkers: Urine kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated 
lipocalin (NGAL), tissue inhibitor of metalloproteinase 2 (TIMP2), insulin-like growth binding 
factor protein 7 (IGFBP7), chemokine ligand 14 (CCL-14), interleukin-18 (IL-18), liver fatty acid 
binding protein (LFABP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) 
• 
Cardiac Biomarkers: Plasma N-terminal-pro-hormone BNP (NT-pro-BNP) and cardiac troponin I 
and T (cTnI, cTnT) 
Changes in immunologic biomarkers 
• 
Immunologic biomarkers to explore the background and mechanism of potential IRRs including 
but not limited to markers of complement activation, cytokine release and mast cell activation. 
Hospitalization time and discharge facility: 
• 
Length of index 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  
o Index hospital stay (in Days) is defined as the duration of stay in the hospital from the 
day of surgery to hospital discharge for the index surgery  
• 
Nature of subject discharge facility (eg, home, skilled nursing facility, rehabilitation center) 
Health-related Quality of Life assessments: 
• 
Change from baseline to Day 90 in the following Patient Reported Outcomes (PROs): 
o Medical Outcomes Study (MOS) 36-Item Short Form Survey Instrument (SF-36) 
o European Quality of Life 5 Domain 5-Level Score (EQ-5D-5L) 


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Methodology:  
This is a Phase 2, randomized, double-blind, adaptive, parallel group clinical study that will evaluate 
RMC-035 compared to placebo with approximately 268 subjects at high risk for CS-AKI based on 
pre-defined risk factors. An interim analysis (IA), including a sample size re-assessment, will be 
performed during which subject enrollment will continue. The study will be performed at 
approximately 30 sites in Europe and North America and consists of 8 visits for each subject with 
four study periods: 
• 
Screening Period: 30 days (Day -30 to -1)  
• 
Treatment Period: 3 days (Day 1-3)  
• 
Follow-Up Period: 27 days (Day 4-30)  
• 
Extended Follow-Up Period: 60 days (Day 31-90) 
See the Schedule of Assessments (SOA, Table 3) for the allowed time window for each study visit. 
During the course of the study, visits and assessments will be performed as defined in the SOA. 
Screening Period and Randomization (Visit 1) 
Prospective subjects may be consented within 30 days (inclusive) prior to the date of scheduled 
surgery. Subjects who have signed the informed consent may undergo initial screening assessments 
during the screening period (full physical examination, medical history, clinical laboratory testing, 
completion of health-related quality of life questionnaires etc.) as described in the SOA.  
All screening clinical laboratory testing to confirm eligibility and determine starting dose based on 
renal function will be performed by local laboratory on Day -1 (Visit 1), ie, the day before surgery is 
intended. In addition, samples for serum creatinine and cystatin C will be collected for central 
laboratory analysis which will provide the baseline values for the purpose of relevant endpoint 
assessment.  
Eligible subjects will be randomized on Day -1 (Visit 1) to receive either RMC-035 or placebo in a 
1:1 randomization ratio. Both region (North America and Europe) and Day -1 eGFR calculated using 
local laboratory results (≥60 and <60 mL/min/1.73m2) will be used as stratification factors to ensure a 
balanced randomization within these groups. 
Note: Some or all screening visit assessments listed in the SOA, including randomization, may be 
performed prior to surgery on Day 1 (Visit 2), ie, the day of surgery, if feasible for the site.  
Note: In case surgery is postponed after randomization has occurred, re-assessment of SCr and body 
weight for the calculation of eGFR is not required. However, if re-assessment is done as part of 
standard of case, and the results indicate an eGFR decrease that places the subject in a different 
stratum (ie <60 mL/min/1.73m2 for a subject who was randomized to the ≥60 mL/min/1.73m2 stratum) 
a decrease of the IMP dose to that of the lower stratum is acceptable if the change is clinically 
significant in the opinion of the investigator. 
Treatment Period (Visit 2-4) 
Surgery will occur on Day 1 (Visit 2). Before administration of IMP, preoperative safety assessments 
and sampling for local and central clinical laboratory testing will be performed per the SOA. 
Centrally processed laboratory samples of morning urine collected pre-surgery on Day 1 will provide 
the baseline values for evaluation of relevant endpoints (UACR and UPCR). 


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The first administration of Investigational Medicinal Product (IMP: RMC-035 or Placebo) will be 
given during surgery, approximately 10 minutes before the expected initiation of cardiopulmonary 
bypass (CPB), as an intravenous (IV) infusion. The start time of the first infusion is time 0, the 
reference point for further dose administrations and protocol-mandated assessments. In total, 5 doses 
of IMP will be administered during the treatment period. Administration of subsequent IV infusions 
start at 6, 12, 24 and 48 hours, respectively, after time 0 (start of the first dose).  
Administration of RMC-035 or placebo:  
• 
The first (0h) and second (6h) doses are administered as IV infusions over 60 minutes 
• 
The third (12h), fourth (24h) and fifth (48h) doses are administered as IV infusions over 30 
minutes  
Due to the pharmacokinetics of RMC-035, the predefined dose levels (prior to surgery), are based on 
renal function (eGFR by CKD-EPI equation with SCr) at screening (Day -1, Visit 1): 
• 
Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first and 
second dose, followed by 0.65 mg/kg (per dose) for the third, fourth and fifth dose  
• 
Subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for all 
five doses  
Differences between eGFR at Day -1 and additional eGFR calculations collected on Day 1 prior to 
surgery as part of the study or per the investigational site’s standard of care will not affect eligibility 
and starting dose unless the change is a decrease that the investigator considers clinically significant 
and that implies the subjects should have a lower starting dose. Should the subject eGFR drop below 
30 ml/min/1.73m2, and in the investigator’s opinion the decrease is clinically significant, the subject 
is no longer fulfilling eligibility criteria and should not start treatment. Discontinuation of IMP: 
• 
Investigational Medicinal Product will be permanently discontinued in subjects developing 
AKI stage 2 or higher as per KDIGO guidelines and for other reasons as detailed in 
Section 5.3.1. 
Investigational Medicinal Product should preferably be administered through a central venous 
catheter (CVC) in a lumen which is reserved for the IMP. If the CVC is removed during the treatment 
period, the IMP may be administered via a catheter in a peripheral vein. This catheter should 
preferably be reserved for IMP administration only.  
Surgery assessments (specified in the SOA) performed before, during, and after surgery will be 
collected per standard of care and documented in the case report form (CRF). All medications 
administered before and during surgery, including anesthesia, will be recorded as concomitant 
medications. Postoperative admission of the subject to the ICU will also be recorded in the CRF. 
Urine will be collected starting on Day 1 and will continue only for as long as the subject has a 
urinary catheter (Foley) in place to calculate urine output (UO), or until 72 hours after first dose of 
IMP (if catheter remains in place). Urine output (volume) will be entered into the CRF at minimum 
by 6-hour time periods up to a maximum of 72 hours after end-of-surgery; the exact time period for 
the collection and the collected volume will be recorded in the CRF. 
If the Foley catheter is removed, urine production will no longer be documented in the CRF but urine 
samples collection will continue as per the SOA. UO can only be used for diagnosing AKI or rating 


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AKI severity if UO has been calculated based on UO measured by a Foley catheter. If the Foley 
catheter is removed, UO will not be used for the AKI definition. 
IMP will be administered at 6, 12, 24 and 48 hours after start of the first dose administration. In case 
the subject is discharged from the ICU to a non-ICU ward prior to last dose administration, the 
remaining dose(s) will be administered either by study-trained non-ICU staff, or preferably by study-
trained ICU staff at the non-ICU ward. Blood and urine samples will be collected every day during 
the treatment period as per SOA, ie, 24 hours after start of initial IMP infusion (Day 2, Visit 3) and 48 
hours after start of initial IMP infusion (Day 3, Visit 4; End-of-Treatment [EOT]).  
Follow Up Period (Visit 5-7) 
After the final dose has been administered (Day 3, Visit 4, EOT), additional study visits will be 
conducted at 72 hours after first dose of IMP (Day 4, Visit 5, Primary endpoint assessment) and 
between Day 5-9 (Visit 6, Discharge) before hospital discharge where blood and spot urine samples 
will be taken as per SOA. When the subject is discharged from the ICU either to the hospital ward, 
another treatment facility or home, this will be recorded separately in the CRF. 
After hospital discharge, subjects will initially be followed up for one month after surgery until the 
next study visit (Day 30, Visit 7). This visit may be performed by qualified and trained study staff at 
the investigational site, at the subject's home, or other suitable location, where appropriate. Blood and 
urine samples collected will be processed centrally. During this follow-up period, all AEs need to be 
reported to the Investigator as soon as possible, eg, by phone. The Investigator will decide whether a 
visit to the clinic or hospital needs to be scheduled.  
Extended Follow Up Period (Visit 8) 
A final study visit will be conducted at 3 months (Day 90, Visit 8, End of Study [EOS]). This visit 
may be performed by qualified and trained study staff at the investigational site, at subject's home, or 
other suitable location, where appropriate. Health related quality of life questionnaires will be 
collected. Blood and urine samples collected will be processed centrally. Subjects are requested to 
provide information about hospitalization periods and other events qualifying as serious adverse 
events (SAEs). Vital status (ie, deceased or alive), hospitalization periods, reason for 
hospitalization(s) and outcome should be confirmed by the Investigator via source data (eg, medical 
records) and recorded in the CRF.  
All Study Periods, as applicable 
Vital signs, physical examination, blood and urine samples and urine collection for efficacy and 
safety assessments, and 12-lead electrocardiogram (ECG) will be recorded as per the SOA. All 
endpoint-related laboratory assessments will be performed by a central laboratory.  
Safety Reporting 
All adverse events (AEs) will be collected from initiation of the first IMP administration through the 
Day 30 study visit. All serious adverse events (SAEs) will be collected from the signing of the 
informed consent form (ICF) through the end of study visit. 
Biomarkers 
Blood and urine samples will be collected and stored to enable exploratory analysis of kidney and 
cardiac biomarkers to explore potential changes between active treatment and placebo treatment that 


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may add to the understanding of the disease mechanism and how the treatment influences these 
mechanisms.  
Blood samples will also be collected to enable analysis of immunologic biomarkers to explore the 
background of potential IRRs. 
Randomization: 
Randomization will occur in a 1:1 manner (RMC-035: placebo) and be stratified by region (North 
America and Europe) and screening eGFR (≥60 and <60 mL/min/1.73m2) assessed at Day -1 
(Visit 1), using the CKD-EPI equation with SCr. 
Sample Size Justification: 
For the primary endpoint, AKI within 72 hours after first dose of IMP, RMC-035 has been assumed 
to lead to a 30% relative risk reduction vs. placebo. The event rate in the placebo group has been 
assumed to be 50%. A sample size of 268 subjects dosed leads to a test power of 80% to show 
statistically significant results at a two-sided significance level (alpha) of 0.10. An interim analysis 
(IA) of the primary endpoint will be performed when 50% of the planned subjects have completed 
Visit 6 (Day 5-9). Conditional power (CP) given ‘the current trend’ will be calculated. Sample size 
may be increased to a maximum of 348 subjects dosed. Sample size will not be decreased. 
Number of Subjects (planned):  
It is planned that approximately 380 subjects (approximately 30% screen failure assumed) will be 
enrolled to ensure 268 subjects dosed with either RMC-035 or placebo in a 1:1 ratio. Based on results 
at an interim analysis, up to 348 subjects may be dosed, requiring approximately 500 subjects to be 
enrolled. 


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Diagnosis and Main Criteria for Inclusion 
Inclusion Criteria: 
A subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB)-/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 is able to 
provide written informed consent  
3. Subject age is ≥18 and <85 years  
4. Estimated glomerular filtration rate (eGFR) is ≥30 mL/min/1.73 m2 (at screening) using the 
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation with SCr 
5. Subject is scheduled for non-emergent CABG surgery AND/OR valve surgery (single or 
multiple valves) AND/OR ascending aorta aneurysm surgery with use of CPB AND AKI risk 
factors are present (at screening) as specified below: 
a. If only one type of surgery is scheduled at least two AKI risk factors should be present 
OR eGFR should be <60 mL/min/1.73m2 (at screening) with or without additional risk 
factors 
b. If any combined surgery is scheduled at least one AKI risk factor should be present 
Risk factors for AKI are defined below: 
• 
Left ventricular ejection fraction (LVEF) <35% at any time during the 3-month 
period before or at the time of screening as assessed by either echocardiography, 
cardiac magnetic resonance imaging (MRI) or nuclear scan.  
• 
Repeat surgery/history of previous open chest cavity cardiac surgery with or without 
CPB 
• 
Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months prior to screening 
AND ongoing treatment with an approved anti-diabetic drug  
• 
Age ≥70 years at the time of screening 
• 
Heart failure New York Heart Association (NYHA) class II or higher at any time 
during the 3-month period before or at the time of screening  
• 
Documented history of previous AKI as per KDIGO criteria longer than 3 months 
before date of screening independent of the etiology of AKI 
• 
Anemia with hemoglobin ≤11 g/dL at any time during the 3-month period before or 
at the time of screening  
• 
Albuminuria, defined as urine albumin-to-creatinine ratio (UACR) >100 mg/g in a 
spot urine sample or > 100 mg/24 hour in a 24-hour urine collection at any time 
during the 3-month period before or at the time of screening.  
• 
Estimated glomerular filtration rate is <60 mL/min/1.73 m2 using the CKD-EPI 
equation with SCr at the time of screening 


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6. Female subject is either:  
a. 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) 
b. Of childbearing potential 
• 
Agree not to try to become pregnant throughout the treatment period, and for 7, days 
after the final Investigational Medicinal Product (IMP) administration  
• 
Must have a negative serum pregnancy test at screening  
• 
If sexually active, agree to consistently use a highly effective form of birth control 
(see Appendix 1) starting at screening and throughout the treatment period, for 7 days 
after final IMP administration. If required by local law, 2 highly effective methods of 
birth control must be used, 1 of which must be a barrier method.  
7. Female subject must not be breastfeeding starting at screening, throughout the treatment 
period and for 7 days after the final IMP administration  
8. Female subject must not donate ova starting at screening, throughout the treatment period and 
for 7 days after the final IMP administration 
9. Male subject and their female spouse/partner(s) who are of childbearing potential must be 
using a condom starting at screening and continue to do so throughout the treatment period 
and for 7 days after final IMP administration. If required by local law, 2 highly effective 
methods of birth control must be used, 1 of which must be a barrier method. 
10. Male subjects must not donate sperm starting from screening, throughout the treatment period 
for up to 7 days after final IMP administration  
11. Subject agrees not to participate in another interventional study from the time of signing the 
informed consent until the EOS visit 
Waivers to the inclusion criteria will NOT be allowed. 
Exclusion Criteria: 
Subject will be excluded from participation if any of the following apply: 
1. Subject has any medical condition that in the opinion of the Investigator makes the subject 
unsuitable for study participation  
2. Subject is scheduled for emergent surgeries (eg, aortic dissection)  
3. Subject is scheduled for CABG and/or valve surgery and/or ascending aorta aneurysm 
surgery combined with additional non-emergent cardiac surgeries (eg, congenital heart 
defects) 
4. Subject is scheduled to undergo transcatheter aortic valve implantation (TAVI) or 
transcatheter aortic valve replacement (TAVR), or off-pump surgeries or left ventricular 


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assist device (LVAD) implantation  
5. Subject experiences a cardiogenic shock 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 
6. 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)  
7. Subject has been diagnosed with AKI (as defined by KDIGO criteria) within 3 months prior 
to surgery 
8. Required cardiopulmonary resuscitation within 14 days prior to cardiac surgery  
9. Ongoing sepsis (as defined by SEPSIS-3, the Third International Consensus Definitions for 
Sepsis and Septic Shock) within the past 2 weeks or, in the opinion of the Investigator, an 
untreated diagnosed clinically significant infection (viral or bacterial) prior to or at screening 
and before randomization.  
10. Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 
times the upper limit of normal (ULN) at screening 
11. Subject has a history of solid organ transplantation 
12. Subject has a history of renal replacement therapy (RRT) 
13. Subject has a medical condition which requires active immunosuppressive treatment 
14. Subject has severe allergic asthma defined as confirmed diagnosis of asthma poorly 
controlled while receiving high-dose inhaled corticosteroid treatment, or with requirement of 
a high level of treatment to maintain control 
15. Subject has an ongoing chemotherapy or radiation therapy for malignancy that may have an 
impact on kidney function as assessed by the medical monitor 
16. Subject has received an investigational medicinal product within the last 90 days (or within 5 
half-lives of the investigational drug, whichever is longer) 
17. Subject has a known allergy to RMC-035 or one of its constituents, or has previously 
received RMC-035 
Investigational Product, Dosage and Mode of Administration:  
RMC-035 (6.0 mg/mL Concentrate for Solution for Infusion) or matching placebo. Dosing will be 
based on renal function at Day -1: 
• 
Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first and 
second dose, followed by 0.65 mg/kg (per dose) for the third, fourth and fifth dose 
• 
Subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for all 
five doses 
The first (0h) and second (6h) doses will be administered as IV infusions over 60 minutes, and the 
third (12h), fourth (24h), and fifth (48h) doses will be administered as IV infusions over 30 minutes. 
Duration of treatment:  
Three days 


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Formal Stopping Rules for Investigational Medicinal Product Administration 
Investigational Medicinal Product will be permanently discontinued in subjects who develop AKI 
stage 2 or higher (KDIGO guidelines) and in subjects meeting other criteria for IMP discontinuation 
per Section 5.3.1. 
Concomitant Medication Restrictions or Requirements: 
• 
Nephrotoxins (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) should be discontinued 
before randomization and should not be used during the first 72 hours after first dose of IMP, 
unless strictly clinically indicated 
• 
Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) should 
be discontinued before randomization and should not be used during the first 72 hours after first 
dose of IMP, unless clinically indicated 
Statistical Methods 
Efficacy: 
Efficacy analyses will be performed in the modified Intention to Treat (mITT) Analysis Set and will 
consist of all subjects in the Intention to Treat (ITT) set who received at least 1 dose of IMP.  
The primary endpoint will be analyzed by the Cochran-Mantel-Haenszel estimate of the common 
relative risk (RMC-035 vs. placebo) across the four stratification groups formed by region (North 
America and Europe) and eGFR at Day -1 (≥60 and <60 mL/min/1.73m2). In addition, the proportion 
of subjects with AKI within 72 hours after first dose of IMP and its 90% confidence interval will be 
calculated for each treatment group.  
Secondary continuous efficacy endpoints, that are measures of renal function will be analyzed using 
robust regression of log-transformed values having sequentially multiply imputed any missing data. A 
sensitivity analysis will be performed using a mixed model for repeated measurements (MMRM) if 
data are approximately normally distributed.  
For the key secondary AUC endpoint, the geometric least square means of the time-corrected AUC 
for Days 1 to 4 will be obtained for each RMC-035 and placebo by transforming the model estimates 
back to the original scale. The AUC will be calculated using the trapezoidal rule with the actual times 
the measurements are taken. The relative difference (RMC-035 vs. placebo) and its 90% confidence 
interval will also be reported. Secondary binary efficacy endpoints will be analyzed using the same 
approach as specified above for the primary endpoint. 
Pharmacokinetics: 
Descriptive statistics will be presented for plasma concentrations by scheduled sample time. Specific 
pharmacokinetic parameters will be presented separately. Summaries will be provided by dose group, 
age group, and by renal function at baseline.  
Exploratory Biomarkers: 
--Plasma/serum, and urine samples will be collected and stored for potential future analysis of 
exploratory biomarkers, eg, urine (KIM-1, NGAL, TIMP2, IGFBP7, CCL-14, IL-18, LFABP); and 


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plasma/serum (NTproBNP, cTnI and/or cTnT). Additional urine and/or plasma/serum biomarkers 
related to the mode of action of RMC-035 (eg, endogenous A1M) may also be analyzed.  
Immunologic Biomarkers: 
Blood samples will also be collected to enable analysis of immunologic biomarkers exploring the 
background and mechanism of potential IRRs. 
Safety: 
Safety analyses will be conducted on the Safety Analysis Set (SAF), which includes all randomized 
subjects who received at least 1 dose of RMC-035. To characterize the safety profile, the number and 
percentage of subjects with TEAEs and AEs per dose group will be tabulated. Descriptive statistics 
will be provided for laboratory tests (hematology, biochemistry, urinalysis) and vital signs (pulse rate, 
respiratory rate and blood pressure) by visit and for the changes from baseline to each visit split by 
dose group. 
Interim Analysis:  
An interim analysis (IA) of the primary endpoint will be performed when 50% of the planned 
randomized subjects have completed Visit 6 (Day 5-9). Conditional power (CP), the probability that 
the final analysis will be statistically significant, will be calculated. Sample size may be increased to a 
maximum of 348 randomized subjects. Sample size will not be decreased. The study may be stopped 
at the IA for futility reasons. Study eligibility criteria may also be modified.  
Given the unblinded nature of this IA, an unblinded Data Monitoring Committee (DMC) of 
independent individuals not involved in any other study activities will be utilized. Further details on 
the IA and the control of the type I error will be provided in the DMC Charter and Statistical Analysis 
Plan. 
An IA of exploratory urinary and blood biomarkers to further elucidate the mechanism of action of 
RMC-035, understand potential immunologic responses, and guide further development in additional 
indications may also be performed during the study at the discretion of the Sponsor. 
 


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Table 3: 
Schedule of Assessments – Complete Study Period 
Assessments 
Screening 
Treatment 
Follow-Up 
Visit Number 
1 h 
2 Day of Surgery 
3 
4 (EOT) 
5 v 
6 (discharge)w 
7 x 
8 (EoS) x, y 
Visit Day 
-30 to -1 
1 
2 (24h) 
3 (48h) 
4 (72h) 
7 
30 
90 
Allowed visit window (days) 
±0 
±0 
±0 
±0 
±0 q 
±2 
±3 
±7 
Visit hour (h) 
 
pre 
0h 
1h 
2h 6h z 12h z 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height a 
x  
 
 
 
 
 
 
x 
x 
x 
 
 
 
Physical examination b 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
Pregnancy test (WOCBP only) c 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Hematology lab d 
x 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Clinical chemistry lab d 
x 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Liver function lab d 
x 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Serum creatinine (SCr) e 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Serum Cystatin C f 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
UACR and UPCR g 
x 
x 
 
 
 
 
 
 
 
x 
 
x 
x 
Urinalysis 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
Randomization h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Record renal replacement therapy 
 
 
 
 
 
 
 
x 
x 
x 
 
x 
x 
IMP administration i 
 
 
x j 
 
 
x k 
x l 
x l 
x l 
 
 
 
 
Plasma PK sampling  
 
x 
 
x 
x 
 
 
x, x, x m 
x, x, x m 
 
 
 
 
12-lead electrocardiogram   
x 
x 
 
 
 
 
 
x 
x 
x 
 
 
 
Vital signs n  
x 
x 
 
 
 
 
 
x 
x 
x 
 
 
 


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Assessments 
Screening 
Treatment 
Follow-Up 
Visit Number 
1 h 
2 Day of Surgery 
3 
4 (EOT) 
5 v 
6 (discharge)w 
7 x 
8 (EoS) x, y 
Visit Day 
-30 to -1 
1 
2 (24h) 
3 (48h) 
4 (72h) 
7 
30 
90 
Allowed visit window (days) 
±0 
±0 
±0 
±0 
±0 q 
±2 
±3 
±7 
Visit hour (h) 
 
pre 
0h 
1h 
2h 6h z 12h z 
 
 
 
 
 
 
Surgery assessments o 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from ICU p 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine output q 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sampling for biomarkers r 
 
x 
 
 
 
x 
 
x 
x 
 
 
 
 
Plasma/serum sampling for 
biomarkers r  
 
x 
 
 
 
 
 
x 
 
x 
 
 
 
Plasma sampling for immunologic 
biomarkers s 
 
x 
 
 
 
 
 
x, x s 
x, x s 
  
 
 
 
HRQoL Assessments t 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
ADA assessment  
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Concomitant medication recording u 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE recording 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE recording 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; AKI = acute kidney injury; EOS = End of Study; EOT = End-of-Treatment; EQ-5D-5L = European Quality of 
Life 5 Domain 5-Level Score; HRQoL = health related quality of life; ICU = intensive care unit; IMP = investigational medicinal product; PK = pharmacokinetic; 
PRO = patient reported outcome; SAE = serious adverse event; SCr = serum creatinine; WOCBP = woman of childbearing potential; UACR = urine albumin to creatinine 
ratio; UAPR = urine albumin to protein ratio 
a. 
Height only measured at screening (Visit 1). Weight during ICU stay only required if possible. 
b. The initial physical examination performed at screening should be comprehensive; all other physical examinations may be abbreviated and symptom driven. 
c. 
A serum pregnancy test completed during the screening period within 48 hours prior to surgery does not need to be repeated on the day of surgery. If the serum pregnancy 
test occurs more than 48 hours prior to the date of surgery, a serum or urine pregnancy test will also be performed on Day 1 prior to surgery. 
d. Hematology Labs: Hematocrit, Hemoglobin (Hb), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration, 
Red cell distribution width, Red blood cells, Platelets, Leucocytes (including Neutrophils, Monocytes, Lymphocytes, Eosinophils, Basophils) 
Clinical Chemistry Labs: Albumin, Calcium, Chloride, Serum creatinine (SCr), C-reactive protein (CRP), Sodium, estimated glomerular filtration rate (eGFR), 
Magnesium, Phosphate, Potassium, Blood urea nitrogen (BUN), Uric acid, Glucose 
Liver Function Labs: Alanine aminotransferase (ALAT), Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Bilirubin (total and conjugated), Gamma 
glutamyltransferase (GGT) 


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e. 
The screening sample for SCr must be collected on Day -1 (or day of surgery, see footnote h) and will be analyzed locally (to evaluate eligibility and determine correct 
start dose of RMC-035 according to renal function) and centrally (as baseline for endpoint assessment). All SCr samples collected during hospital stay will be analyzed 
both locally (to support AKI evaluation) and in a central lab (for the purpose of endpoint assessments). Day 30 and 90 samples will be analyzed centrally.  
f. 
Cystatin C samples will be collected and analyzed in a central lab only for the purpose of endpoint assessments  
g. UACR: screening sample will be collected as a spot urine sample and analyzed locally to evaluate albuminuria as an eligibility criterion (in the absence of historical 
albuminuria data within 3 months prior to randomization). UACR and UPCR: In-hospital samples (Day 1, Visit 2 and Day 4, Visit 5) will be collected either as a First 
Morning Void (FMV) sample or drawn directly from a Foley catheter and analyzed in a central lab only. Follow-up samples (Day 30, Visit 7 and Day 90, Visit 8) will be 
collected as FMV samples as possible and analyzed in a central lab only.  
h. Randomization must occur on Day 1, ie the day before surgery is intended. All screening assessments may be performed on Day 1 prior to surgery, including 
randomization. These assessments must be completed prior to any pre-surgical activities, such as administration of fluids or medications, including anesthesia. 
i. 
All 5 doses to be calculated using the same weight measurement that is used for randomization / stratification. IMP will be permanently discontinued in subjects 
developing AKI stage 2 or higher as per KDIGO guidelines (Appendix 3) or per criteria in Section 5.3.1. 
j. 
IV infusion over 60 minutes, first infusion should start approximately 10 minutes before expected onset of CPB (time point 0 is defined as start of IMP administration) 
k. IV infusion over 60 minutes at 6 h (±30 min) after the start of first infusion 
l. 
IV infusion over 30 minutes at 12 h, 24 h and 48 h (±30 min) after the start of first infusion 
m. PK sampling at Day 2 and 3 should occur 30 min (±5 min) and 90 min (±15 min) from start of IMP infusion 
 
n. Vital signs: body temperature, blood pressure, heart rate, respiratory rate, SpO2 
o. Data points to collect are type of CPB pump (pulsatile or non-pulsatile, if applicable) and duration of CPB (exact time of initiation and end of CPB), duration of surgery 
(beginning of surgery defined as exact time of initial skin incision, end of surgery defined as exact time of skin closure), blood loss volume, administration of any fluids 
during surgery (blood products [red blood cells, plasma, cryoprecipitate, platelets, etc.], crystalloids, colloids, and others), target body temperature during CPB and time at 
temperature range, duration of cross clamp (minutes), number, position, and graft source bypasses performed, length of time with mean arterial pressure <50 mmHg, valve 
surgery type (replacement or repair), replacement valve origin (bioprosthetic or mechanical), aortic repair type, and time of admission to the ICU. 
p. Time of discharge from ICU to hospital ward, another treatment facility or home 
q. Only required as long as Foley catheter is in place 
r. 
Urine samples for evaluation of exploratory urinary (kidney) biomarkers and plasma/serum samples for evaluation of cardiac biomarkers 
 
 
 
Plasma PK Sampling 
Study Day 
 
Time Window  
Predose 
≤30 min 
30 min 
±5 min 
1 h 
±5 min 
90 min 
±15 min 
2 h 
±15 min 
Day 1 
Start of Infusion 1 (t=0 h) 
x 
 
x 
 
x 
Day 2 
Start of Infusion 4 (t=24 h) 
x 
x 
 
x 
 
Day 3 
Start of Infusion 5 (t=48 h) 
x 
x 
 
x 
 
Biomarker Sampling 
Time Window (in relation to Start of Infusion 1 (t=0 h)) 
Predose 
≤60 min 
6 h 
±30 min 
24 h 
±30 min 
48 h 
±30 min 
72 h 
±30 min 
Urine 
x 
x 
x 
x 
 
Plasma/serum 
x 
 
x 
 
x 


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s. 
Plasma samples for assessment of immunologic biomarkers will be collected at the intervals described below, respectively: 
 
 
 
 
 
 
 
t. 
PRO HRQoL assessment: SF 36 and EQ-5D-5L. PRO HRQoL assessments to be performed as early as possible in the screening period. 
u. Medications taken within 30 days prior to the day surgery is intended are to be collected. Use of contrast agent within 72 hours prior to the day surgery is intended should 
be documented as a prior/concomitant medication. When possible, type and quantity of contrast agent should be recorded.  
v. Visit 5 must occur at 72 hours from start of first infusion of IMP, with a scheduling window of +/-2 hours.  
w. Visit 6 and all associated assessments should occur on the day of hospital discharge. In case subject is discharged on Day 4, discharge (Visit 6) assessments performed 
prior to discharge on that day are acceptable. 
x. Visit may be performed by qualified and trained study staff at the subject's home or other suitable location, where appropriate  
y. In case of subject withdrawal, subject should be encouraged to undergo all EOS assessments as an Early Termination visit.  
z. 
Assessments must be performed prior to IMP administration  
 
Immunology Biomarker Sampling 
Study Day  
 
 
 
 
Time Window 
Predose 
≤30 min 
90 min 
±20 min 
Day 1 
Start of Infusion 1 (t=0 h) 
x 
 
Day 1 
Start of Infusion 2 (t=6 h) 
 
 
Day 1 
Start of Infusion 3 (t=12 h) 
 
 
Day 2 
Start of Infusion 4 (t=24 h) 
x 
x 
Day 3 
Start of Infusion 5 (t=48 h) 
x 
x 


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Figure 1: 
Study Flow Chart 
 
 


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2. 
INTRODUCTION 
Acute Kidney Injury (AKI) is a clinical syndrome characterized by rapid loss of renal function 
and is associated with increased morbidity and short and long-term mortality. The 
pathophysiology of AKI is multifactorial and includes renal ischemia, heme toxicity, 
inflammatory responses, oxidative stress, and cytokine release amongst others (Figure 2).  
 
Figure 2: 
Pathophysiological Pathways in CS-AKI   
 
Cardiac surgery-associated acute kidney injury (CS-AKI) can be caused by reduced renal perfusion that results from 
vasoconstriction after cardiac surgery. 
A number of pathophysiological pathways can lead to vasoconstriction (red boxes).  
CS-AKI can also be caused by ischemia-reperfusion injury that occurs in extracorporeal circulation (blue boxes), 
leading to the opening of mitochondrial permeability transition pores in the kidneys and to cell injury or cell death. 
In addition, nephrotoxic agents (orange box) and other factors (green box) can contribute to CS-AKI. CPB, 
cardiopulmonary bypass; RAAS renin-angiotensin-aldosterone system.    
Source: (Wang 2017) 
 
Acute kidney injury is a global public health concern impacting more than 13 million patients 
annually. It is associated with high morbidity and mortality, approximately 1.7 million deaths per 
year, and remains a major unmet medical need. AKI leads to long-term complications including 
the development of Chronic Kidney Disease (CKD), exacerbation of pre-existing CKD, and 
accelerating the progression to end-stage renal disease . Thus, a single AKI episode can lead to a 
significant burden of comorbidities, poor quality of life and high long-term costs .  
AKI is frequently observed during hospitalizations and is considered one of the most important 
complications among hospitalized patients. A systematic review (2004 to 2012) of 154 large 
cohort studies was conducted to estimate AKI and its stages of severity and associated mortality. 
AKI definitions were reclassified according to the Kidney Disease Improving Global Outcomes 
(KDIGO 2012) staging system. The study included a total of more than 3.5 million patients and 
showed a pooled incidence rate of AKI of 21.6% in adults and 33.7% in children 
(Susantitaphong 2013).  


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AKI is a broad clinical syndrome encompassing various etiologies, including specific kidney 
diseases (eg, acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-
specific conditions (eg ischemia, toxic injury); as well as extrarenal pathology (eg, prerenal 
azotemia, and acute postrenal obstructive nephropathy). More than one of these conditions may 
coexist in the same patient and, more importantly, epidemiological evidence supports the notion 
that even mild, reversible AKI has important clinical consequences, including increased risk of 
death (Section 2: AKI Definition (KDIGO 2012)). 
Globally, an estimated 2 million cardiovascular surgeries (including coronary artery bypass 
grafting [CABG], Heart Valve operations and other) per year are performed (Parikh 2011). In 
2014 in the USA there were 371,000 CABG procedures (Salim et al, 2020). According to data 
from the Organisation for Economic Cooperation and Development, CABG is on average 
performed at a rate of 44 per 100,000 individuals. The incidence of CABG was 79/100,000 in 
2010 in the USA and with considerable differences between EU countries (91/100,000 in 
Hungary and 18/100,000 in Spain) (Head 2017). AKI is considered an important determinant of 
mortality in patients undergoing cardiovascular surgery (Lenihan 2013, Khadzhynov 2019).  
The reported incidence of AKI in this setting varies depending on the specific population studied 
and the definitions used. The following publications are all on the basis of modern standardized 
definitions of AKI. Cardiac surgery related AKI (CS-AKI) occurs in up to 30% of cardiac 
surgery patients (Vives 2019). The pooled rate of cardiopulmonary bypass (CPB)-associated 
AKI was 18.2%, and of renal replacement therapy 2.1% (Pickering 2015). Approximately 18% 
of patients undergoing cardiac surgery experience AKI, and approximately 2-6% will require 
hemodialysis (Thiele 2015).  In a global meta-analysis of 91 observational studies including 
more than 320,000 patients undergoing cardiac surgery, the pooled incidence of AKI was 22.3% 
(Stage 1 AKI: 13.6%, Stage 2 AKI: 3.8% and Stage 3 AKI: 2.7% and 2.3% of patients received 
renal replacement therapy). The pooled short-term and long-term mortality rate were 10.7% 
and 30% respectively and increased along with severity of stages (Hu 2016). Heart failure, 
chronic hyperglycemia, anemia, obesity, preoperative exposure to nephrotoxic drugs or contrast 
media, inflammation, proteinuria, and pre-existing kidney disease were systematically reviewed 
and were found to be associated with an increased risk of postoperative CS-AKI (Tinica 2020).  
In clinical studies evaluating potential treatments to prevent CS-AKI in high-risk groups, event 
rates of AKI up to 65.5% in a high-risk population (McCullough 2016) and 71.7% in patients 
with a positive biomarker test (that identifies patients at very high risk for AKI) shortly after 
surgery (Meersch 2017). In a recent study of CS-AKI, in a population similar to that of 
21-ROS-05 study, the pooled incidence of AKI was 34.2% (Serraino 2021) and in another recent 
study 28% patients developed CS-AKI (20%, 5% and 3% in KDIGO 1, 2 and 3, respectively) 
(Leballo 2021).  
Current treatment strategies and clinical management of CS-AKI are mainly supportive, 
including optimal fluid management and maintenance of hemodynamic stability (O'Neal 2016). 
At present, no specific therapeutic interventions are available for prevention or treatment of CS-
AKI. 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 
(RRT), progression to 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.  


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The investigational medicinal product (IMP), RMC-035, contains the pharmacologically active 
protein RMC-035, which is a recombinant variant of endogenous human alpha-1-microglobulin 
(A1M). Oxidative stress is a mechanism inherent to many disorders of acute cellular injury. The 
kidneys are particularly vulnerable to oxidative stress, hence the clinical development of 
RMC-035 is primarily focused on the prevention of AKI. RMC-035 has a short half-life and is 
mostly distributed to the kidney, and thus is well suited to treat acute renal conditions  
Employing several antioxidation mechanisms, A1M can protect cells and tissues from various 
forms of cell damage caused by oxidative stress, including free radicals and reactive oxygen 
species (ROS) (Olsson 2008, Olsson 2010, May 2011, Olsson 2011). Four different molecular 
mechanisms have been implicated in the actions of A1M including heme binding, reductase 
activity, radical scavenging, and binding to, thereby protecting, mitochondria (Akerstrom 2014).  
RMC-035 is being developed for the prevention of AKI in patients undergoing cardiac surgery 
and has been evaluated in four Phase 1 clinical studies: 17-ROS-01 (single ascending dose 
[SAD] study); 19-ROS-02 (multiple ascending dose [MAD] study); 19-ROS-03 (renal 
impairment study); and 20-ROS-04 (Phase 1b study in subjects undergoing nonemergent on-
pump CABG and/or valve surgery. Based on available clinical and non-clinical data, RMC-035 
is assessed as safe and generally well tolerated across study populations, ie in healthy subjects, 
renally impaired subjects and in cardiac surgery subjects, supporting its continued development 
in CS-AKI. This is considered a suitable indication for RMC-035 since it effectively targets 
common pathophysiological pathways, combined with a well-defined time point after the 
potential initial renal insult (ie at onset of CBP) as reference point for initiation of treatment.  
Study Rationale 
This is a Phase 2, randomized, placebo-controlled, double-blind, adaptive, parallel group clinical 
study to evaluate the efficacy and safety of RMC-035 in subjects at high risk for AKI following 
open-chest cardiac surgery. This is the second RMC-035 clinical study in cardiac surgery 
subjects and is being conducted to provide proof-of-concept efficacy data and 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 well-
tolerated (see Section 6.2.1) 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. 
2.1. 
Background 
For a complete summary of the non-clinical and clinical RMC-035 development program, please 
refer to the Investigator’s Brochure (IB).  
2.1.1. 
Pharmacology 
RMC-035 is a recombinant variant of the endogenous human protein A1M. RMC-035 is a potent 
antioxidant, harboring 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 derives from animal models of 
ischemic AKI. In addition, a number of other animal models related to renal injuries, eg, 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 


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models is to a certain extent similar, where oxidative stress is considered to be a central disease 
mechanism. 
2.1.2. 
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. 
In marmoset and cynomolgus monkey GLP-studies, RMC-035 related histopathological changes 
in kidneys with tubular degenerative changes and casts were 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. Immuno-
histochemical 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). 
The no observed adverse effect levels (NOAEL) were established in all GLP-studies and have 
been set at 20 (females) to 25 (males) 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 (area under the curve, AUC).  
In 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). In rat repeat dose GLP studies, Cmax exposures at NOAEL were observed up to 269 
and 405 µg/mL (M&F) on day 1. However, as a conservative approach to dose setting, the 
marmoset 28-day repeat dose study Cmax at 10 mg/kg NOAEL (60 µg/mL) has been employed 
for human dose setting and designation of exposure margins. 
2.1.3. 
Summary of Completed Clinical Studies 
2.1.3.1. 
Single Ascending Dose Study (17-ROS-01) 
In study 17-ROS-01 (SAD), five dose levels were evaluated in healthy subjects 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 adverse events (AEs), vital signs, electrocardiograms 
(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 RMC035 at 2.6 mg/kg, which was not considered as related to IMP in a 
subject known to have a history of syncope. 


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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 hours after dosing in the highest dose 
group.  
2.1.3.2. 
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. Six healthy subjects were included per dose group to receive either RMC-035 or placebo 
(4:2 randomization) as multiple doses over 48 hours. 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 hours 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. Infusion Site Reactions were characterized by varying symptomatology 
including localized redness, tenderness, pain, and swelling. In one subject, an ISR led to early 
discontinuation after the fifth administration of IMP. 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.  
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 leukocyte count was observed in higher dose groups at the 12 h time point, which was 
considered not clinically significant by the investigator. Furthermore, apparent reductions in 
serum creatinine, blood 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. 
2.1.3.3. 
Renal Impairment Study (19-ROS-03) 
Study 19-ROS-03 is an 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 estimated glomerular filtration rate (eGFR) ≥15 and 
<90 mL/min/1.73 m2 not on dialysis were included and allocated into one of five eGFR strata 
based on renal function at screening. Distribution of subjects were as follows: 1 subject in 
stratum 1 (≥75-<90 mL/min/1.73 m2), 1 subject in stratum 2 (≥60-<75 mL/min/1.73 m2) and 2 
subjects per stratum in strata 3 to 5, ie, ≥45-<60 mL/min/1.73 m2, ≥30-<45 mL/min/1.73 m2 and 
≥15-<30 mL/min/1.73 m2, respectively. The screening eGFR of included subjects ranged from 
16 to 75 mL/min/1.73 m2 (Modification of Diet in Renal Disease equation).  
All subjects received a single IV infusion of RMC-035 over 30 minutes. Dose levels were set 
based on available interim pharmacokinetic (PK) data in the MAD study: subjects in strata 1 to 4 
received 0.43 mg/kg and subjects in stratum 5 received 0.22 mg/kg.  
RMC-035 was considered safe and well tolerated based on AEs, vital signs, ECGs, physical 
examinations and safety laboratory parameters. There were no deaths or other 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 


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term feeling cold). The event was of mild severity, possibly related to IMP and resolved 
spontaneously approximately 2 hours after onset. 
The plasma clearance of RMC-035 correlated to renal function across the spectrum of eGFR and 
declined with lower renal function. AUC was increased in subjects with renal impairment as 
compared to healthy subjects, whereas the Cmax remained essentially unaltered.  
2.1.3.4. 
Exploratory Safety Study in Cardiac Surgery Subjects (20-ROS-04) 
Study 20-ROS-04 is a Phase 1b, randomized, double-blind, parallel treatment group study to 
evaluate the safety, tolerability and pharmacokinetics of RMC-035 in subjects undergoing non-
emergent on-pump Coronary Artery Bypass Graft (CABG) and/or valve surgery.  
This was the first clinical study in cardiac surgery subjects and was conducted to guide further 
clinical development in this patient population. Primary endpoint was the nature, frequency and 
severity of AEs. Twelve subjects undergoing elective on-pump CABG and/or valve surgery with 
additional risk factors to develop CS-AKI were enrolled in the study; 8 subjects received 
RMC-035 and 4 received placebo (2:1 randomization).  
The study consisted of three study periods: Screening (Day -1), Treatment period (Day 1-3) and 
a Safety follow-up period (Day 4-31). A total of five doses of RMC-035 or placebo were 
administered as IV infusions during the treatment period. First dose of RMC-035 was 1.3 mg/kg 
or placebo and was administered over 60 minutes. Dose administration started during surgery, 
approximately 10 minutes before the expected start of CPB. Second, third, fourth and fifth doses 
of RMC-035 were 1.3 mg/kg per dose or placebo and were administered over 30 minutes at 6, 
12, 24, and 48 hours after the start of the first dose administration. The dose of RMC-035 was 
reduced by 50% (ie 0.65 mg/kg per dose administration) in subjects with eGFR 30 to 
<60 mL/min/1.73 m2 at screening. After the first 2 doses, further permanent dose reductions 
were mandated (guided by Creatinine Clearance and/or eGFR) to either 0.65 mg/kg or 
0.43 mg/kg if Creatinine Clearance and/or eGFR declined below 60 or 30 mL/min, respectively.   
Preliminary review of the safety results support that RMC-035 was generally well tolerated 
based on AEs, vital signs, ECGs, physical examination and safety laboratory parameters. AEs 
and SAEs were reported mainly during and just after surgery and were within the expected range 
of events in relation to the surgical procedure. There were no reports of treatment related AEs. 
The only events reported in more than one subject were acute kidney injury, pleural effusion and 
pericardial effusion. No ISRs were reported and no ADAs were detected in this study.  
One subject receiving RMC-035 died at Day 12 due to surgical complications: a rupture of a 
coronary vessel with cardiac tamponade followed by subsequent persistent hypoperfusion, 
cardiogenic shock and initiation of dialysis treatment on Day 2. The subject later developed 
sepsis due to a caecal perforation which was assessed to be caused by a non-occlusive 
mesenterial ischemia on the basis of long-term hypoperfusion with inotropic support.  
One subject receiving RMC-035 started with dialysis at Day 3. The subject underwent a complex 
CABG surgery (CPB x 2, total surgical time above 6 hours) for the third time and had a low 
renal function prior to surgery (pre-operative eGFR 30 mL/min/1.73 m2) with a history of 
prolonged dialysis treatment after the previous cardiac surgery.  
For further details, please see the Investigator’s Brochure.  


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2.1.4. 
Key Safety Information 
Preclinical experience includes an extensive safety toxicology program with 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 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) and 
subsequent tubular protein (RMC-035) overload. Nonclinical studies support that renal findings 
are primarily related to the peak concentration (Cmax) and not cumulative exposure (AUC) of 
RMC-035. Importantly, no adverse renal effects of RMC-035 were observed in clinical studies. 
The maximum Cmax levels in the SAD study was 38.8 μg/mL (2.6 mg/kg) and in the MAD study 
16.3 μg/mL (when administered 6 times over 48 hours at 1.3 mg/kg). In cardiac surgery subjects 
(Study 20-ROS-04) the maximum observed Cmax was 23.3 μg/mL following a 30-minute 
infusion (1.3 mg/kg) and 13.1 μg/mL following a 60-minute infusion at the same dose level. 
These levels are still below the NOAEL levels of 60 μg/mL (marmoset 28-day study) and 
161 μg/mL (cynomolgus 3 day study) in the relevant toxicology studies. 
RMC-035 was so far evaluated in 52 subjects in four clinical studies including healthy subjects 
(17-ROS-01 and 19-ROS-02), renally impaired subjects across a wide spectrum of renal function 
(19-ROS-03) and in cardiac surgery subjects (20-ROS-04), respectively. RMC-035 was 
generally well tolerated, and the most commonly reported adverse events (mostly mild) in 
healthy subjects receiving peripheral dose administrations were non-serious local infusion site 
reactions (ISRs), headache and gastro-intestinal events (abdominal discomfort, nausea and 
vomiting). Notably, no ISRs were reported in single dose studies (SAD and Renal Impairment), 
and more importantly, in cardiac surgery subjects receiving five dose administrations of RMC-
035 via a central venous catheter at relatively higher infusion flow rates.  
In Study 20-ROS-04 including subjects undergoing open-chest cardiac surgery with additional 
AKI risk factors (8 received RMC-035, 4 received placebo), the only AEs reported in more than 
one subject were acute kidney injury, pleural effusion and pericardial effusion. These events, and 
other AEs in the study which were single events, reflect the type of events that would be 
anticipated in the underlying patient population undergoing cardiac surgery. No anti-drug 
antibodies (ADAs) were detected in cardiac surgery subjects receiving multiple dose 
administrations via central venous catheters.   
Overall, RMC-035 is generally well tolerated across study populations and supports its further 
evaluation in a larger multi-centre phase 2 study.  
Update from an early blinded review of the present study: 
For a detailed overview of the key safety information, please see the Investigator’s Brochure. A 
blinded review of safety data from the ongoing study 21-ROS-05 showed that a relevant number 
of study subjects had experienced single or repeat episodes of non-serious chills or potential 
infusion related reactions. In some cases, the chills were associated with pyrexia, hypertension, 
and/or tachycardia. Onset of events was generally within 30 to 60 minutes and most common 
following completion of the 4th and/or 5th infusion. More details can be found in the 
Investigator’s Brochure. 
 


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2.1.4.1. 
Risk Mitigation Measures  
ISRs 
The only identified risk of RMC-035 (ie observed in clinical studies) is non-serious local 
infusion site reactions (ISRs) which were reported in the majority of healthy subjects receiving 
multiple peripheral dose administrations. No ISRs were reported in single dose studies of 
RMC-035 or in cardiac surgery subjects who received multiple dose administrations in a central 
venous line. Overall, the risk for ISRs is therefore considered to be low, with the following risk 
mitigation measures being applied for this study: 
• Administration of IMP in a central venous line whenever possible (use of central venous 
catheters is considered standard of care in cardiac surgery) 
• Dilution of IMP in a sodium chloride infusion buffer prior to administration and 
administration rate with higher infusion rate to minimize local irritancy 
• Discontinuation of IMP in case a subject develops an ISR grade 3 or higher and which is 
considered immune related  
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, eg, with topical anti-
coagulants and cooling 
Chills and infusion related reactions (IRR) 
A blinded review of safety data from the ongoing study 21-ROS-05 showed that a relevant 
number of study subjects had experienced single or repeat episodes of non-serious chills or other 
signs suggestive of IRR. 
The following risk management measures apply: 
• Exclusion of subjects with severe asthma 
• Close observation of patients during and after the administration of the IMP infusions, in 
particular after the 4th and 5th dose 
• Management of signs or symptoms suggestive of IRR according to local standard of care 
including a recommendation for pre-treatment with paracetamol (acetaminophen)  
• Discontinuation of IMP in case a subject develops an IRR grade 3 or higher and which is 
considered immune related  
Renal tubular pathology (renal protein overload) 
Renal protein overload was observed at high peak concentrations of RMC-035 in nonclinical 
toxicology studies and remains a potential risk. No evidence for tubular cell stress/damage or 
other adverse renal effects of RMC-035 were observed in clinical studies. The following risk 
mitigation measures are applied:  
• The maximum clinical dose is 1.3 mg/kg per dose administration. This dose has already 
been proven safe and well tolerated in healthy subjects (Study 17-ROS-01 and 19-ROS-
02) and in cardiac surgery subjects (Study 20-ROS-04) 


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• Reduced dose to 0.65 mg/kg for subjects with eGFR<60 mL/min/1.73m2 as modeling of 
pharmacokinetic (PK) data in renally impaired subjects demonstrated an approximate 
doubling of RMC-035 exposure (AUC) at this eGFR level 
• Exclusion of subjects with baseline eGFR<30 mL/min/1.73 m2 
• Permanent discontinuation of IMP if development of AKI stage 2 or higher as per 
KDIGO criteria (also including renal replacement therapy, ie, dialysis) 
• Monitoring of renal function parameters (serum creatinine [SCr], cystatin C, eGFR) will 
be performed throughout the study  
Development of ADAs 
Confirmatory ADAs were observed in a few subjects receiving a single dose administration of 
RMC-035 (Study 17-ROS-01) and in the majority of subjects receiving multiple dose 
administrations of RMC-035 (Study 19-ROS-02) with peripheral dose administration. No ADAs 
were detected in cardiac surgery subjects receiving central venous dose administrations (Study 
20-ROS-04) and no adverse consequences of ADA formation have been observed in clinical 
trials of RMC-035.  
Potential risks associated with ADAs are considered limited given the short treatment duration 
(<3 days) and rapid initial plasma clearance of RMC-035. Accordingly, ADAs are not expected 
to impact 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. Furthermore, any potential cross-reaction with endogenous 
A1M is unlikely to impact the native protein function due to its high abundance in plasma and 
high synthesis and turnover rate (Gunnarsson 2017). Analysis of ADAs from Study 19-ROS-02 
also demonstrates lack of cross-reactivity with endogenous A1M.   
Potential ADAs in this study will be measured and further characterized, eg regarding Ig 
subtype, neutralizing capacity and cross-reactivity, to support and guide further clinical 
development of RMC-035.  
2.1.5. 
Risk / Benefit Assessment 
More detailed information about the known and expected benefits and risks and expected 
adverse events of RMC-035 may be found in the IB. 
Efficacy of RMC-035 for prevention of AKI is currently unknown. Based on the experimental 
data from relevant animal studies and the mechanism of action of RMC-035 towards relevant 
pathophysiological pathways of CS-AKI it is anticipated that RMC-035 will reduce the 
occurrence and severity of AKI in subjects undergoing cardiac surgery who are at high risk for 
development of AKI. Prevention of AKI is expected to provide clinical benefit for subjects 
undergoing cardiac surgery.  
All subjects will receive the current standard of care. For subjects allocated to receive placebo, 
no additional benefit can be expected. 
RMC-035 has been evaluated in healthy subjects, subjects with reduced renal function and 
subjects undergoing cardiac surgery. No serious adverse reactions (SARs) have been identified 
with RMC-035 treatment. The identified risk of non-serious local ISRs and potential risks of 
renal protein overload and ADA formation, respectively, are considered limited and manageable 


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in the target patient population with a short treatment duration (<3 days). Appropriate risk 
mitigation measures (see Section 2.1.4.1) have been implemented in the design of this study.  
Taking the hypothesized efficacy to prevent AKI and the potential risks identified in association 
with RMC-035 into account the risk-benefit is considered favorable, justified and well-balanced 
for subjects undergoing cardiac surgery who are at high risk to develop AKI.  


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3. 
TRIAL OBJECTIVES AND ENDPOINTS 
3.1. 
Primary, Secondary, and Exploratory Objectives 
3.1.1. 
Primary Objectives 
• To evaluate the efficacy of RMC-035 for prevention of AKI (KDIGO definition) in 
subjects undergoing CABG and/or valve surgery and/or aorta surgery with additional risk 
factors for developing cardiac surgery associated AKI 
• To evaluate the safety and tolerability of RMC-035  
3.1.2. 
Secondary Objectives 
Key Secondary Objectives 
• To evaluate RMC-035 for the prevention of post-operative decline (within 72 hours) in 
renal function  
• To evaluate RMC-035 for the reduction of post-operative AKI duration  
Other Secondary Objectives 
• To evaluate RMC-035 for preserving post-surgery renal function up to Day 90 
• To evaluate RMC-035 for the prevention of post-operative dialysis up to Day 90 
• To evaluate RMC-035 for the prevention of major adverse kidney events (MAKE) at 
Days 30 and 90, respectively 
• To further evaluate RMC-035 for the  
o Prevention of AKI within 72 hours (based on cystatin C and/or Urine Output 
[UO]) 
o Persistence and severity of AKI within 72 hours (based on serum creatinine [SCr] 
and/or UO or cystatin C and/or UO) 
o Prevention, persistence, and severity of AKI within 7 days (based on SCr and/or 
UO or cystatin C and/or UO) 
• To evaluate RMC-035 for reducing post-operative albuminuria and proteinuria up to 
Day 90 
• To evaluate the pharmacokinetics of RMC-035  
• Identification and characterization of anti-drug-antibodies (ADA) developed after 
intravenous administration of RMC-035 
3.1.3. 
Exploratory Objectives 
• To evaluate post-baseline changes in kidney and cardiac biomarkers 
• To evaluate changes in immunologic biomarkers  
• To evaluate the length of post-operative stay in Intensive Care Unit (ICU) and overall 
hospitalization time 
• To evaluate health-related Quality of Life 


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3.2. 
Primary, Secondary, and Exploratory Endpoints 
3.2.1. 
Primary Efficacy Endpoint 
• AKI within 72 hours after first dose of IMP based on SCr and/or UO (AKI of any 
stage/severity according to KDIGO definition, ie, SCr ≥1.5 times baseline, or increase of 
SCr of ≥0.3 mg/dL [≥26.5 µmol/L], or UO <0.5 mL/kg/h for ≥6 hours) 
3.2.2. 
Primary Safety Endpoint 
• Nature, frequency and severity of treatment-emergent adverse events (TEAEs) 
3.2.3. 
Secondary Endpoints 
Key Secondary Endpoints 
• Time-corrected area under the curve (AUC) of SCr for Day 1 to Day 4 (72 hours after 
first dose of IMP) 
• Duration of AKI defined as the number of days meeting the definition of AKI (KDIGO 
definition) starting within 72 hours after first dose of IMP until resolution  
Other Secondary Endpoints 
• Post-baseline changes in renal function  
o SCr and cystatin C (and corresponding eGFR values) at 12, 24, 48, and 72 hours, 
respectively, and at Day 7/discharge, Day 30 and Day 90 
o Change from baseline, up to Day 7/discharge, of peak SCr and cystatin C 
• Time-corrected AUC of cystatin C for Day 1 to Day 4 (72 hours after first dose of IMP) 
• Need for renal replacement therapy 
o Dialysis treatment (for any reason) within 72 hours and within 7 days after end of 
surgery  
o Dialysis free days from end of surgery to Day 30 and Day 90, respectively 
• MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of eGFR 
compared to baseline Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation (either SCr, cystatin C, or both)  
• AKI Characteristics  
o AKI within 72 hours after first dose of IMP based on cystatin C and/or UO (AKI 
of any stage/severity defined as cystatin C ≥1.5 baseline, OR UO <0.5 mL/kg/h 
for ≥6 hours) 
o AKI within 7 days after first dose of IMP (based on SCr and/or UO criteria, or 
cystatin C and/or UO criteria)  
o AKI persistence, defined as an AKI (KDIGO definition) developing within 72 
hours after first dose of IMP and with a duration of ≥72 hours. Persistence will 
also be assessed per AKI severity stage*    
o AKI severity stage* within 72 hours and within 7 days after first dose of IMP  


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 *Severity of AKI defined as the following:  
• Stage 1: SCr 1.5 to 1.9 times baseline within 7 days, OR ≥0.3 
mg/dL (≥26.5 µmol/L), OR urine output <0.5 mL/kg/h for 6 to <12 
hours 
• Stage 2: SCr 2.0-2.9 times baseline within 7 days OR urine output 
<0.5 mL/kg/h for ≥12 hours 
• Stage 3: SCr 3.0 times baseline within 7 days, OR increase in SCr 
4.0 mg/dL (≥353.6 µmol/L), OR initiation of renal replacement 
therapy OR urine output <0.3 mL/kg/h for ≥24 hours OR anuria for 
≥12 hours    
• Post-baseline changes in urine albumin to creatinine ratio (UACR) and urine protein to 
creatinine ratio (UPCR) at Day 4, Day 30, and Day 90 
• Pharmacokinetics of RMC-035 in plasma (AUC and Cmax) 
• Presence and titers of ADA at Day 1 (pre-surgery), Day 30, and Day 90    
• Characteristics of ADA developed at Day 30 and Day 90 with regards to isotype, 
neutralizing capacity, and cross-reactivity with endogenous alpha-1-microglobulin 
(A1M) 
3.2.4. 
Exploratory Endpoints 
Post-baseline changes in kidney and cardiac biomarkers 
• Kidney biomarkers: Urine kidney injury molecule 1 (KIM-1), neutrophil gelatinase-
associated lipocalin (NGAL), tissue inhibitor of metalloproteinase 2 (TIMP2), insulin-
like growth binding factor protein 7 (IGFBP7), chemokine ligand 14 (CCL-14), 
interleukin-18 (IL-18), liver fatty acid binding protein (LFABP) and 8-hydroxy-2'-
deoxyguanosine (8-OHdG) 
• Cardiac Biomarkers: Plasma N-terminal-pro-hormone BNP (NT-pro BNP) and cardiac 
troponin I and T (cTnI, cTnT) 
Changes in immunologic biomarkers 
• Immunologic biomarkers to explore the background and mechanism of potential IRRs 
including but not limited to markers of complement activation, cytokine release and mast 
cell activation. 
Hospitalization time and discharge facility 
• Length of index 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  
o Index hospital stay (in Days) is defined as the duration of stay in the hospital from 
the day of surgery to hospital discharge for the index surgery  
• Nature of subject discharge facility (eg, home, skilled nursing facility, rehabilitation 
center) 


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Health-related Quality of Life assessments  
• Change from baseline to Day 90 in the following Patient Reported Outcomes (PROs): 
o MOS 36-Item Short Form Survey Instrument (SF-36) 
o European Quality of Life 5 Domain 5-Level Score (EQ-5D-5L) 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2, randomized, double-blind, adaptive, parallel group clinical study that will 
evaluate RMC-035 compared to placebo in approximately 268 subjects at high risk for AKI 
following open-chest cardiac surgery (based on predefined risk factors). An interim analysis, 
including a sample size re-assessment, will be performed, during which subject enrollment will 
continue. Another IA involving exploratory biomarkers may be performed at the Sponsor’s 
discretion. The study consists of 8 visits for each subject with four study periods: 
• Screening Period: 30 days (Day-30 to -1)  
• Treatment Period: 3 days (Day 1-3)  
• Follow-Up Period: 27 days (Day 4-30)  
• Extended Follow-Up Period: 60 days (Day 31-90) 
See the Schedule of Assessments (SOA, Table 3) for the allowed time window for each study 
visit. During the course of the study, visits and assessments will be performed as defined in the 
SOA. 
Screening Period and Randomization (Visit 1) 
Prospective subjects may be consented within 30 days (inclusive) prior to the date of scheduled 
surgery. Subjects who have signed the informed consent may undergo initial screening 
assessments during the screening period (full physical examination, medical history, clinical 
laboratory testing, completion of health-related quality of life questionnaires etc.) as described in 
the SOA (Table 3). 
All screening clinical laboratory testing to confirm eligibility and determine starting dose based 
on renal function will be performed by local laboratory on Day -1 (Visit 1), ie, the day before 
surgery is intended. In addition, sampling for serum creatinine and cystatin C will be collected 
for central laboratory analysis and will provide the baseline values for the purpose of relevant 
endpoint assessment. 
Eligible subjects who comply with all inclusion criteria and none of the exclusion criteria will be 
randomized on Day -1, Visit 1 to receive either RMC-035 or placebo in a 1:1 randomization 
ratio. Both region (North America and Europe) and Day -1 eGFR calculated using local 
laboratory results (≥60 and <60 mL/min/1.73m2) will be used as stratification factors to ensure a 
balanced randomization within these groups. 
Note: Some or all screening visit assessments listed in the SOA, including randomization, may 
be performed prior to surgery on Day 1 (Visit 2), ie, the day of surgery, if feasible for the site. 
All screening labs and assessments performed on Day 1 must be collected prior to anesthesia.  
Note: In case surgery is postponed after randomization has occurred, re-assessment of SCr and 
body weight for the calculation of eGFR is not required. However, if re-assessment is done as 
part of standard of care, and the results indicate an eGFR decrease that places the subject in the 
lower eGFR category (ie <60 mL/min/1.73m2 for a subject who was randomized within the ≥60 
mL/min/1.73m2 stratum) a decrease of the IMP dose to that of the lower eGFR category is 
acceptable if the change is clinically significant in the opinion of the investigator. 
 
 


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Treatment Period (Visits 2-4) 
Surgery will occur on Day 1 (Visit 2). Before administration of IMP, preoperative safety 
assessment and sampling for local and central clinical laboratory testing will be performed per 
the SOA. Centrally processed laboratory samples of morning urine collected pre-surgery on Day 
1 will provide the baseline values used for the purpose of relevant endpoint evaluations (UACR 
and UPCR). 
The first administration of IMP will be given during surgery, to be started approximately 10 
minutes before the expected initiation of CPB, as an IV infusion. The start time of the first 
infusion is time 0, the reference point for further dose administrations and protocol-mandated 
assessments. In total, 5 doses of RMC-035 or matching placebo will be administered during the 
treatment period. Administration of subsequent IV infusions start at 6, 12, 24 and 48 hours, 
respectively, after the start of the first dose administration. 
IMP will be administered per the schedule below:  
• The first (0h) and second (6h) doses are administered as IV infusions over 60 minutes 
• The third (12h), fourth (24h) and fifth (48h) doses are administered as IV infusions over 
30 minutes 
Differences between eGFR at Day -1 (randomization) and additional eGFR readings collected on 
Day 1 prior to surgery as part of the study or per the investigational site’s standard of care will 
not affect eligibility and starting dose unless the change is a decrease that the investigator 
considers clinically significant and that implies the subjects should have a lower starting dose. 
Should the subject eGFR drop below 30 ml/min/1.73m2, and in the investigator’s opinion the 
decrease is clinically significant, the subject is no longer fulfilling eligibility criteria and should 
not start treatment. 
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 during the treatment period, the IMP may 
be administered via a catheter in a peripheral vein. This catheter should preferably be reserved 
for IMP administration only. 
Surgery assessments (specified in the SOA and Section 8.6.1) performed before, during, and 
after surgery will be collected per standard of care and documented in the case report form 
(CRF). All medications administered before and during surgery, including anesthesia, will be 
recorded as concomitant medications. Postoperative admission of the subject to the ICU will also 
be recorded in the CRF. 
Urine will be collected starting on Day 1 prior to surgery and will continue only for as long as 
the subject has a catheter (Foley) in place to calculate urine output (UO), or until 72 hours after 
first dose of IMP (if catheter remains in place). While the subject remains hospitalized in the 
ICU, site staff will measure UO in hourly intervals or per site’s standard of care. If the subject is 
transferred to a non-ICU ward, UO will be measured in 6-hour intervals (see Section 8.8). Urine 
output (volume) will be entered into the CRF at 6-hour time periods as much as possible. The 
exact time period for the collection and the collected volume will be recorded in the CRF. 
If the Foley catheter is removed, urine production will no longer be entered in the CRF but spot 
urine samples will continue to be collected as per SOA. UO can only be used for diagnosing AKI 
or rating AKI severity if UO has been calculated based on UO measured by a Foley catheter. If 
the Foley catheter is removed, UO will not be used for the AKI definition. 


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In case the subject is discharged from the ICU to a non-ICU ward prior to last dose 
administration, the remaining dose(s) will be administered either by study-trained non-ICU staff, 
or preferably, by study-trained ICU staff at the non-ICU ward. Blood and spot urine samples will 
be collected every day during the treatment period as per SOA, ie, 24 hours after start of initial 
IMP infusion (Day 2, Visit 3) and 48 hours after start of initial IMP infusion (Day 3, Visit 4; 
End-of-Treatment [EOT]). At a minimum, all subjects will remain hospitalized for the first 
72 hours post-surgery (until completion of Visit 5). 
Follow Up Period (Visits 5-7) 
After the final dose has been administered (Day 3, Visit 4, EOT), additional study visits will be 
conducted at 72 hours after first dose of IMP (Day 4, Visit 5, primary endpoint assessment) and 
between Day 5-9 (Visit 6, Discharge) where blood and spot urine samples will be taken as per 
SOA. When the subject is discharged from the ICU either to the hospital ward, another treatment 
facility or home, this will be recorded separately in the CRF. 
Note: Visit 6 and all associated assessments and sample collections should occur on the day of 
discharge from hospital. If Visit 6 samples are collected on day of scheduled discharge, but 
subject discharge is subsequently delayed, these samples should still be processed and entered as 
Visit 6 (discharge). In case a subject is not scheduled to be discharged until after the Visit 6 
scheduling window (Days 5-9), it is preferred that Visit 6 (discharge) samples be collected on 
Day 7. In case subject is discharged on Day 4, Visit 6 (discharge) samples collected prior to 
discharge on that day are acceptable. 
Subjects will initially be followed up for one month after surgery until the next study visit 
(Day 30, Visit 7). This visit may be performed by qualified and trained study staff at the 
investigational site, at the subject's home, or other suitable location, where appropriate. Blood 
and urine samples collected will be processed centrally. During this follow-up period, all AEs 
need to be reported to the Investigator as soon as possible, eg, by phone. The Investigator will 
decide whether a visit to the clinic or hospital needs to be scheduled.  
Extended Follow Up Period (Visit 8) 
A final study visit will be conducted at 3 months (Day 90) after surgery (Visit 8, End of Study 
[EOS]). This visit may be performed by qualified and trained study staff at the investigational 
site, at the subject's home, or other suitable location, where appropriate. Health related quality of 
life questionnaires will be collected. Blood and urine samples collected will be processed 
centrally. Subjects will be requested to provide information about hospitalization periods and 
other events qualifying as SAEs. Vital status (ie, deceased or alive), hospitalization periods, 
reason for hospitalization(s) and outcome should be confirmed by the investigator via source 
data (eg, medical records) and recorded in the CRF. 
 Upon completion of all EOS visit procedures, subjects will have completed the study. 
All Study Periods, as applicable 
Vital signs, physical examination, blood and spot urine samples and urine collection for efficacy 
and safety assessments, 12-lead ECG, as well as samples for PK analysis, ADA and exploratory 
biomarkers will be collected and recorded as per the SOA. 


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4.2. 
Participating Sites 
Approximately 30 centers located in North America and Europe will participate in this study. 
During the conduct of the study, additional regions, countries or sites may be added, as 
necessary. 
4.3. 
Number of Subjects 
It is planned that approximately 380 subjects (approximately 30% screen failure assumed) will 
be enrolled to ensure 268 subjects dosed with either RMC-035 or placebo in a 1:1 ratio. Based on 
results at an interim analysis, up to 348 subjects may be dosed, requiring approximately 500 
subjects to be enrolled. 
4.4. 
Replacement of Subjects 
Subjects who are randomized but do not receive the first dose of IMP may be replaced; these 
subjects (randomized but not dosed) will be followed for safety (SAE) and for the following 
endpoints: 
• Acute kidney injury within 72 hours after the first dose of IMP (Visit 5, Day 4) 
• Time-corrected AUC of SCr for Day 1 to Day 4 (72 hours after first dose of IMP) 
• Major adverse kidney event at Day 30 (Visit 7) and Day 90 (Visit 8, EOS) 
Additional assessments are not required to be collected. 
Subjects included to replace others will be randomized (ie, may not be automatically allocated to 
the same arm to the replaced subject). 
Any subject receiving at minimum the first dose of IMP will not be replaced. 
4.5. 
Completion of Study 
Completion of the study is defined as the time at which the last randomized subject completes 
the final follow-up period visit, is considered lost to follow-up, withdraws consent, or dies. 
4.6. 
Early Study Termination 
The Sponsor 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.  
In the case of early termination of the study, the Sponsor (or designee) will provide written 
notification to the Investigators and regulatory authorities specifying the reason(s) for 
termination. The Investigator will be responsible for notifying their institution’s Institutional 
Review Board (IRB) / Independent Ethics Committee (IEC), if appropriate. 
4.6.1. 
Discontinuation of a Site 
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 a study site by the Sponsor or Investigator may include but are 
not limited to:  


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• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or Good Clinical Practice (GCP) 
guidelines  
• Inadequate recruitment of subjects by the Investigator  
• Determination of unexpected, significant, or unacceptable risk to subjects  
• Insufficiently complete and/or evaluable data.  
• Plans to modify, suspend, or discontinue the development of the IMP  
A study 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 will complete the study and approve the final CRFs in satisfactory compliance 
with the protocol. 


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5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Subject Inclusion Criteria 
A subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB)-/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 is able 
to provide written informed consent  
3. Subject age is ≥18 and <85 years  
4. Estimated glomerular filtration rate (eGFR) is ≥30 mL/min/1.73 m2 (at screening) using 
the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation with SCr  
5. Subject is scheduled for non-emergent CABG surgery AND/OR valve surgery (single or 
multiple valves) AND/OR ascending aorta aneurysm surgery with use of CPB AND AKI 
risk factors are present (at screening) as specified below: 
a. If only one type of surgery is scheduled at least two AKI risk factors should be 
present OR eGFR should be <60 mL/min/1.73m2 (at screening) with or without 
additional risk factors 
b. If any combined surgery is scheduled at least one AKI risk factor should be present 
Risk factors for AKI are defined below: 
• Left ventricular ejection fraction (LVEF) <35% at any time during the 3-month 
period before or at the time of screening as assessed by either echocardiography, 
cardiac magnetic resonance imaging (MRI) or nuclear scan.  
• Repeat surgery/history of previous open chest cavity cardiac surgery with or 
without CPB 
• Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months prior to 
screening AND ongoing treatment with an approved anti-diabetic drug  
• Age ≥70 years at the time of screening 
• Heart failure New York Heart Association (NYHA) class II or higher at any time 
during the 3-month period before or at the time of screening (see Appendix 3) 
• Documented history of previous AKI as per KDIGO criteria longer than 3 months 
before date of screening independent of the etiology of AKI 
• Anemia with hemoglobin ≤11 g/dL at any time during the 3-month period before 
or at the time of screening  
• Albuminuria, defined as urine albumin-to-creatinine ratio (UACR) >100 mg/g in 
a spot urine sample or > 100 mg/24 hour in a 24-hour urine collection at any time 
during the 3-month period before or at the time of screening.  
• Estimated glomerular filtration rate is <60 mL/min/1.73 m2 using the CKD-EPI 
equation with SCr at the time of screening 


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6. Female subject is either:  
a. 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) 
b. Of childbearing potential 
• Agree not to try to become pregnant throughout the treatment period, and for 7 
days after the final IMP administration  
• Must have a negative serum pregnancy test at screening  
• If sexually active, agree to consistently use a highly effective form of birth control 
(see Appendix 1) starting at screening and throughout the treatment period, for 7 
days after final IMP administration. If required by local law, 2 highly effective 
methods of birth control must be used, 1 of which must be a barrier method.  
7. Female subject must not be breastfeeding starting at screening, throughout the treatment 
period and for 7 days after the final IMP administration  
8. Female subject must not donate ova starting at screening, throughout the treatment period 
and for 7 days after final IMP administration 
9. Male subject and their female spouse/partner(s) who are of childbearing potential must be 
using a condom starting at screening and continue to do so throughout the treatment 
period and for 7 days after final IMP administration. If required by local law, 2 highly 
effective methods of birth control must be used, 1 of which must be a barrier method. 
10. Male subjects must not donate sperm starting from screening, throughout the treatment 
period for up to 7 days after final IMP administration  
11. Subject agrees not to participate in another interventional study from the time of signing 
the informed consent until the EOS visit 
Waivers to the inclusion criteria will NOT be allowed. 
5.2. 
Subject Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. Subject has any medical condition that in the opinion of the Investigator makes the 
subject unsuitable for study participation  
2. Subject is scheduled for emergent surgeries (eg, aortic dissection)  
3. Subject is scheduled for CABG and/or valve surgery and/or ascending aorta aneurysm 
surgery combined with additional non-emergent cardiac surgeries (eg, congenital heart 
defects) 
4. Subject is scheduled to undergo transcatheter aortic valve implantation (TAVI) or 
transcatheter aortic valve replacement (TAVR), or off-pump surgeries or left ventricular 
assist device (LVAD) implantation  


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5. Subject experiences a cardiogenic shock 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 
6. 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)  
7. Subject has been diagnosed with AKI (as defined by KDIGO criteria) within 3 months 
prior to surgery 
8. Required cardiopulmonary resuscitation within 14 days prior to cardiac surgery  
9. Ongoing sepsis (as defined by SEPSIS-3, the Third International Consensus Definitions 
for Sepsis and Septic Shock, Appendix 3) within the past 2 weeks or, in the opinion of 
the Investigator, an untreated diagnosed clinically significant infection (viral or bacterial) 
prior to or at screening and before randomization.  
10. Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥ 2 times the upper limit of normal (ULN) at screening 
11. Subject has a history of solid organ transplantation 
12. Subject has a history of renal replacement therapy (RRT) 
13. Subject has a medical condition which requires active immunosuppressive treatment 
14. Subject has severe allergic asthma defined as confirmed diagnosis of asthma poorly 
controlled while receiving high-dose inhaled corticosteroid treatment, or with 
requirement of a high level of treatment to maintain control 
15. Subject has an ongoing chemotherapy or radiation therapy for malignancy that may have 
an impact on kidney function as assessed by the medical monitor 
16. Subject has received an investigational medicinal product within the last 90 days (or 
within 5 half-lives of an investigational drug, whichever is longer) 
17. Subject has a known allergy to RMC-035 or one of its constituents, or has previously 
received RMC-035 
5.3. 
Subject Withdrawal Criteria 
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, behavioral, compliance, or 
administrative reasons.  
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 all EOS assessments performed as 
described in the SOA. Any ongoing SAE at the time of withdrawal will be followed as described 
in Section 9.7. 
Subject data collected up to withdrawal of consent will be retained and included in the analysis 
of the study, and where permitted by local regulations, publicly available data (death records) 
can be included after withdrawal of consent. If the subject withdraws consent for disclosure of 


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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 CRF.  
5.3.1. 
Discontinuation of Investigational Medicinal Product 
5.3.1.1. 
Permanent discontinuation of IMP 
Local laboratory results will be utilized for clinical care and real time evaluation of AKI for 
purposes of IMP discontinuation. Subjects who meet any of the following IMP discontinuation 
criteria during the treatment period will be discontinued from IMP and continue study 
participation and procedures and follow up as per the SOA until the EOS visit: 
• Development of stage ≥2 AKI, according to KDIGO definition (see Appendix 3) 
• Need for RRT, ie, dialysis, including continuous RRT 
• Need for percutaneous or surgical mechanical circulatory support (MCS) or 
extra-corporeal membrane oxygenator (ECMO) 
• Reporting of a grade 3 (per Table 8, Section 9.3) or higher adverse event of ISR or IRR, 
and which is considered to be an immune-mediated reaction 
The IMP will be discontinued in case of any of the following abnormal liver chemistry tests in 
blood: 
• ALT > 3 × ULN combined with total bilirubin > 2 × ULN in the same sample  
• ALT > 3 × 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)  
• ALT > 3 x ULN if confirmed in a second sample within 24 hours AND in the second 
sample International Normalized Ratio (INR) is increased to >1.5 x ULN 
• ALT > 8 x ULN in any individual sample during the treatment period 
All liver chemistry abnormalities as summarized above need to be followed up regularly (at least 
every 24 hours) until values have returned to baseline or are considered stable. See Appendix 2 
for more detailed instructions.  
If IMP is discontinued, the subject will remain in the study to be evaluated until the EOS Visit 
(as much as possible) or complete the EOS visit assessments. 
5.3.1.2. 
Temporary discontinuation IMP 
A temporary discontinuation of IMP may be considered if, in the opinion of the investigator, a 
subject's medical condition precludes IMP dosing due to a documented serious safety concern. 


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In case of a temporary discontinuation of IMP, the missed dose will not be replaced or 
administered at a later time point. 
5.3.2. 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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6. 
TREATMENT OF SUBJECTS 
6.1. 
Investigational Medicinal Product 
The IMPs for this study are RMC-035 or matching placebo.  
6.1.1. 
RMC-035 
RMC-035 6.0 mg/mL Concentrate for Solution for Infusion (RMC-035) contains the 
pharmacologically active protein RMC-035, a recombinant variant of endogenous human A1M. 
Properties and appearance of RMC-035 are described in Table 4. 
 
Table 4: 
RMC-035 Characteristics 
Pharmaceutical 
form: 
RMC-035 is a concentrate (6.0 mg/mL) for solution for infusion for IV 
administration.  
Appearance: 
Clear, colorless to slightly yellowish solution. Practically free from visible 
particles, may contain translucent-to-white proteinaceous particles 
Excipients: 
Tris 10 mM pH 8.0. 
Packaging: 
RMC-035 is filled in 10 mL glass vials, closed with a 20 mm rubber stopper 
and aluminum crimp with a plastic cap. 
Storage: 
RMC-035 vials should be stored at -20 ± 5ºC (-4 ± 10ºF) and can be kept at 
room temperature (not above +25ºC (77°F)) for maximum 6 hours.  
RMC-035 diluted in 0.9% sodium chloride solution can be stored for 72 hours 
at 2-8oC (36-46°F), or a shorter time period as specified in the Pharmacy 
Manual, if applicable. 
Abbreviations: IV=intravenous 
 
6.1.2. 
Placebo 
The formulation of the matching placebo is identical to RMC-035 except that it contains no 
active ingredient. Placebo vials should be stored at -20 ± 5°C (-4°F) and can be kept at room 
temperature (not above +25ºC) for maximum 6 hours. Placebo diluted in 0.9% sodium chloride 
solution can be stored for 72 hours at 2-8°C (36-46°F). 
6.1.3. 
Concomitant Medications 
Concomitant medication refers to all drugs and therapies used from the time the Informed 
Consent Form (ICF) is signed through the end of study participation, including all medications 
used during surgery (for instance anesthesia). 
Any prescription and non-prescription medications (eg, 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: 


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• Trade name or generic name 
• Indication/reason for use 
• Dates of administration including start and stop dates 
• Dosage information including dose, route, and frequency 
Changes, additions, or discontinuations to medications will be assessed and recorded in the CRF 
during each study visit. If a change is due to an AE, then this must be reported according to 
Section 9.7. The Sponsor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Treatment and prevention of potential IRRs (see section 2.1.4.1) should follow local standard of 
care. This includes a recommendation to administer paracetamol (acetaminophen) during the 
treatment period.  
6.1.3.1. 
Restricted Concomitant Medications 
The following medications are prohibited prior to randomization into the study: 
• Nephrotoxins (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) should be 
discontinued before randomization and should not be used during the first 72 hours after 
first dose of IMP, unless strictly clinically indicated 
• Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) 
should be discontinued before surgery and should not be used during the first 72 hours 
after first dose of IMP, unless clinically indicated 
6.2. 
Investigational Medicinal Product Administration 
Dose levels of IMP will be predefined based on renal function (eGFR calculated using the CKD-
EPI equation with SCr) at screening (Day -1): 
• Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first 
and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth and fifth dose  
• Subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for 
all 5 doses 
The start time of the first infusion of IMP is time 0, the reference point for further dose 
administrations. In total, 5 doses of IMP or matching placebo will be administered during the 
treatment period. Administration of subsequent IV infusions will start at 6, 12, 24 and 48 hours, 
respectively, after the start of the first dose administration.  
The first (0h) and second (6h) dose are administered as IV infusions over 60 minutes. The third 
(12h), fourth (24h) and fifth (48h) doses are administered as IV infusions over 30 minutes.  
Guidelines for storage, preparation and administration of the IMP are outlined in Section 7; for 
detailed administration instructions, refer to the Pharmacy Manual. 


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6.2.1. 
Rationale for RMC-035 Dosing 
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, as a 
multiple dose (MAD study).  
RMC-035 has lower clearance in renally impaired subjects resulting in higher AUC 
(Study 19ROS-03), ie, AUC is approximately doubled when eGFR is reduced by 50%.  
In a Phase 1b study in cardiac surgery subjects (20-ROS-04), RMC-035 was administered 5 
times in 48 hours. The first dose was 1.3 mg/kg administered over a one-hour infusion, and 
subsequent doses were 1.3 mg/kg administered during 30 minutes at 6, 12, 24 and 48 hours after 
the start of the first administration. The start dose was 1.3 mg/kg if pre-surgery eGFR>60 
mL/min/1.73m2 and 0.65 mg/kg if pre-surgery eGFR ≥30 and <60 mL/min/1.73m2. Protocol-
guided dose adjustments and/or IMP discontinuation criteria were also imposed to limit 
cumulative exposure due to renal impairment. The resulting median Cmax were well below the 
Cmax at the most conservatively set NOAEL (in the marmoset). The median AUC0-24h were close 
to or below the AUC0-24h at the NOAEL in the marmoset and cynomolgus, respectively. By 
protocol design, these exposure levels are not predicted to be exceeded in the phase 2 study 
(20-ROS-05).  
In summary, the dose/dosing regimen in the planned Study 21-ROS-05 has been carefully 
determined considering available clinical PK and safety data in healthy subjects, renally 
impaired subjects and cardiac surgery patients. A 5-dose regimen for this first efficacy study of 
RMC-035 is selected based on its mode-of-action and relevant disease mechanisms in CS-AKI 
and is considered to provide relevant intra-and post-operative renal protection of RMC-035. It 
has been conservatively guided by preceding nonclinical and clinical studies including the 
cardiac surgery study 20-ROS-04 with a similar dosing regimen. Please see Section 2.1.3.4 on 
PK and safety data from study 20-ROS-04. The predicted exposures in the planned Study 
21-ROS-05 are pharmacologically active and within the clinically safe exposure range, including 
preservation of relevant nonclinical exposure margins. 
For further details, please see the Investigator’s Brochure.  
6.3. 
Dose Adjustment Criteria 
Dose adjustment will not be permitted throughout the study. 
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 CRF. 
6.5. 
Randomization and Blinding 
Each subject who enters the screening period, which starts when the subject signs the ICF, will 
receive a unique subject identification number. This number will be used to identify the subject 
throughout the study and must be used on all study documentation related to the subject.  


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Eligible subjects will be randomized prior to surgery to receive either RMC-035 or placebo in a 
1:1 randomization ratio using a centralized randomization process. Both region (North America 
and Europe) and Day -1 eGFR calculated using local laboratory results (≥60 and 
<60 mL/min/1.73m2) will be used as stratification factors to ensure a balanced randomization 
within these groups. 
The Investigator, study personnel, and subject will be blinded to the identity of the IMP 
(RMC-035 or placebo). The investigational pharmacist will be responsible for the preparation of 
IMP for each subject and will be unblinded to the randomization assignment. 
6.5.1. 
Breaking the Blind 
The treatment code for a given randomized subject will be provided in the event of a medical 
emergency requiring knowledge of the treatment assigned to the subject. The time, date, subject 
number and reason for obtaining any of these codes, and therefore breaking the blind, must be 
documented in the study file. The treatment code can only be requested by the Investigator or 
other persons designated as sub-investigators. No subjects or other study personnel will be made 
aware of the treatment given unless a medical emergency necessitates such disclosure. 
Except for determining whether a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
requires expedited reporting to regulatory authorities, unblinding of the study medication should 
only be considered for subject safety or when critical therapeutic decisions are contingent upon 
knowing the blinded IMP assignment. Any unblinding by the investigational staff must be 
reported immediately to the Sponsor or designee and must include an explanation of why the 
study medication was unblinded. If possible, the Sponsor and/or designee should be contacted 
prior to unblinding of the study medication. 


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7. 
INVESTIGATIONAL MEDICINAL PRODUCT MATERIALS 
AND MANAGEMENT 
7.1. 
Investigational Medicinal Product 
The IMP, RMC-035 and placebo, are described in Sections 6.1.1 and 6.1.2, respectively. Refer to 
the Pharmacy Manual for detailed instructions on preparation, handling, storage and 
accountability of the IMP. 
7.2. 
Investigational Medicinal Product Packaging and Labelling 
RMC-035 concentrate for solution for infusion and its corresponding placebo are filled in glass 
vials each containing an extractable volume of 5 mL solution. The vials will be packaged in a 
suitable carton box. 
RMC-035 concentrate for solution for infusion 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. 
The IMP will be released to the site upon receipt of all required essential documents. All 
medication provided to the study site will be prepared, packaged, and labelled by the Sponsor 
according to Standard Operating Procedures (SOPs), Good Manufacturing Practice guidelines, 
International Conference on Harmonisation Good Clinical Practice guidelines (ICH GCP), and 
applicable local laws/regulations. 
7.3. 
Investigational Medicinal Product Storage 
Vials with RMC-035 and vials with placebo must be stored at -20 ± 5°C (-4°F) 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 storage within the correct 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. 
7.4. 
Investigational Medicinal Product Preparation 
Preparation of the IMP will be done by trained staff in a dedicated area, as detailed in the 
Pharmacy Manual.  
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 subject. The pre-surgery body weight collected on 
Day -1 (Visit 1) should be used to calculate the dose for all 5 dose administrations.  


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The diluted product may be stored in a prefilled infusion syringe in a refrigerator (2-8°C / 36-
46°F) for a maximum of 72 hours (or a shorter time period as specified in the Pharmacy Manual, 
if applicable). Administration to the subject shall be completed within 2 hours after the syringe 
has been taken out of the refrigerator. 
7.5. 
Administration 
Only subjects enrolled in the study may receive IMP and only trained and authorized site staff 
may prepare or administer it. 
IMP 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 each investigational site. 
The IMP should be administered via a CVC whenever possible. One lumen of the CVC should 
be reserved for IMP administration in order to avoid potential 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, approximately 10 minutes before the expected 
initiation of CPB. The first infusion and second infusion will be administered IV over 
approximately 60 minutes (infusion rate of 0.83 mL/min). The start time of the first dose 
administration will serve as reference point for the 4 remaining dose administrations and 
protocol-mandated assessments. The second infusion will be administered at 6 hours after the 
start of the first infusion. The remaining 3 doses will be given as IV infusions, each over 
approximately 30 minutes (infusion rate of 1.67 mL/min), at 12, 24 and 48 hours respectively 
after start of the first dose administration. 
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. 
Refer to the Pharmacy Manual for detailed guidance for administration of the IMP including use 
of syringe pump and auxiliary supplies. 
7.6. 
Investigational Medicinal Product Accountability 
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. 
7.7. 
Investigational Medicinal Product Handling and Disposal 
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 according to local 
procedures. Before destruction of vials, appropriate accountability of vials and reconciliation by 
the monitor should be performed. Documentation on destruction will be forwarded to the 
Sponsor. 


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Any unused IMP will be returned to the Sponsor at the conclusion of the study or destroyed 
according to the clinical site’s SOP, as mutually agreed upon by the Sponsor and the site, after 
drug accountability has been performed and verified by the monitor. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures are described below. All assessments are to be performed 
according to the timing and frequency described in the SOA (Table 3). 
8.1. 
Informed Consent 
The nature of the risks and benefits associated with participation in the study will be explained to 
all potential study subjects. Written informed consent (including consent for the use and 
disclosure of research related health information) must be obtained before the subject can begin 
any screening procedures that are not considered standard patient care. See Section 13.3 for 
details on the consenting process. 
8.2. 
Demographic Data 
Demographic data will be collected and will include gender, age, race, and ethnicity. 
8.3. 
Medical and Surgical History 
Medical/surgical history and disease characteristics, a listing of relevant past diseases (within 5 
years prior to Screening) and current diseases (ongoing at the time of Screening), and the details 
of active diseases will be obtained from medical records and recorded in the CRF.  
8.4. 
Prior and Concomitant Medications 
Medications are classified as prior if the stop date is before or on the day the ICF is signed. 
Prior prescription and non-prescription medications (eg, over-the-counter drugs and herbal 
supplements) taken within 30 days prior to scheduled date of surgery up to the date of consent 
will be obtained by the Investigator or designee by interview and/or medical history. 
Concomitant medications refer to all drugs and therapies used from the time the ICF was signed 
through the end of study participation and are described in Section 6.1.3. 
All medications (including anesthesia) given before and during surgery will be recorded and 
transferred to the CRF. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
8.5. 
Weight and Height 
Weight and height will be collected at screening. Weight will be collected at all timepoints as 
noted in the SOA. During the subject’s stay at the ICU, collection of weight is required only if 
possible. The pre-surgery weight taken on Day -1 will be used to calculate the IMP doses for all 
5 infusions. 
8.6. 
Safety Assessments 
Any abnormalities in the safety assessments will be specified and documented as clinically 
significant or not clinically significant by the Investigator. Abnormal post-dose findings assessed 
by the Investigator as clinically significant will be reported as AEs. 


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Any abnormal laboratory test results (hematology, clinical chemistry, liver function or 
urinalysis) or other safety assessments (eg, ECG, vital signs measurements), including those that 
worsen from the screening visit, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease or medical 
procedure, ie, cardiac surgery) is an AE (Section 9.1). 
8.6.1. 
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 CRF. 
Data points to collect are: 
• Type of CPB pump (pulsatile or non-pulsatile, if applicable) and duration of CPB (exact 
time of initiation and end of CPB) 
• Duration of surgery (beginning of surgery defined as exact time of initial skin incision, 
end of surgery defined as exact time of skin closure) 
• Blood loss volume  
• Administration of any fluids during surgery (blood products [red blood cells, plasma, 
cryoprecipitate, platelets, etc.], crystalloids, colloids, and others) 
• Target body temperature during CPB and time at temperature range  
• Duration of cross clamp (minutes)  
• Number, position, and graft source of bypasses performed  
• Length of time with mean arterial pressure <50 mmHg 
• Valve surgery type (replacement or repair), replacement valve origin (bioprosthetic or 
mechanical), and aortic repair type 
• Time of admission to the ICU. 
8.6.2. 
Physical Examination 
The Investigator or qualified designee will conduct the exams, determine findings, and assess 
any abnormalities as to clinical significance. The physical examination performed at screening 
should be comprehensive; all other physical examinations may be abbreviated and symptom 
driven. 
8.6.3. 
Vital Signs 
Vital signs will include body temperature (°C), systolic and diastolic blood pressure (mmHg), 
heart rate (bpm) and respiratory rate (breaths per min), and oxygen saturation (SpO2).  
Vital signs should when possible be measured after a period of at least 5 minutes of rest and 
should be collected prior to blood draw for laboratory tests. Blood pressure should be recorded in 
a supine position when possible. Blood pressure, heart rate, and respiratory rate measurements 
will be assessed using either manual techniques or an automated device.  


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8.6.4. 
Electrocardiograms 
A single 12-lead electrocardiogram (ECG) will be obtained in supine position using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Twelve-lead ECGs will be reviewed and assessed for clinical significance by the 
Investigator. Other cardiac monitoring, eg, telemetry, will follow local standard of care and not 
recorded in the CRF. 
8.7. 
Laboratory Assessments 
The samples will be collected at the time points indicated in the SOA (Table 3). Actual sampling 
times will be recorded in the CRF. A list of clinical laboratory tests to be processed by the local 
laboratory is provided in Table 5. A list of clinical laboratory tests to be processed at the central 
laboratory is provided in Table 6. 
 
Table 5: 
Protocol Required Laboratory Assessments – Local Laboratory 
Laboratory Assessments 
Parameters 
Hematology 
Hematocrit (Hct) 
Red cell distribution 
width (RDW) 
Monocytes 
Hemoglobin (Hb) 
Red blood cells 
Lymphocytes 
Mean corpuscular 
volume (MCV) 
Platelets 
Eosinophils 
Mean corpuscular 
hemoglobin (MCH) 
Leucocytes  
Basophils 
Mean corpuscular 
hemoglobin 
concentration 
(MCHC) 
Neutrophils 
 
Clinical Chemistry (excluding liver 
function labs) 
Albumin 
Sodium 
Blood urea nitrogen 
Calcium 
Estimated glomerular 
filtration rate (based 
on Serum creatinine) 
Uric acid 
Chloride 
Magnesium 
Glucose 
Serum creatinine 
(SCr) 
Phosphate 
 
C-reactive protein 
(CRP) 
Potassium 
Liver Function Labs 
Alanine 
aminotransferase 
(ALT) 
Aspartate 
aminotransferase 
(AST) 
Gamma 
glutamyltransferase 
(GGT) 
Alkaline phosphatase 
(ALP) 
Bilirubin (total and 
conjugated)  
 
Urinalysis 
Specific gravity 
pH 
Leukocytes 
Erythrocytes 
Protein 
Glucose 


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Laboratory Assessments 
Parameters 
Nitrite 
Urobilinogen 
Bilirubin 
Ketones 
Microscopic 
examination (if blood 
or protein is 
abnormal) 
 
Urine albumin creatinine ratio  
Urine albumin 
Urine creatinine  
 
Other Screening Tests 
Highly sensitive serum human chorionic gonadotropin (hCG) serum 
pregnancy test (as needed for WOCBP) 
 
Table 6: 
Protocol Required Laboratory Assessments – Central Laboratory 
Laboratory Assessments 
Parameters 
Clinical Chemistry  
Serum creatinine (SCr) 
Cystatin C 
 
Urine albumin creatinine 
ratio (UACR), Urine 
protein creatinine ratio 
(UPCR) 
Urine albumin  
Urine creatinine 
Urine protein 
Urine Kidney Biomarkers 
KIM-1, NGAL, TIMP2, IGFBP7, CCL-14, IL-18, LFABP, 8-OHdG, and urine 
creatinine 
Cardiac Biomarkers 
NT-pro-BNP 
Troponin-I (cTnI) 
Troponin T (cTnT). 
Immunologic biomarkers 
Parameters characteristic for formation of including but not limited to markers of 
complement activation, cytokine release and mast cell activation  
Pharmacokinetics 
Concentration of RMC-035 in plasma 
ADA 
Determination of ADAs in plasma 
Abbreviations: 8-OHdG=8-hydroxy-2'-deoxyguanosine; CCL-14=chemokine ligand 14; IGFBP7=insulin-like 
growth binding factor protein 7; IL-18=interleukin-18; KIM-1=kidney injury molecule 1; LFABP=liver fatty acid 
binding protein; NGAL=neutrophil gelatinase-associated lipocalin; NT-pro-BNP= N-terminal-pro-b-type natriuretic 
peptide; TIMP2=tissue inhibitor of metalloproteinase 2 
 
Blood samples for analysis of clinical chemistry (including SCr, cystatin C and liver function 
tests), cardiac and immunologic biomarkers and hematology parameters will be collected 
through venipuncture or an indwelling venous or arterial catheter.  
Blood samples will be analyzed for SCr both locally and centrally; local results will be utilized 
for eligibility, randomization / stratification, IMP dose assignment, clinical care and real time 
evaluation of AKI for purposes of IMP discontinuation (Section 5.3.1), while centrally processed 
blood samples will be utilized for purposes of endpoint evaluation. 
The Investigator must review the laboratory reports, document the result of the review (ie, 
clinical assessment for values out of range) on the laboratory report, and record any clinically 
significant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. 


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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 which are considered to be clinically significant by the Investigator during 
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. 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. 
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 (eg, SAE or AE), then the results must be recorded in the CRF. 
8.7.1. 
Urine Albumin Creatinine Ratio and Urine Protein Creatinine Ratio 
The UACR screening sample (Day -1, Visit 1) will be collected as a spot urine sample and 
analyzed locally to evaluate albuminuria as an eligibility criterion (in the absence of historical 
albuminuria data within 3 months prior to randomization).  
The UACR and UPCR in-hospital samples (Day 1, Visit 2 and Day 4, Visit 5) will be collected 
either as a First Morning Void (FMV) sample or drawn directly from a Foley catheter and 
analyzed via central lab only. 
Follow-up samples (Day 30, Visit 7 and Day 90, Visit 8) will be collected preferably as FMV 
samples and analyzed in a central lab only. If FMV is not feasible, spot urine sample should be 
collected in its place.  
Detailed instructions for urine collection protocol will be provided in the laboratory manual.  
8.7.2. 
Urinalysis 
Urinalysis by means of a regular dipstick test will be performed locally. 
8.7.3. 
Pregnancy Testing 
All female subjects of child-bearing potential will have a serum pregnancy test performed at 
Screening; pregnant subjects are excluded from participation in the study. A serum pregnancy 
test completed within 48 hours prior to surgery does not need to be repeated on the day of 
surgery. If the screening visit occurs more than 48 hours prior to the date of surgery, a serum or 
urine pregnancy test will also be performed on Day 1 prior to surgery.  
8.8. 
Urine Output 
Urine output (UO) will be documented starting on Day 1 from the insertion of the Foley catheter 
and continue for as long as the subject has a catheter (Foley) in place, or until 72 hours after the 
first dose of IMP (whichever occurs first).  
While the subject remains hospitalized in the ICU, site staff will measure UO in hourly intervals 
or per site’s standard of care. Urine output (volume) will be entered into the CRF at 6-hour time 
periods as much as possible. The exact time period for the collection and the collected volume 
will be recorded in the CRF. 


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If the subject is transferred to a non-ICU ward, and the catheter is still in place, UO will be 
measured at 6-hour intervals or per site’s SOC, until catheter is removed or until 72 hours after 
the first dose of IMP. The exact time period for the collection and the collected volume will be 
recorded in the CRF at 6-hour intervals as much as possible.  
If the Foley catheter is removed, urine production will no longer be entered in the CRF but spot 
urine samples will continue to be collected as per the SOA. UO can only be used for diagnosing 
AKI or rating AKI severity if the UO has been calculated based on urine output measured by a 
Foley catheter. If the Foley catheter is removed, UO will not be used for the AKI definition. 
8.9. 
Major Adverse Kidney Events 
Major adverse kidney events (MAKE) will be assessed at Days 30 and 90. The MAKE endpoint 
is a composite of death, new RRT (any RRT after surgery), or sustained loss of kidney function, 
defined as a 25% or greater decline in eGFR as it represents a clinically meaningful endpoint as 
suggested by the National Institutes of Diabetes and Digestive and Kidney Diseases .  
8.10. 
Pharmacokinetic 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 line in relation to IMP dose 1, 4 and 
5.  
The actual date and time (24-hour clock time) of each sample will be recorded and transferred to 
the CRF. 
Samples will be taken at the pre-specified time points described in Table 7. 
 
Table 7: 
Plasma Pharmacokinetic Sampling Timepoints 
Plasma PK Sampling 
Time Window  
Predose 
≤30 min 
30 min 
±5 min 
1 h 
±5 min 
90 min 
±15 min 
2 h 
±15 min 
Start of IMP dosing 1 (t=0 h) 
x 
 
x 
 
x 
Start of IMP dosing 4 (t=24 h) 
x 
x 
 
x 
 
Start of IMP dosing 5 (t=48 h) 
x 
x 
 
x 
 
Abbreviations: PK=pharmacokinetic; t=time; min=minutes; h=hour 
 
Drug concentration information that may unblind the study will not be reported to investigational 
site or blinded personnel until the study has been unblinded. Both the bioanalytical laboratory 
and the pharmacokineticist will be blinded to treatment. 
Samples may be stored at the analytical laboratory until the database lock has been performed. 
8.11. 
Immunogenicity Assessments 
Blood samples for the determination of ADA after administration of IMP will be collected 
through an indwelling arterial or venous catheter or venipuncture at all timepoints as described in 
the SOA and will be processed via central lab.  


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Instruction on the sample collection and handling will be detailed in the Laboratory Manual. 
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 considering 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 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 will be further characterized with regard to Ig subtype, neutralizing capacity and 
cross-reactivity with endogenous A1M. 
Assessment of exploratory immunologic biomarkers investigating the background of potential 
IRRs is described in section 8.13.2. 
8.12. 
Health-Related Quality of Life Assessments 
Two patient recorded outcome (PRO) questionnaires will be collected at all timepoints as 
described in the SOA (during screening and Visit 8, Day 90). Questionnaires should be 
completed by the subjects themselves and should be administered and completed prior to any 
study specific procedures on the specific visit days. In the event that a subject has limitations that 
preclude them from completing the questionnaire, the questionnaire may be completed for them, 
based on their verbal responses by study personal and/or legally acceptable representative 
following questionnaire administration instructions outlined in the Study Manual. 
Medical Outcomes Study (MOS) 36-Item Short Form Health Survey (SF-36) 
The MOS SF-36 (see Appendix 4) is a set of generic, coherent, and easily administered Quality 
of Life measures. The SF-36 includes one multi-item scale that assesses eight health concepts:  
• limitations in physical activities because of health problems 
• limitations in social activities because of physical or emotional problems 
• limitations in usual role activities because of physical health problems 
• bodily pain 
• general mental health (psychological distress and well-being) 
• limitations in usual role activities because of emotional problems 
• vitality (energy and fatigue) 
• general health perceptions 
European Quality of Life 5 Domain 5-Level Score (EQ-5D-5L) 
The European Quality of Life 5 Domain 5-Level Score (EQ-5D-5L) (see Appendix 5) is a self-
report survey that measures quality of life across 5 domains: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ-5D-5L is consists of two parts: the EQ-5D 
descriptive system and the EQ visual analogue scale (EQ VAS). 


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The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems. The subject is asked to 
indicate his/her health state by ticking the box next to the most appropriate statement in each of 
the five dimensions. This decision results in a 1-digit number that expresses the level selected for 
that dimension. The digits for the five dimensions can be combined into a 5-digit number that 
describes the subject’s health state. 
The EQ VAS records the subject’s self-rated health on a vertical visual analogue scale, where the 
endpoints are labelled “The best health you can imagine” and “The worst health you can 
imagine.” The VAS can be used as a quantitative measure of health outcome that reflect the 
subject’s own judgement. 
8.13. 
Exploratory Biomarkers 
Plasma and urine samples for kidney, cardiac and immunologic biomarker assessment will be 
collected as per the SOA.  
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 pharmacodynamic and immunologic responses to the IMP. 
8.13.1. 
Kidney and Cardiac Biomarkers 
Blood and urine samples for kidney and cardiac biomarker research will also be collected at all 
timepoints as described in the SOA. 
• Blood samples will be collected through an indwelling arterial or venous 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. 
Urine samples will be assessed for KIM-1, NGAL, TIMP2, IGFBP7, CCL-14, IL-18, LFABP, 
8-OHdG, and urine creatinine. Plasma samples will be assessed for NT-pro-BNP and cardiac 
troponin I and T (cTnI, cTnT).  
Additional biomarkers may be measured from already collected samples.  
8.13.2. 
Immunologic Biomarkers 
Additional plasma samples will be collected at all timepoints as described in the SOA to explore 
the background and mechanism of potential IRRs.  
 
 


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9. 
SAFETY MONITORING AND REPORTING 
9.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of medicinal product, whether or not considered related to this IMP. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of medicinal 
product. 
By definition, a treatment-emergent adverse event (TEAE) is any AE that occurs after the initial 
IMP administration through 72 hours (inclusive) after the final IMP administration. 
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 (ie, not related to progression of underlying disease or 
surgical procedure). 
• 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 (eg, 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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9.2. 
Definition of a Serious Adverse Event 
An SAE is defined as an AE that meets at least one of the following serious criteria: 
• Results in death 
• Is life-threatening 
o 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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o 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. 
o Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• Results in persistent disability/incapacity 
o The term disability means a substantial disruption of a person's ability to conduct 
normal life functions. 
o This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Other medically important serious event  
o 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. 
o 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. 
9.2.1. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious adverse events that are 
not listed in the IB and the Investigator or Sponsor identifies as related to investigational product 


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or procedure. The Sponsor or designee has procedures in place for the expedited reporting of 
SUSARS that are consistent with global regulations and associated guidelines. 
9.3. 
Adverse Events of Special Interest 
Injection Site Reaction (ISR) and 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 reporting protocol described in Section 9.7. The criteria of intensity grading for ISR and 
IRR are provided in Table 8 below.  
 
Table 8:  
Intensity Grading For Injection Site Reactions (ISR) and Infusion Related 
Reactions (IRR) 
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Definition 
MedDRA PT: 
Injection site 
reaction 
MedDRA 
SOC: General 
disorders and 
administration 
site 
conditions 
Tenderness 
with or 
without 
associated 
symptoms 
(eg, 
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. 
MedDRA PT: 
Infusion 
related 
reaction 
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 (eg, 
antihistamines, 
NSAIDS, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤24 hrs 
Prolonged (eg, 
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. 
 
Abbreviations: IV=intravenous; MedDRA=Medical Dictionary for Regulatory Activities; NSAID=non-steroidal 
anti-inflammatory drug; SOC=system organ class 
 
9.4. 
Relationship to Investigational Medicinal Product 
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: 
• Not related (unlikely) 
o Does not follow a reasonable temporal sequence from drug administration 


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o Is readily explained by the subject's clinical state or by alternative etiologies such 
as underlying disease(s), concomitant therapy and other risk factors  
• Related (possible/probable) 
o Follows a reasonable temporal sequence from IMP administration 
o Cannot be reasonably explained by the known characteristics of the subject's 
clinical state 
Alternative etiology should be provided for all AEs assessed as possibly 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 IB 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. However, it is very important that the Investigator 
always assess causality for every event before the initial transmission of the SAE data to the 
Sponsor or CTI Safety. 
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. 
9.5. 
Assessment of Intensity 
Intensity will occur according to the following scale: 
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 Activities of Daily Living (ADL). 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
Grade 4  Life-threatening consequences; urgent intervention indicated 
Grade 5  Death related to AE 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. Self-care ADLs refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 9.2. An AE of severe intensity may 
not be considered serious. 


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9.6. 
Recording Adverse Events 
All AEs will be collected from initiation of the first IMP administration through the Day 30 
study visit. 
All SAEs will be collected from the signing of the ICF through the EOS visit. 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. The 
AE/SAE term should be reported in standard medical terminology when possible. For each 
event, the Investigator will evaluate and report the onset, resolution, intensity, causality, action 
taken, serious outcome (if applicable), and whether or not it caused the subject to discontinue the 
study. 
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 (eg, became blind, deaf, paralyzed). 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. 
Any requested supporting documentation (eg, laboratory or diagnostic test results, clinical or 
progress notes, admission and/or discharge records) requested by the Sponsor or CTI Safety, 
related to SAEs for the evaluation of safety must be faxed or emailed to CTI Safety as soon as 
available at the study site. Specific email address and fax numbers and instructions will be 
specified in the Study Manual. 
If a subject dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Sponsor or designee with a copy of any post-mortem findings 
including histopathology. 
9.7. 
Reporting Adverse Events 
All AEs must be recorded in the electronic data capture (EDC) system in a timely manner and 
will be described by seriousness, duration (event start and resolution), severity, outcome, action 
taken, and relationship to investigational product. The Investigator should take all appropriate 
measures to ensure the safety of the subjects and should follow-up the outcome of any AE 
(clinical, laboratory values, or other, etc.) until the return to normal, until the subject’s condition 
has stabilized, or the event is chronic. In the event of an SAE, the Investigator should follow-up 


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with the outcome until the clinical recovery is complete and laboratory results have returned to 
normal or until progression has been stabilized. 
All SAEs, regardless of causality, must be promptly recorded in the EDC system within 24 hours 
of learning of its occurrence. If the site experiences a temporary disruption of the EDC system, a 
back-up paper SAE report form will be available for completion and is located in The Study 
Manual. 
Additional follow-up information must also be recorded in the EDC system within 24 hours of 
awareness. 
The Investigator must also report all SAEs promptly to the appropriate IRB/IEC as required. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 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 IMP or 
study participation, the Investigator must promptly notify the Sponsor. 
9.8. 
Pregnancy and Lactation 
Refer to Appendix 1 for more details on contraceptive guidance and collection of pregnancy 
information.  
There is no relevant clinical experience with RMC-035 in pregnant or lactating women. Women 
of child-bearing potential must have a negative pregnancy test prior to enrollment because of the 
unknown risk of potential effects on the fetus. Women of childbearing potential should be 
monitored according to local and country-specific regulations. This IMP should not be 
administered to pregnant women or women who are breastfeeding. Any female subject who 
becomes pregnant while participating in the study will discontinue IMP administration.  
Female subjects of childbearing potential are required to use highly effective contraception from 
screening up to 7 days after the final IMP administration. Male subjects with female partners of 
childbearing potential must be using a condom starting at screening and continue to do so 
throughout the treatment period and for 7 days after final IMP administration. If required by 
local law, 2 highly effective methods of birth control must be used, 1 of which must be a barrier 
method. Refer to Appendix 1 for a complete list of highly effective contraception methods. 
Pregnancy in itself is not regarded as an AE unless there is suspicion that the investigational 
product may have interfered with the effectiveness of a contraceptive medication. However, 
complications of pregnancy and abnormal outcomes of pregnancy are AEs and may meet serious 
criteria for an SAE (eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly). Elective abortions without complications should not be 
reported as AEs. 
A pregnancy or positive pregnancy test must be recorded immediately using the Pregnancy 
Report Form in the EDC system. The Investigator must follow-up and document in the EDC 
system the course and outcome of all pregnancies even if the subject discontinued from the 
study. 
 


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9.9. 
Data Monitoring Committee 
An Independent DMC including clinical expertise in kidney injury will perform review of safety 
findings including possible adverse drug effects on the kidney at regular intervals during the 
study. The DMC evaluation will be based on all available accumulated safety data. The DMC 
will also be responsible for recommendation on the study conduct following their reviews, 
including the review in relation to interim analysis (see section 10.4.1). 
Communication from the DMC will be blinded. All DMC activities and processes will be 
outlined in the DMC Charter.  
 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Analysis Sets 
Intent to Treat (ITT): The ITT will consist of all randomized subjects. 
Modified Intent to Treat (mITT) Set: The mITT will consist of all subjects in the ITT set who 
received at least 1 dose of IMP. The mITT will be used for the primary analysis of efficacy 
endpoints. Subjects will be included in the efficacy analysis based on randomized treatment 
group.  
Safety Analysis (SAF) Set: The SAF will consist of all subjects in the mITT set; however, 
subjects will be included in the analysis based on treatment actually received.  
Per Protocol (PPS) Set: The PPS will consist of all subjects in the mITT set who did not have 
any major protocol deviations or other conditions (eg insufficient exposure) that were judged to 
influence the efficacy analysis. Prior to database lock, subjects who had a major protocol 
deviation will be identified in a blinded manner by the study team. 
PK Analysis (PK) Set: The PK Analysis Set will be used for the PK evaluation and will consist 
of all randomized subjects with no relevant protocol deviations affecting the evaluation of the PK 
parameters. 
10.2. 
Sample Size Determination 
For the primary endpoint, AKI within 72 hours after first dose of IMP, RMC-035 has been 
assumed to lead to a 30% relative risk reduction vs. placebo. The event rate in the placebo group 
has been assumed to be 50%. A sample size of 268 subjects dosed leads to a test power of 80% 
to show statistically significant results at a two-sided significance level (alpha) of 0.10. An IA of 
the primary endpoint will be performed when 50% of the planned subjects dosed have completed 
Visit 6 (Day 5-9). Conditional power (CP) given ‘the current trend’ will be calculated. Sample 
size may be increased to a maximum of 348 subjects dosed. Sample size will not be decreased. 
10.3. 
Stratification and Randomization 
Eligible subjects will be randomized to receive either RMC-035 or placebo in a 1:1 
randomization ratio. Both region (North America and Europe) and Day -1 eGFR calculated using 
the CKD-EPI equation with SCr on local laboratory results (≥60 and <60 mL/min/1.73m2) will 
be used as stratification factors to ensure a balanced randomization within these groups. 
10.4. 
Interim Analyses 
10.4.1. 
Primary Endpoint 
An interim analysis (IA) of the primary endpoint will be performed when 50% of the planned 
randomized subjects have completed Visit 6 (Day 5-9). The analysis will be performed as 
detailed in Section 10.5.2. Conditional power (CP), the probability that the final analysis will be 
statistically significant, will be calculated. Sample size may be increased to a maximum of 348 
randomized subjects. Sample size will not be decreased. The Study may be stopped at the IA for 
futility reasons. Study eligibility criteria may also be modified. 


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Given the unblinded nature of this IA, an unblinded Data Monitoring Committee (DMC) of 
independent individuals not involved in any other study activities will be utilized. Further details 
on the IA and the control of the type I error will be provided in the DMC Charter and Statistical 
Analysis Plan. 
The Sponsor and all other CRO personnel will remain blinded. The unblinded materials, data, 
and analysis results will be stored securely and separately from blinded clinical material and will 
not be accessible by blinded personnel. Results of the IA will not be shared with the Sponsor or 
blinded CRO personnel; only a decision on whether sample size expansion criteria have been 
met will be shared with the blinded team.  
Control of the type I error will be done by adjusting the final critical value as proposed by Gao et 
al. (Gao 2008) and further developed by Mehta and Pocock (Mehta 2011). Further details on the 
IA and the control of the type I error will be provided in the DMC Charter and the Statistical 
Analysis Plan (SAP). 
10.4.2. 
Exploratory Kidney and Cardiac Biomarkers 
An IA of exploratory biomarkers from urine or blood may be performed at a time point 
determined by the Sponsor. The purpose is providing background information on the mechanism 
of action and to help guiding additional development programs for RMC-035. 
This analysis, if conducted, is not part of, and is run independently from, the IA of the primary 
endpoint described in section 10.4.1. The analysis will be conducted as detailed in section 10.5.6. 
The unblinded materials, data, and analysis results will be stored securely and separately from 
blinded clinical material. In order to minimize impact on the scientific integrity of the study, 
access to these unblinded data on an individual subject level will be restricted to Sponsor or CRO 
personnel not involved in the conduct or supervision of the study. A Data Access Plan will detail 
which personnel will have access to unblinding subject level data. 
 
10.5. 
Planned Method of Data Presentation and Analysis 
The primary analysis will be performed after the last subject has completed the last study visit. 
Full details of the statistical analyses to be performed will be included in the SAP. 
All continuous data will be summarized using N, mean, standard deviation (SD), minimum, 
median and maximum value. Summary statistics for categorical variables will contain count and 
percentage. For log-normal endpoints, geometric mean and geometric standard deviation will 
also be produced.  
10.5.1. 
Demographic and Baseline Characteristics 
Demographic data, medical and surgical history, risk factors for AKI, and other relevant baseline 
characteristics will be summarized by group using summary statistics. 
10.5.2. 
Efficacy 
The primary endpoint will be analyzed by the Cochran-Mantel-Haenszel estimate of the common 
relative risk (RMC-035 vs. placebo) across the four stratification groups formed by region (North 
America and Europe) and eGFR at Day -1 (≥60 and <60 mL/min/1.73m2). In addition, the 


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proportion of subjects with AKI within 72 hours after first dose of IMP and its 90% confidence 
interval will be calculated for each treatment group. The hypotheses to be tested are as follows: 
• Null hypothesis: the proportion of subjects developing AKI within 72 hours after first 
dose of IMP is the same for the RMC-035 and the placebo treatment groups 
(pRMC-035 = pplacebo) 
• Alternative hypothesis: the proportion of subjects developing AKI within 72 hours after 
first dose of IMP is different for the RMC-035 and the placebo treatment groups 
(pRMC-035 ≠ pplacebo) 
Secondary continuous efficacy endpoints, that are measures of renal function will be analyzed 
using robust regression of log-transformed values having sequentially multiply imputed any 
missing data.  A sensitivity analysis will be performed using a mixed model for repeated 
measurements (MMRM) if data are approximately normally distributed. 
For the key secondary AUC endpoint, the geometric least square means of the time-corrected 
AUC for Days 1 to 4 will be obtained for each RMC-035 and placebo by transforming the model 
estimates back to the original scale. The AUC will be calculated using the right Riemann sum 
with the dates/times the measurements are planned. The relative difference (RMC-035 vs. 
placebo) and its 90% confidence interval will also be reported.  
Supportive analyses of renal function will be performed cystatin C levels (and corresponding 
eGFR values assessed by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 
equations with either SCr, cystatin C, or both) and cumulative AUC values up to each timepoint. 
Secondary binary efficacy endpoints will be analyzed using the same approach as specified 
above for the primary endpoint.  
Evaluation of the exploratory endpoints, sensitivity analyses and other continuous secondary 
endpoints, will be detailed in the SAP. 
10.5.3. 
Subgroup Analyses 
Subgroup analyses will be defined prior to database lock in the SAP. 
10.5.4. 
Safety 
Safety analyses will be conducted on the safety set. To characterize the safety profile, the 
number and percentage of subjects with TEAEs and AEs per dose group will be tabulated per 
System Organ Class (SOC) and Preferred Term (PT) according to the Medical Dictionary for 
Regulatory Activities (MedDRA). Descriptive statistics will be provided for laboratory tests 
(hematology, biochemistry, urinalysis) and vital signs (pulse rate, respiratory rate and blood 
pressure) by visit and for the changes from baseline to each visit split by dose group. 
10.5.5. 
Pharmacokinetics 
Descriptive statistics will be presented for plasma concentrations by scheduled sample time. 
Specific pharmacokinetic parameters will be presented separately. Summaries will be provided 
by dose group, age group and by renal function at baseline. 
 
 


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10.5.6. 
Exploratory Biomarkers 
Descriptive statistics will be obtained by parameter and visit by dose group. This will be done 
both for the actual values and the changes from baseline. Statistical testing will be performed for 
exploratory purposes. 
10.5.6.1. Kidney and Cardiac Biomarkers 
Serum/plasma and urine samples will be collected and stored for potential future analysis of 
exploratory biomarkers, eg, urine KIM-1, NGAL, TIMP2, IGFBP7, CCL-14, IL-18, LFABP; 
and plasma NTpro-BNP, cTnI and cTnI. Additional urine and/or plasma biomarkers related to 
the mode of action of RMC-035 (eg, endogenous alpha-1-microglobulin) may also be analyzed. 
10.5.6.2. Immunologic Biomarkers 
Plasma samples will be collected for future analysis of parameters relevant for exploration of 
potential infusion related reactions.  
 
 
 


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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Documents 
Source documents are original documents, data and records for which the study data are 
collected and verified. Example of such source documents may include, but are not limited to, 
hospital records and subject charts; laboratory, pharmacy, and radiology records; subject diaries; 
microfiches; correspondence; and death registries. Data entered in the CRF 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. 
The Investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated. These individuals who are authorized to fulfil these responsibilities should be outlined 
and included in the Delegation of Authority Form. 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system of all subject records that are readily retrieved to be monitored and or audited at 
any time by the key sponsor contact, regulatory authorities, and IRB/IECs. The filing system will 
include at a minimum the following: 
• Subject content including ICFs and subject ID lists 
• Protocols and protocol amendments, IB, copies of pre-study documentation and all 
IRB/IEC and sponsor communication 
• Proof of receipt, experimental treatment flow records, and experimental product-related 
correspondence 
Original source documents supporting entries into CRFs must be maintained at the site and 
readily available upon request. No study documents should be discarded without prior written 
agreement between the Sponsor and the Investigator. Should storage no longer be available to 
archive source documents or must be moved to an alternative location, the research staff should 
notify the key sponsor contact prior to the shipping the documents. 
11.2. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of the Sponsor 
or designee may visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities under the 
protocol as well as the responsibilities of the Sponsor. This will be documented in a 
Clinical Study Agreement between the Sponsor and the Investigator. 
During the study, a monitor from the Sponsor or its designee will have regular contacts with the 
investigational site and conduct on-site monitoring visits as described in the Study Monitoring 
Plan. Sponsor approved monitoring and auditing procedures will ensure that the study is 
conducted in accordance with the protocol and regulatory requirements while ensuring the safety 
of all study subjects. 


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The monitor will perform source data verification, including a comparison of the data in the CRF 
with the subject’s medical records at the hospital or clinic, and other records relevant to the 
study. Source data verification requires direct access to all original records for each subject. The 
review of medical records will be performed in a manner that ensures subject confidentiality. 
Regulatory authorities and the IRB /IEC may request access to all source documents for on-site 
inspection or an audit. Likewise, the Sponsor or its designee may conduct a quality assurance 
audit to ensure compliance with GCP and all applicable regulatory requirements. Direct access to 
source documents must be guaranteed by the Investigator, who will provide support at all times 
for these activities. 
Upon completion of the study the monitor will make a final assessment of the conduct of the 
study and inventory all clinical supplies to be returned to the Sponsor or designee. Unused or 
used vials of IMP will be stored until the monitor is able to perform a physical inventory and 
reconciliation with the drug accountability records. At the completion of this study, all unused or 
used vials must be returned to the Sponsor, or designee, or if authorized, disposed of at the study 
site and documented. 
11.3. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an IEC, or an IRB may visit 
the site to perform audits or inspections, including source data verification. The purpose of a 
Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, ICH GCP, and any 
applicable regulatory requirements. The Investigator should contact the Sponsor immediately if 
contacted by a regulatory agency about an inspection. 
11.4. 
Institutional Review Board and Independent Ethics Committee  
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study including the subject consent 
form/process must be maintained by the Investigator and made available for inspection. 


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12. 
DATA QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the Sponsor may conduct a quality assurance audit. See Section 11.3 for more details regarding 
the audit process. 
All subject data relating to the study will be recorded in an eCRF unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
CRF. The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF and must permit study-related monitoring, audits, IRB/IEC 
review, and regulatory agency inspections 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. Study monitors will perform ongoing source data verification to confirm 
that data entered into the CRF 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.  
12.1. 
Inspection of Records 
The Sponsor or its designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, IMP stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
12.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for the Sponsor or the 
Regulatory Authority to review any documentation relating to the study, the Investigator must 
permit access to such records. 
12.3. 
Data Protection 
Subjects will be assigned a unique identifier by the clinical site staff. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 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. The 
subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.  
 
 


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13. 
ETHICS 
13.1. 
Ethics Review 
A copy of the protocol, ICF, and any additional subject or trial information such as subject 
recruitment materials must be submitted to each sites respective IRB/IEC for approval. Once 
approval is obtained from the IRB/IEC, all documents must be provided to the key sponsor 
contact before subject recruitment can begin. 
The Investigator must also receive IRB/IEC approval for all protocol and ICF changes or 
amendments. Investigators must ensure that ongoing/continuous IRB/IEC approval (ie, annual 
approval) is provided throughout the conduct of the study. Copies of IRB/IEC approval are to be 
forwarded to the key sponsor contact for archiving. 
During the course of the study, Investigators are to submit site-specific and study SAEs 
(provided to the site by the key sponsor contact) along with any protocol deviations to their 
IRB/IEC in accordance with their respective IRB/IEC policies. 
13.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines and are consistent with applicable ICH/GCP Guidelines, and 
applicable laws and regulations. 
The Investigator will be thoroughly familiar with the appropriate use of the investigational 
product as described in the protocol and IB. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. A Trial Master File 
(TMF) will be established at the beginning of the study, maintained for the duration of the study, 
and retained according to appropriate regulations. 
13.3. 
Written Informed Consent 
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study. Subjects 
must be informed that their participation is voluntary. Subjects or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines, Personal Information Protection and 
Electronic Documents Act (PIPEDA) requirements, where applicable, and the IRB/IEC or study 
center. The subject’s signed and dated informed consent will be obtained before conducting any 
study procedures.  
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. A copy of the ICF(s) 
must be provided to the subject or the subject’s legally authorized representative.  
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study, as appropriate. 


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13.4. 
Financial Disclosure 
The Principal Investigator and all sub-investigators 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. 
13.5. 
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. 


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14. 
REPORT AND PUBLICATION  
Results from the study will be presented in a Clinical Study Report (CSR) as per ICH E3. The 
CSR will be signed by the sponsor and the Lead investigator in his role as Coordinating 
investigator for the study.  
All information regarding RMC-035 supplied by the Sponsor to the Investigator or generated by 
the Investigator in accordance with the conduct of the study is privileged and confidential 
information of the Sponsor. The Investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without written consent from the Sponsor. It is 
understood that there is an obligation to provide the Sponsor with complete data obtained during 
the study. The information obtained from the clinical study will be used by the Sponsor in 
connection with the development of RMC-035 and may be disclosed by the Sponsor to 
regulatory authorities, other Investigators, corporate partners, or consultants as required. 
The Investigator’s right and obligations with respect to publishing or otherwise presenting 
information regarding the study are detailed in the Publication provisions of the Clinical Study 
Agreement among the Investigator, the clinical site, and the Sponsor. The Investigator shall 
comply with such provisions. 


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15. 
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Surgical Coronary Revascularization." Circulation 136(14): 1331-1345. 
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Manzi, F. Van Lente, Y. L. Zhang, J. Coresh and A. S. Levey (2012). "Estimating glomerular filtration 
rate from serum creatinine and cystatin C." N Engl J Med 367(1): 20-29. 
KDIGO (2012). "Clinical Practice Guideline for Acute Kidney Injury." JOURNAL OF THE 
INTERNATIONAL SOCIETY OF NEPHROLOGY 2(1). 
Khadzhynov, D., D. Schmidt, J. Hardt, G. Rauch, P. Gocke, K. U. Eckardt and K. M. Schmidt-Ott (2019). 
"The Incidence of Acute Kidney Injury and Associated Hospital Mortality." Dtsch Arztebl Int 116(22): 
397-404. 
Khwaja, A. (2012). "KDIGO clinical practice guidelines for acute kidney injury." Nephron Clin Pract 
120(4): c179-184. 
Leballo, G., H. J. Moutlana, M. K. Muteba and P. M. Chakane (2021). "Factors associated with acute 
kidney injury and mortality during cardiac surgery." Cardiovasc J Afr 32: 1-7. 


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Lenihan, C. R., M. E. Montez-Rath, C. T. Mora Mangano, G. M. Chertow and W. C. Winkelmayer 
(2013). "Trends in acute kidney injury, associated use of dialysis, and mortality after cardiac surgery, 
1999 to 2008." Ann Thorac Surg 95(1): 20-28. 
Levey, A. S., L. A. Stevens, C. H. Schmid, Y. L. Zhang, A. F. Castro, 3rd, H. I. Feldman, J. W. Kusek, P. 
Eggers, F. Van Lente, T. Greene and J. Coresh (2009). "A new equation to estimate glomerular filtration 
rate." Ann Intern Med 150(9): 604-612. 
May, K., L. Rosenlof, M. G. Olsson, M. Centlow, M. Morgelin, I. Larsson, M. Cederlund, S. Rutardottir, 
W. Siegmund, H. Schneider, B. Akerstrom and S. R. Hansson (2011). "Perfusion of human placenta with 
hemoglobin introduces preeclampsia-like injuries that are prevented by alpha1-microglobulin." Placenta 
32(4): 323-332. 
McCullough, P. A., E. Bennett-Guerrero, L. S. Chawla, T. Beaver, R. L. Mehta, B. A. Molitoris, A. 
Eldred, G. Ball, H. J. Lee, M. T. Houser and S. Khan (2016). "ABT-719 for the Prevention of Acute 
Kidney Injury in Patients Undergoing High-Risk Cardiac Surgery: A Randomized Phase 2b Clinical 
Trial." J Am Heart Assoc 5(8). 
Meersch, M., C. Schmidt, A. Hoffmeier, H. Van Aken, C. Wempe, J. Gerss and A. Zarbock (2017). 
"Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk 
patients identified by biomarkers: the PrevAKI randomized controlled trial." Intensive Care Med 43(11): 
1551-1561. 
Mehta, C. R. and S. J. Pocock (2011). "Adaptive increase in sample size when interim results are 
promising: A practical guide with examples." Statistics in Medicine 30(28): 3267-3284. 
O'Neal, J. B., A. D. Shaw and F. T. t. Billings (2016). "Acute kidney injury following cardiac surgery: 
current understanding and future directions." Crit Care 20(1): 187. 
Olsson, M. G., M. Allhorn, J. Larsson, M. Cederlund, K. Lundqvist, A. Schmidtchen, O. E. Sorensen, M. 
Morgelin and B. Akerstrom (2011). "Up-regulation of A1M/alpha1-microglobulin in skin by heme and 
reactive oxygen species gives protection from oxidative damage." PLoS One 6(11): e27505. 
Olsson, M. G., M. Centlow, S. Rutardóttir, I. Stenfors, J. Larsson, B. Hosseini-Maaf, M. L. Olsson, S. R. 
Hansson and B. Åkerström (2010). "Increased levels of cell-free hemoglobin, oxidation markers, and the 
antioxidative heme scavenger α1-microglobulin in preeclampsia." Free Radical Biology and Medicine 
48(2): 284-291. 
Olsson, M. G., T. Olofsson, H. Tapper and B. Akerstrom (2008). "The lipocalin alpha1-microglobulin 
protects erythroid K562 cells against oxidative damage induced by heme and reactive oxygen species." 
Free Radic Res 42(8): 725-736. 
Palevsky, P. M., B. A. Molitoris, M. D. Okusa, A. Levin, S. S. Waikar, R. Wald, G. M. Chertow, P. T. 
Murray, C. R. Parikh, A. D. Shaw, A. S. Go, S. G. Faubel, J. A. Kellum, V. M. Chinchilli, K. D. Liu, A. 
K. Cheung, S. D. Weisbord, L. S. Chawla, J. S. Kaufman, P. Devarajan, R. M. Toto, C. Y. Hsu, T. 
Greene, R. L. Mehta, J. B. Stokes, A. M. Thompson, B. T. Thompson, C. S. Westenfelder, J. A. Tumlin, 
D. G. Warnock, S. V. Shah, Y. Xie, E. G. Duggan, P. L. Kimmel and R. A. Star (2012). "Design of 
clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology." Clin J Am 
Soc Nephrol 7(5): 844-850. 
Parikh, C. R., S. G. Coca, H. Thiessen-Philbrook, M. G. Shlipak, J. L. Koyner, Z. Wang, C. L. Edelstein, 
P. Devarajan, U. D. Patel, M. Zappitelli, C. D. Krawczeski, C. S. Passik, M. Swaminathan, A. X. Garg 
and T.-A. Consortium (2011). "Postoperative biomarkers predict acute kidney injury and poor outcomes 
after adult cardiac surgery." J Am Soc Nephrol 22(9): 1748-1757. 
Pickering, J. W., M. T. James and S. C. Palmer (2015). "Acute kidney injury and prognosis after 
cardiopulmonary bypass: a meta-analysis of cohort studies." Am J Kidney Dis 65(2): 283-293. 


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Serraino, G. F., M. Provenzano, F. Jiritano, A. Michael, N. Ielapi, P. Mastroroberto, M. Andreucci and R. 
Serra (2021). "Risk factors for acute kidney injury and mortality in high risk patients undergoing cardiac 
surgery." PLoS One 16(5): e0252209. 
Singer, M., C. S. Deutschman, C. W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G. 
R. Bernard, J. D. Chiche, C. M. Coopersmith, R. S. Hotchkiss, M. M. Levy, J. C. Marshall, G. S. Martin, 
S. M. Opal, G. D. Rubenfeld, T. van der Poll, J. L. Vincent and D. C. Angus (2016). "The Third 
International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)." JAMA 315(8): 801-810. 
Susantitaphong, P., D. N. Cruz, J. Cerda, M. Abulfaraj, F. Alqahtani, I. Koulouridis, B. L. Jaber and N. 
Acute Kidney Injury Advisory Group of the American Society of (2013). "World incidence of AKI: a 
meta-analysis." Clin J Am Soc Nephrol 8(9): 1482-1493. 
Thiele, R. H., J. M. Isbell and M. H. Rosner (2015). "AKI associated with cardiac surgery." Clin J Am 
Soc Nephrol 10(3): 500-514. 
Tinica, G., C. Brinza, A. Covic, I. V. Popa, A. Tarus, A. E. Bacusca and A. Burlacu (2020). 
"Determinants of acute kidney injury after cardiac surgery: a systematic review." Rev Cardiovasc Med 
21(4): 601-610. 
Vives, M., A. Hernandez, F. Parramon, N. Estanyol, B. Pardina, A. Munoz, P. Alvarez and C. Hernandez 
(2019). "Acute kidney injury after cardiac surgery: prevalence, impact and management challenges." Int J 
Nephrol Renovasc Dis 12: 153-166. 
Wang, Y. and R. Bellomo (2017). "Cardiac surgery-associated acute kidney injury: risk factors, 
pathophysiology and treatment." Nat Rev Nephrol 13(11): 697-711. 
 


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16. 
APPENDICES 
 
Appendix 1: Contraceptive Guidance and Collection of Pregnancy Information 
Appendix 2: Liver Laboratory Test Abnormalities 
Appendix 3: Requisite Clinical Guidelines and Grading Scales 
Appendix 4: Medical Outcomes Study (MOS) 36-Item Short Form Health Survey (SF-36) 
Appendix 5: European Quality of Life 5 Domain 5-Level Score (EQ-5D-5L) 


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APPENDIX 1. 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 (eg, 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, (eg, 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 Guidance: 
Highly effective forms of birth control include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 


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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 
• Vasectomized partner 
• True sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the IMP. 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. 


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• 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 9.7. 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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APPENDIX 2. LIVER LABORATORY TEST ABNORMALITIES  
 
Liver Safety Monitoring and Assessment 
Any subject enrolled in this clinical study receiving IMP that reveals an increase of serum 
aminotransferases (AT) to >3 × Upper Limit of Normal (ULN), or total bilirubin (TBL) >2 × 
ULN, should undergo detailed testing for liver laboratory test abnormalities (including at least 
ALT, and TBL). Liver laboratory tests per protocol are performed at Screening, Baseline (before 
start of surgery), 24 hours, 48 hours and 72 hours after first IMP administration (see SOA, 
Table 3).  
Testing should be repeated within 24 hours of notification of the initial test results in order to 
confirm the laboratory abnormality. Subjects should be asked if they have any symptoms 
suggestive of hepatobiliary dysfunction.  
 
Definition of Liver Laboratory Test Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe: 
Moderate >ALT 3× ULN or >TBL 2× ULN 
Severe* >ALT 3× ULN and >TBL 2× ULN 
In addition, the subject should be considered to have severe liver laboratory test abnormalities 
for any of the following: 
• ALT or AST >8× ULN 
• ALT or AST >5× ULN for more than 2 weeks 
• ALT or AST >3× ULN and INR > 1.5 (If INR testing is applicable/evaluated). 
• ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver laboratory test results, other than as 
described above, may qualify as moderate or severe abnormalities and require additional 
monitoring and follow-up. 
 
*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a significant obstructive 
component, has a high rate of bad outcomes, from 10–50% mortality (or transplant). The two “requirements” for 
Hy’s Law are:  
1) Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase in transaminase 
elevations higher 3 times the upper limit of normal (“2 x ULN elevations are too common in treated and untreated 
subjects to be discriminating”) 
2) Cases of increased bilirubin (at least 2 x ULN) with concurrent transaminase elevations at least 3x ULN and no 
evidence of intra- or extrahepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. 
[Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006 Apr;15(4):241-3.] 
 
 


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Follow-up Procedures 
Confirmed moderate and severe abnormalities in liver laboratory tests should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF) that has been developed globally and can be activated for any study or an 
appropriate document.  
Subjects with confirmed abnormal liver function testing should be followed up appropriately: 
Confirmed moderate and severe liver laboratory test abnormalities should be repeated 2-3 times 
weekly then weekly or less until the abnormalities have normalized or considered stabilized. 
Severe liver laboratory test abnormalities as defined above, in the absence of another etiology, 
may be considered an important medical event and may be reported as a Serious AE (SAE). The 
Sponsor should be contacted and informed of all subjects for whom severe liver laboratory test 
abnormalities possibly attributable to IMP are observed. 
To further assess abnormal liver laboratory test findings, the investigator is expected to:  
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms and 
new onset-diseases should be recorded as ‘AEs’ on the AE page of the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead to 
secondary liver abnormalities should be noted. Non-alcoholic steatohepatitis (NASH) is seen in 
obese hyperlipoproteinemic, and/or diabetic subjects and may be associated with fluctuating 
aminotransferase levels. The investigator should ensure that the medical history form captures 
any illness that pre-dates study enrollment that may be relevant in assessing hepatic function. 
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and special 
diets. Medications, including dose, should be entered on the concomitant medication page of the 
(e)CRF. Information on alcohol, other substance use, and diet should be entered on the LA-CRF 
or an appropriate document. 
Obtain a history of exposure to environmental chemical agents. Based on the subject’s history, 
other testing may be appropriate including: 
• acute viral hepatitis (A, B, C, D, E or other infectious agents) 
• ultrasound or other imaging to assess biliary tract disease 
• other laboratory tests including INR, direct bilirubin 
Consider gastroenterology or hepatology consultations.  
Submit results for any additional testing and possible etiology on the LA-CRF or an appropriate 
document. 
 
 


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Investigational Medicinal Product Discontinuation 
In the absence of an explanation for increased liver laboratory test abnormalities, such as viral 
hepatitis, pre-existing or acute liver disease or exposure to other agents associated with liver 
injury, the subject may be discontinued from the IMP. The investigator may determine that it is 
not in the subject’s best interest to continue study treatment. IMP is to be discontinued in case of 
any of the following abnormal liver laboratory tests in blood (see also section 5.3.1): 
• ALT >8 × ULN in any individual sample during the treatment period  
• ALT >3 x ULN if confirmed in a second sample within 24 hours AND in the second 
sample International Normalized Ratio (INR) is increased to >1.5 x ULN  
• ALT > 3 × 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) 
• ALT > 3 × ULN combined with total bilirubin > 2 × ULN in the same sample  
If IMP is discontinued, the subject will remain in the study to be evaluated until the EOS Visit 
(as much as possible) or complete the EOS visit assessments.  
 
Reference 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009. 
 
 
 
 


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APPENDIX 3. REQUISITE CLINICAL GUIDELINES AND 
GRADING SCALES 
 
KDIGO Guidelines for Grading Severity of Acute Kidney Injury 
Stage 
Serum Creatinine 
Urine Output 
1 
1.5–1.9 times baseline 
OR 
≥0.3 mg/dL (≥26.5 mmol/L) increase from baseline 
<0.5 mL/kg/h for 6–12 hours 
2 
2.0–2.9 times baseline 
<0.5 mL/kg/h for ≥12 hours 
3 
3.0 times baseline 
OR 
Increase in serum creatinine to ≥4.0 mg/dL (≥353.6 mmol/L) 
from baseline 
OR 
Initiation of RRT 
<0.3 mL/kg/h for ≥24 hours 
OR 
Anuria for ≥12 hours 
Abbreviation: RRT = renal replacement therapy. 
Adapted from (Khwaja 2012) 
 
 
New York Heart Association (NYHA) Functional Classification 
NYHA Grading 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure 
at rest. If any physical activity is undertaken, discomfort increases. 
Adapted from (Dolgin 1994) 
 
 
 


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The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) 
Guidelines 
Adapted from (Singer 2016): 
 
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to 
infection. Organ dysfunction can be identified as an acute change in total Sequential (Sepsis-
related) Organ Failure Assessment (SOFA) score ≥2 points consequent to the infection. 
 
Sequential [Sepsis-Related] Organ Failure Assessment (SOFA) Score a 
 
Score 
System 
0 
1 
2 
3 
4 
Respiration 
 
 
 
 
 
PaO2/FIO2, 
mmHg (kPa) 
≥400 (53.3) 
<400 (53.3) 
<300 (40) 
<200 (26.7) 
with respiratory 
support 
<100 (13.3) 
with respiratory 
support 
Coagulation 
 
 
 
 
 
Platelets, ×103/µL 
≥150 
<150 
<100 
<50 
<20 
Liver 
 
 
 
 
 
Bilirubin, mg/dL 
(µmol/L) 
<1.2 (20) 
1.2-1.9  
(20-32) 
2.0-5.9 
(33-101) 
6.0-11.9  
(102-204) 
>12.0  
(204) 
Cardiovascular 
MAP ≥70 mm 
Hg 
MAP <70 mm 
Hg 
Dopamine <5 
or 
dobutamine 
(any dose) b 
Dopamine 
5.1-15 
or epinephrine 
≤0.1 
or 
norepinephrine 
≤0.1 b 
Dopamine >15 
or 
epinephrine 
>0.1 
or 
norepinephrine 
>0.1 b 
Central nervous 
system 
 
 
 
 
 
Glasgow Coma 
Scale score c 
15 
13–14 
10-12 
6-9 
<6 
Renal 
 
 
 
 
 
Creatinine, mg/dL 
(µmol/L) 
<1.2 (110) 
1.2-1.9 
(110-170) 
2.0-3.4 
(171-299) 
3.5-4.9 
(300-440) 
>5.0 (440) 
Urine output, 
mL/d 
 
 
 
<500 
<200 
Abbreviations: FIO2, fraction of inspired oxygen; MAP, mean arterial pressure; PaO2, partial pressure of oxygen. 
a. Adapted from Vincent et al. 
b. Catecholamine doses are given as µg/kg/min for at least 1 hour. 
c. Glasgow Coma Scale scores range from 3–15; higher score indicates better neurological function. 
 


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The baseline SOFA score can be assumed to be zero in patients not known to have preexisting 
organ dysfunction. 
A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general hospital 
population with suspected infection. Even patients presenting with modest dysfunction can 
deteriorate further, emphasizing the seriousness of this condition and the need for prompt and 
appropriate intervention, if not already being instituted. 
In lay terms, sepsis is a life-threatening condition that arises when the body’s response to an 
infection injures its own tissues and organs. 
Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the 
hospital can be promptly identified at the bedside with qSOFA, ie, alteration in mental status, 
systolic blood pressure ≥100 mm Hg, or respiratory rate ≥22/min. 
Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic 
abnormalities are profound enough to substantially increase mortality. 
Patients with septic shock can be identified with a clinical construct of sepsis with persisting 
hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate 
level >2 mmol/L (18mg/dL) despite adequate volume resuscitation. With these criteria, hospital 
mortality is in excess of 40%. 
 
 
 


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APPENDIX 4. MEDICAL OUTCOMES STUDY (MOS) 36-ITEM 
SHORT FORM HEALTH SURVEY (SF-36) 
 
 
 


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Placehold 
 
 


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APPENDIX 5. EUROPEAN QUALITY OF LIFE 5 DOMAIN 5-
LEVEL SCORE (EQ-5D-5L) 
 
 
 


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Placehold 
 
 


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SAP_003.pdf: 
 
 
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A Phase 2, Randomized, Placebo-Controlled, Double-Blind, Adaptive, Parallel Group Clinical 
Study to Evaluate the Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute 
Kidney Injury Following Open-Chest Cardiac Surgery 
 
 
Protocol Number: 21-ROS-05 
Protocol Version: 3.1 
Protocol Date: 08 October 2022 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 2.0 
30 August 2023 
 


 
 
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A Phase 2, Randomized, Placebo-Controlled, Double-Blind, Adaptive, Parallel Group 
Clinical Study to Evaluate the Efficacy and Safety of RMC-035 in Subjects at  
High Risk for Acute Kidney Injury Following Open-Chest Cardiac Surgery 
 
STATISTICAL ANALYSIS PLAN 
Version 2.0 
 
 
 
Author: 
 
Danelle Staebler, MS  
 
 
 
 
Principal Biostatistician  
CTI  
 
 
 
 
 
 
CTI Biostatistics 
Reviewer: 
 
Rachael Gilbert Runyan, MS  
 
 
 
 
Assistant Director, Biostatistics 
CTI  
 
 
 
 
 
 
Sponsor Approval: Alberto Garcia Hernandez, MS 
 
 
 
 
 
 
Study Statistician 
 
 
 
Guard Therapeutics International AB  
 
 
 
 
 
 
Note that the last signature date is the effective date of the plan. 
 


 
 
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Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
CHANGES FROM PROTOCOL ................................................................................................ 9 
CHANGES FROM SAP V1 TO SAP V2 .................................................................................... 9 
1. 
INTRODUCTION ............................................................................................................... 19 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................... 19 
2.1 
Objectives ............................................................................................................................................... 19 
2.1.1 
Primary Objective ................................................................................................................................... 19 
2.1.2 
Key Secondary Objectives ...................................................................................................................... 19 
2.1.3 
Other Secondary Objectives ................................................................................................................... 19 
2.1.4 
Exploratory Objective ............................................................................................................................. 20 
2.2 
Endpoints ............................................................................................................................................... 20 
2.2.1 
Primary Endpoint ................................................................................................................................... 20 
2.2.2 
Key Secondary Endpoints ....................................................................................................................... 21 
2.2.3 
Other Secondary Endpoints .................................................................................................................... 21 
2.2.4 
Exploratory Endpoints ............................................................................................................................ 22 
3. 
INVESTIGATIONAL PLAN ............................................................................................. 23 
3.1 
Study Design .......................................................................................................................................... 23 
3.2 
Treatment .............................................................................................................................................. 24 
3.2.1 
Randomization Scheme and Treatment Arm Assignment ..................................................................... 25 
3.2.2 
Replacement of Subjects ........................................................................................................................ 25 
3.2.3 
Blinding .................................................................................................................................................. 25 
3.2.4 
Dosing Schedule ..................................................................................................................................... 26 
3.2.5 
Treatment Compliance........................................................................................................................... 26 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ........................................... 26 
4.1 
Analysis Quality Control Procedures ...................................................................................................... 27 
4.2 
Analysis Sets ........................................................................................................................................... 27 
4.3 
Assessment Windows............................................................................................................................. 27 
4.4 
Handling of Dropouts or Missing Data .................................................................................................. 29 
4.5 
Multiple Comparisons ............................................................................................................................ 29 
4.6 
Data Derivations and Transformations .................................................................................................. 29 
4.6.1 
Primary Efficacy Endpoint Considerations ............................................................................................. 32 
4.6.2 
Other Efficacy Endpoint Considerations ................................................................................................. 32 
5. 
STUDY SUBJECTS ............................................................................................................ 32 
5.1 
Disposition of Subjects ........................................................................................................................... 32 
5.2 
Protocol Deviations ................................................................................................................................ 33 
5.3 
Demographic and Baseline Characteristics ............................................................................................ 33 
5.4 
Medical History ...................................................................................................................................... 33 


 
 
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5.5 
Prior and Concomitant Medications ...................................................................................................... 33 
6. 
EFFICACY ANALYSIS ..................................................................................................... 33 
6.1 
Primary Efficacy Endpoint and Analysis ................................................................................................. 34 
6.1.1 
Supplementary Analyses of the Primary Endpoint ................................................................................. 34 
6.1.2 
Sensitivity Analyses of the Primary Endpoint ......................................................................................... 35 
6.2 
Key Secondary Efficacy Endpoints and Analyses .................................................................................... 35 
6.3 
Other Secondary Efficacy Endpoints and Analyses ................................................................................ 37 
6.4 
Exploratory Efficacy Endpoints and Analyses......................................................................................... 40 
6.5 
Subgroup Analysis .................................................................................................................................. 41 
7. 
SAFETY ANALYSIS .......................................................................................................... 41 
7.1 
Extent of Exposure ................................................................................................................................. 41 
7.2 
Adverse Events ....................................................................................................................................... 41 
7.2.1 
Treatment-emergent Adverse Events .................................................................................................... 42 
7.2.2 
Post-treatment Adverse Event ............................................................................................................... 42 
7.2.3 
Adverse Event Severity ........................................................................................................................... 42 
7.2.4 
Adverse Event Relationship to Study Medication .................................................................................. 43 
7.2.5 
Serious Adverse Events .......................................................................................................................... 43 
7.2.6 
Adverse Events of Special Interest ......................................................................................................... 43 
7.2.7 
Adverse Event Summaries ...................................................................................................................... 44 
7.3 
Clinical Laboratory Assessments ............................................................................................................ 46 
7.4 
Vital Signs .............................................................................................................................................. 46 
7.5 
ECG ......................................................................................................................................................... 47 
7.6 
Physical Examination ............................................................................................................................. 47 
8. 
SAMPLE SIZE AND POWER CALCULATIONS ......................................................... 47 
9. 
INTERIM ANALYSIS ........................................................................................................ 48 
9.1 
Conditional Power .................................................................................................................................. 49 
9.2 
Sample Size Readjustment ..................................................................................................................... 50 
9.3 
Alpha Level ............................................................................................................................................. 50 
9.4 
Conduct of Unblinded Interim Analysis .................................................................................................. 50 
10. BLINDING AND UNBLINDING ...................................................................................... 51 
10.1 
Blinded Statistician ................................................................................................................................ 51 
10.2 
Management of Accidental Unblinding ................................................................................................. 51 
10.3 
Unblinding for Analysis Purposes at the End of the Trial ....................................................................... 51 
11. REFERENCES .................................................................................................................... 51 
12. APPENDICES ...................................................................................................................... 52 
12.1 
APPENDIX A: SCHEDULE OF ASSESSMENTS ........................................................................................... 52 
12.2 
APPENDIX B: CKD-EPI CALCULATIONS.................................................................................................... 56 
12.3 
APPENDIX C: DOSING TABLES ................................................................................................................ 58 
12.3.1 Table C1: Volumes of IMP and diluent for dose level 1.3 mg/kg ........................................................... 58 


 
 
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12.3.2 Table C2: Volumes of IMP and diluent for dose level 0.65 mg/kg ......................................................... 61 
12.4 
APPENDIX D: eCRF DOCUMENTATION ................................................................................................... 64 
12.4.1 Table D1: Risk Factors ............................................................................................................................ 64 
12.4.2 Table D2: Inclusion/Exclusion Criteria .................................................................................................... 64 
12.5 
APPENDIX E: DERIVATION OF URINE OUTPUT ....................................................................................... 69 
12.6 
APPENDIX F: CONDITIONAL POWER ANALYSIS ...................................................................................... 73 
 
 


 
 
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LIST OF ABBREVIATIONS 
Abbreviation or Specialist 
Term 
Explanation 
8-OHdG 
8-hydroxy-2'-deoxyguanosine 
A1M 
Alpha-1-microglobulin 
ADA 
Anti-drug antibodies 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AKI 
Acute kidney injury 
ATC 
Anatomical, Therapeutic, and Chemical 
AUC 
Area under the curve 
BPM 
Beats per minute 
CABG 
Coronary artery bypass grafting 
CCL-14 
Chemokine ligand 14 
CDF 
Cumulative Distribution Function 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum (peak) concentration observed 
CP 
Conditional power 
CPB 
Cardiopulmonary bypass 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
cTnI 
Cardiac Troponin I 
cTnT 
Cardiac Troponin T 
ECG 
Electrocardiogram  
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
EQ-5D-5L 
European Quality of Life 5 Domain 5-Level Score 
GCP 
Good Clinical Practice 
GCV 
Geometric coefficient of variation 


 
 
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Abbreviation or Specialist 
Term 
Explanation 
GM 
Geometric mean 
GSD 
Geometric standard deviation 
h 
Hour(s) 
IA 
Interim analysis 
IBW 
Ideal Body Weight 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IGFBP7 
Insulin-like growth binding factor 7 
IL-18 
Interleukin-18 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IRR 
Infusion related reaction 
ISR 
Infusion site reaction 
ITT 
Intent to Treat 
IV 
Intravenous 
KDIGO 
Kidney Disease Improving Global Outcomes 
KIM-1 
Kidney injury molecule 1 
LFABP 
Liver fatty acid binding protein 
MAKE 
Major adverse kidney events 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
mITT 
Modified Intent to Treat 
MMRM 
Mixed model for repeated measurements  
MOS 
Medical outcomes study 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NSAID 
Non-steroidal anti-inflammatory drugs 
NT-pro-BNP 
N-terminal-pro-b-type natriuretic peptide 
PK 
Pharmacokinetic 


 
 
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Abbreviation or Specialist 
Term 
Explanation 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
PT 
Preferred term 
PTAE 
Post-treatment adverse event 
Q1 
First quartile 
Q2 
Second quartile (median) 
Q3 
Third quartile 
RRT 
Renal replacement therapy 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SCr 
Serum creatinine 
SD 
Standard deviation 
SF-36 
Medical Outcomes Study 36-Item Short Form Survey Instrument 
SOC 
System organ class 
SpO2 
Oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment emergent adverse event 
TESAE 
Treatment emergent serious adverse event 
TIMP2 
Tissue inhibitor of metalloproteinase 2 
UACR 
Urine albumin-to-creatinine ratio 
UPCR 
Urine protein-to-creatinine ratio 
UO 
Urine output 
VAS 
Visual analogue scale 
WHO 
World Health Organization 


 
 
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CHANGES FROM PROTOCOL 
Protocol Verbiage 
Modification 
Rationale 
The AUC will be calculated using the trapezoidal 
rule with the actual times the measurements are 
taken. 
The AUC will be calculated using the right 
Riemann sum with the dates/times the 
measurements are planned. 
Updated to be consistent 
with planned analysis.  
Section 6.3 
 
Endpoint: SCr, cystatin C, and eGFR at 12, 24, 48, 
and 72 hours, respectively, and at Day 7/discharge, 
Day 30, and Day 90 
 
Endpoint: Change from baseline, up to Day 
7/discharge, of peak SCr and cystatin C 
See changes outlined below in “Changes 
from SAP V1 to V2” 
 
Updated planned analysis. 
CHANGES FROM SAP V1 TO SAP V2 
Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
Introduction  
 
(Section 1) 
 
Original Verbiage: 
This document details the statistical methods planned to 
perform the interim and final analyses of the study. An 
interim sample-size re-assessment will be performed, 
during which subject enrollment will continue. Sample 
size may be increased to a maximum of 348 subjects 
dosed, but will not be decreased. 
Verbiage changed to: 
This document details the statistical 
methods planned to perform the final 
analyses of the study. An interim 
sample-size re-assessment was 
performed and it was determined to 
stop subject enrollment. Updates to 
SAP v2 reflect any changes from the 
original planned SAP v1 (e.g., data 
might be provided as opposed to 
generating a statistical analysis). 
Updated after 
determination to 
stop study 
enrollment. 
 
 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
Other Secondary 
Endpoints 
 
(Section 2.2.3) 
 
Original Verbiage: 
MAKE at Day 30 and Day 90, defined as death, any 
dialysis, or ≥25% reduction of estimated glomerular 
filtration rate (eGFR) compared to baseline using the 
Chronic Kidney Disease-Epidemiology Collaboration 
(CKD-EPI) equations (with either SCr, cystatin C, or 
both) 
 
Verbiage changed to: 
MAKE at Day 30 and Day 90, 
defined as death, any dialysis, or 
≥25% reduction of estimated 
glomerular filtration rate (eGFR) 
compared to baseline using the 
Chronic Kidney Disease-
Epidemiology Collaboration (CKD-
EPI) equations (with SCr, cystatin 
C, and both). 
 
Updated for 
clarification and to 
be consistent with 
planned analysis. 
General 
Considerations for 
Data Analysis  
 
(Section 4) 
 
Original Verbiage: 
CTI Clinical Trial and Consulting Services (Covington, 
KY) will perform all efficacy and safety statistical 
analyses described in this SAP. Mercodia AB will manage 
the pharmacokinetic (PK) portion of the study.  
Descriptive statistics of drug concentrations over time will 
be provided. 
 
Verbiage changed to: 
CTI Clinical Trial and Consulting 
Services (Covington, KY) will 
perform all efficacy and safety 
statistical analyses described in this 
SAP. Mercodia AB will manage the 
bioanalysis of pharmacokinetic (PK) 
measurements of the study and 
descriptive statistics of drug 
concentrations over time will be 
performed and provided by Clinical 
Trial Consultants AB. 
Updated for 
clarification and to 
be consistent with 
planned analysis. 
Table 1  
 
(Section 4.3) 
 
 
Addition of Visit Day 1 (Pre-Dose) 
and analysis visit windows. 
Updated for 
thorough listing of 
data. 
Actual Dose 
 
(Section 4.6) 
 
 
Updated definition of Actual Dose to 
encompass placebo as well as IMP. 
Updated for clarity 
in presentation of 
data. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
Demographic and 
Baseline 
Characteristics 
 
(Section 5.3) 
 
 
Added verbiage: 
Surgical details for the cardiac 
surgery include types and location of 
surgery, surgical duration, CPB 
details, and vital assessments will be 
summarized and listed as well. 
Updated to be 
consistent with 
planned analysis. 
Analysis for Other 
Secondary Endpoints: 
SCr, cystatin C, and 
eGFR at 12, 24, 48, 
and 72 hours, 
respectively, and at 
Day 7/discharge, Day 
30, and Day 90  
 
(Section 6.3) 
 
For SCr, cystatin C, and eGFR, robust regression will be 
utilized to determine the between-arm difference at each 
visit.  
The existing 3-phase multiple imputation approach 
detailed above will be re-used for this analysis. In the 
analysis step, AUC (dependent variable) will be replaced 
by either VAL1, VAL2, VAL3, VAL4, VAL5, VAL6, or 
VAL7 representing the missing-data-free log-transformed 
SCr or cystatin C values at Day 1 (12 hour), Day 2 (24 
hour), Day 3 (48 hour), Day 4 (72 hour), Day 7, Day 30, 
and Day 90. Imputed eGFR values will be calculated from 
the imputed SCr data, as well as the imputed cystatin C 
data. 
Between-arms differences of the Robust regression 
estimates will be averaged over imputations using Rubin's 
rules. Between-arms differences of the Robust regression 
estimates will be transformed back to the original scale 
using 100×(e(statistic)-1) and reported as geometric mean 
percent changes (RMC-035 vs. placebo). The estimate of 
the geometric mean percent change from baseline per arm, 
90% confidence interval (CI), and p-value will be 
reported. 
 
For SCr, cystatin C, and eGFR, 
descriptive statistics will be produced 
by analysis visit on the raw 
untransformed data. eGFR values will 
be calculated from the raw 
untransformed SCr data and cystatin 
C data. This summary will include all 
analysis visits including the screening 
and Day 1 (Pre-Operative) visit. 
Columns for actual values, changes 
from baseline, and percent change 
from baseline (calculated as 
100*(change/baseline)) will be 
included. Changes from baseline will 
be reported for all visits except 
screening. 
For SCr, cystatin C, and eGFR, robust 
regression will be utilized to 
determine the between-arm difference 
at each visit. The existing 3-phase 
multiple imputation approach detailed 
above will be re-used for this 
analysis. Imputed eGFR values will 
be calculated from the imputed SCr 
data, as well as the imputed cystatin C 
data. After imputation, all observed 
and imputed log-transformed SCr, 
Updated planned 
analysis. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
cystatin C, and eGFR values will be 
transformed back to the original scale. 
In the analysis step, AUC (dependent 
variable) will be replaced by either 
VAL1, VAL2, VAL3, VAL4, VAL5, 
VAL6, or VAL7 representing the 
missing-data-free SCr, cystatin C, or 
eGFR values at Day 1 (12 hour), Day 
2 (24 hour), Day 3 (48 hour), Day 4 
(72 hour), Day 7, Day 30, and Day 
90. The untransformed baseline 
values will be subtracted from the 
resulting values in order to obtain, for 
each subject, absolute changes from 
baseline to each of the 7 
aforementioned timepoints.  
The analysis phase will be therefore 
slightly different from that done for 
AUC in the sense that the model will 
be applied to the absolute change 
from baseline. The untransformed 
baseline values will be used as an 
independent variable. Between-arms 
differences of the Robust regression 
estimates will be averaged over 
imputations using Rubin's rules. The 
estimated mean change from baseline 
per arm and respective 90% CI and p-
value will be calculated. Additionally, 
the estimated between-arm difference 
will be calculated, along with the 
respective 90% CI and p-value. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
A sensitivity analysis will be 
performed using a mixed model for 
repeated measurements (MMRM) 
separately for each of the 
untransformed SCr, cystatin C, and 
eGFR values. The (untransformed) 
change from baseline values for Day 
1 (12 hour), Day 2 (24 hour), Day 3 
(48 hour), Day 4 (72 hour), Day 
7/Discharge, Day 30 & Day 90 will 
be modelled in the response vector. A 
14-level visit-by-treatment class 
variable and a 7-level visit-by-
screening and visit-by-pre-operation 
covariate will be included. In 
addition, region will be used as a 
fixed factor. For the sensitivity 
analysis only, subjects without a 
screening value will use the Day 1 
pre-operative value for screening. 
Additionally for the sensitivity 
analysis only, subjects without a Day 
1 pre-operative value will use the 
screening value for Day 1 pre-
operative. The estimated mean change 
from baseline per arm and respective 
90% CI and p-value will be 
calculated. Additionally, the 
estimated between-arm difference 
will be calculated, along with the 
respective 90% CI and p-value. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
Analysis for Other 
Secondary Endpoints: 
Change from baseline, 
up to Day 7/discharge, 
of peak SCr and 
cystatin C 
 
(Section 6.3) 
 
The results of the combined analyses of imputations 
completed with PROC MIANALZE above will be utilized 
for this analysis.  
 
The raw untransformed data will be 
utilized for this analysis. The 
dependent variable is peak change 
from baseline (peak value-baseline 
value). The untransformed baseline 
values will be used as an independent 
variable, as well as region. The 
estimated between-arm difference 
will be calculated, along with the 
respective 90% CI and p-value. 
Updated planned 
analysis. 
Analysis for Other 
Secondary Endpoint: 
MAKE by Day 30 and 
90  
 
(Section 6.3) 
 
• Any dialysis BY Day X; or 
• A ≥25% reduction of estimated glomerular filtration rate 
(eGFR) BY Day X compared to baseline using the 
Chronic Kidney Disease-Epidemiology Collaboration 
(CKD-EPI) equations 
• Any dialysis THROUGH Day X; 
or 
• A ≥25% reduction of estimated 
glomerular filtration rate (eGFR) 
ON Day X compared to baseline 
using the Chronic Kidney Disease-
Epidemiology Collaboration (CKD-
EPI) equations 
Updated for 
clarification and 
to be consistent 
with planned 
analysis. 
Analysis for Other 
Secondary Endpoint: 
MAKE by Day 30 and 
90  
 
(Section 6.3) 
 
 
Added verbiage: 
A sensitivity analysis utilizing the 
alternative definition of MAKE X 
will be performed as described above, 
where the alternative definition 
utilizes cystatin C only. A second 
sensitivity analysis utilizing the 
alternative definition of MAKE X 
will be performed as described above, 
where the alternative definition 
utilizes SCr and cystatin C. See 
Appendix B for the three calculations.  
Updated for 
clarification and 
to be consistent 
with planned 
analysis. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
Analysis for Other 
Secondary Endpoint: 
Post-baseline changes 
in urine albumin to 
creatinine ratio 
(UACR) and urine 
protein to creatinine 
ratio (UPCR) at Day 
4, Day 30, and Day 90 
 
(Section 6.3) 
Original SAP Verbiage: 
 
This endpoint will be analyzed as described in Section 6.2 
for the key secondary AUC endpoint. 
 
Removed original SAP verbiage and 
replaced with:  
 
The data will be reported separately. 
Updated after 
determination to 
stop study 
enrollment and to 
discontinue 
collection of 
UACR/UPCR 
values. 
Exploratory Endpoint: 
Pharmacokinetics of 
RMC-035 in plasma 
(AUC and Cmax)  
 
(Section 6.3) 
Original Verbiage: 
 
Mercodia AB will manage the pharmacokinetic portion of 
the study.  Descriptive statistics of drug concentrations 
over time will be provided. 
Verbiage changed to: 
 
Mercodia AB will conduct 
bioanalysis of PK samples with PK 
parameters and reporting carried out 
by CTC.  Descriptive statistics of 
drug concentrations over time will be 
provided by dose group and by renal 
function at baseline. 
 
Updated to be 
consistent with 
planned analysis. 
Appendix B 
 
Addition of Appendix B: CKD-EPI 
CALCULATIONS 
Updated for 
clarity. 
Appendix C 
 
Moved Appendix B (DOSING 
TABLES) to Appendix C 
Updated for 
inclusion of other 
appendices.  
Appendix D 
 
Addition of Appendix C: eCRF 
Documentation. Appendix C includes 
a table for Risk Factors and 
Inclusion/Exclusion criteria 
Updated for 
clarity. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
Appendix E 
 
Moved Appendix C (Derivation of 
Urine Output) to Appendix E 
Updated for 
inclusion of other 
appendices  
Appendix F 
 
Moved Appendix D (Sample Size 
Assessment Utilizing Primary 
Endpoint (AKI)) to Appendix F 
Updated for 
inclusion of other 
appendices  
Exploratory Endpoint: 
Presence and titers of 
ADA at Day 1 (pre-
surgery), Day 30, and 
Day 90  
 
(Section 6.3) 
Original SAP Verbiage: 
Summary tables will be provided, including a shift table 
for presence of ADA between Visit 2 (Day 1/pre-dose) 
and Visits 7 (Day 30) and 8 (EOS). ADA samples 
obtained beyond the protocol specified time window for 
Visits 7 and 8 will be accepted. For ADA evaluation, 
presence of ADA at a visit will be defined as follows: 
Presence of ADA at a visit is negative if: 
• Initial result is reported as negative, or 
• Initial result is reported as positive and confirmatory 
result is reported as negative 
Presence of ADA at a visit is positive if: 
• 
Both initial and confirmatory result is reported as 
positive 
If the confirmatory result is missing, presence of ASA will 
be identical to the initial reported result. Otherwise, 
presence of ASA will not be evaluable. 
Removed original SAP verbiage and 
replaced with:  
Presence and titers of ADA and ADA 
characterization will be reported 
separately 
Updated after 
determination to 
stop study 
enrollment. 
Exploratory Endpoint: 
Index ICU stay (in 
Days)  
 
Original SAP Verbiage: 
 
Removed original SAP verbiage and 
replaced with:  
 
Data will be presented separately. 
Updated after 
determination to 
stop study 
enrollment. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
(Section 6.3) 
Descriptive statistics (n, mean, standard deviation, Q1, 
median, Q3, minimum, maximum) will be displayed by 
treatment group. 
Exploratory Endpoint: 
Index hospital stay (in 
Days)  
 
(Section 6.3) 
Original SAP Verbiage: 
 
Descriptive statistics (n, mean, standard deviation, Q1, 
median, Q3, minimum, maximum) will be displayed by 
treatment group. 
Removed original SAP verbiage and 
replaced with:  
 
Data will be presented separately. 
Updated after 
determination to 
stop study 
enrollment. 
Exploratory Endpoint: 
Nature of subject 
discharge facility  
 
(Section 6.3) 
Original SAP Verbiage: 
 
Descriptive statistics (n, mean, standard deviation, Q1, 
median, Q3, minimum, maximum) will be displayed by 
treatment group. 
Removed original SAP verbiage and 
replaced with:  
 
Data will be presented separately. 
Updated after 
determination to 
stop study 
enrollment. 
Exploratory Endpoint: 
Change from baseline 
to Day 90 for Medical 
Outcomes Study 
(MOS) 36-Item Short 
Form Survey 
Instrument (SF-36)  
 
(Section 6.3) 
Original SAP Verbiage: 
 
SF-36 includes one multi-item scale that assesses eight 
health concepts with two summary measures and is an 
indicator of overall health status. Lower scores indicate 
more disability and higher scores indicate less disability.  
Total scores (by eight health concepts, two summary 
measures, and overall) will be summarized by treatment 
group and analysis visit. Actual values and changes from 
baseline will be tabulated separately. All total scores and 
sub-scale scores will be listed. 
Removed original SAP verbiage and 
replaced with:  
 
These parameters will be reported 
separately. 
Updated after 
determination to 
stop study 
enrollment. 
Exploratory Endpoint: 
Change from baseline 
to Day 90 for 
European Quality of 
Life 5 Domain 5-
Level Score (EQ-5D-
5L) 
EQ-5D-5L is a health-related quality of life measurement 
and consists of five dimensions, and each dimension has 
five response levels.   
Descriptive statistics (frequency and proportions) by 
domain (5 questions), and treatment group will be 
Removed original SAP verbiage and 
replaced with:  
 
These parameters will be reported 
separately. 
Updated after 
determination to 
stop study 
enrollment. 


 
 
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Endpoint or Variable SAP Verbiage 
Modification 
Rationale 
 
(Section 6.3) 
displayed, as well as a shift table. All responses will be 
listed. 
Exploratory Endpoint: 
The European Quality 
Visual Analog Scale 
(VAS) 
 
(Section 6.3) 
Original SAP Verbiage: 
 
VAS is a quantitative measure of health outcome that 
reflect the subject’s own judgement. A number between 0-
100 is selected, where 100 is “the best health you can 
imagine” and 0 is “the worst health you can imagine”.  
For the 0-100 VAS, descriptive statistics (n, mean, 
standard deviation, Q1, median, Q3, minimum, maximum) 
will be displayed by treatment group for actual value and 
change from baseline. Scores will be listed. 
Removed original SAP verbiage and 
replaced with:  
 
These parameters will be reported 
separately. 
Updated after 
determination to 
stop study 
enrollment. 
Subgroup Analysis 
 
(Section 6.5) 
 
Removed verbiage: 
 
If at least 20 subjects have a history 
of diabetes, the history of diabetes 
(yes/no) will be included in the 
subgroup analysis as well. 
Updated to be 
consistent with 
planned analysis. 
 


 
 
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1. INTRODUCTION 
Acute Kidney Injury (AKI) is a clinical syndrome characterized by rapid loss of renal function 
and is associated with increased morbidity and short and long-term mortality. This study is being 
conducted to provide proof-of-concept efficacy data and provide targeted protection against 
oxidative stress and heme toxicity in this patient population, with the aim to prevent or 
ameliorate post-surgery renal injury. 
This statistical analysis plan (SAP) is based on Protocol 21-ROS-05, titled “A Phase 2, 
Randomized, Placebo-Controlled, Double-Blind, Adaptive, Parallel Group Clinical Study to 
Evaluate the Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury 
Following Open-Chest Cardiac Surgery”. See the study protocol for full details.  
This document details the statistical methods planned to perform the final analyses of the study. 
An interim sample-size re-assessment was performed and it was determined to stop subject 
enrollment. Updates to SAP v2 reflect any changes from the original planned SAP v1 (e.g., data 
might be provided as opposed to generating a statistical analysis). 
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
The primary objectives of this study are: 
• To evaluate the efficacy of RMC-035 for prevention of AKI (Kidney Disease Improving 
Global Outcomes [KDIGO] definition) in subjects undergoing coronary artery by-pass graft 
(CABG) and/or valve surgery and/or aorta surgery with additional risk factors for developing 
cardiac surgery associated AKI 
• To evaluate the safety and tolerability of RMC-035  
2.1.2 
Key Secondary Objectives 
The key secondary objectives of this study are: 
• To evaluate RMC-035 for the prevention of post-operative decline (within 72 hours) in renal 
function  
• To evaluate RMC-035 for the reduction of post-operative AKI duration  
2.1.3 
Other Secondary Objectives 
The other secondary objectives of this study are: 
• To evaluate RMC-035 for preserving post-surgery renal function up to Day 90 
• To evaluate RMC-035 for the prevention of post-operative dialysis up to Day 90 


 
 
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• To evaluate RMC-035 for the prevention of major adverse kidney events (MAKE) at Days 
30 and 90, respectively 
• To further evaluate RMC-035 for the  
o Prevention of AKI within 72 hours (based on cystatin C and/or Urine Output [UO]) 
o Persistence and severity of AKI within 72 hours (based on serum creatinine [SCr] 
and/or UO or cystatin C and/or UO) 
o Prevention, persistence, and severity of AKI within 7 days (based on SCr and/or UO 
or cystatin C and/or UO) 
• To evaluate RMC-035 for reducing post-operative albuminuria and proteinuria up to Day 90 
• To evaluate the pharmacokinetics of RMC-035  
• Identification and characterization of anti-drug-antibodies (ADA) developed after 
intravenous administration of RMC-035 
2.1.4 
Exploratory Objective 
The exploratory objectives of this study are: 
• To evaluate post-baseline changes in kidney and cardiac biomarkers 
• To evaluate changes in immunologic biomarkers 
• To evaluate the length of post-operative stay in Intensive Care Unit (ICU) and overall 
hospitalization time 
• To evaluate health-related Quality of Life 
2.2 
Endpoints 
2.2.1 
Primary Endpoint 
The primary efficacy endpoint is: 
• AKI within 72 hours after first dose of IMP based on SCr and/or UO (AKI of any 
stage/severity according to KDIGO definition), where severity of AKI defined as the 
following:  
o 
Stage 1: SCr 1.5 to 1.9 times baseline within 7 days, OR ≥0.3 mg/dL (≥26.5 µmol/L) 
OR urine output <0.5 mL/kg/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/kg/h for 
≥12 hours 
o 
Stage 3: SCr 3.0 times baseline within 7 days, OR increase in SCr 4.0 mg/dL (≥353.6 
µmol/L), OR initiation of renal replacement therapy OR urine output <0.3 mL/kg/h for 
≥24 hours OR anuria for ≥12 hours 
The primary safety endpoint is: 
• Nature, frequency, and severity of treatment-emergent adverse events (TEAEs) 


 
 
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2.2.2 
Key Secondary Endpoints 
The key secondary endpoints of the study are: 
• Time-corrected area under the curve (AUC) of SCr for Day 1 to Day 4 (72 hours after first 
dose of IMP) 
• Duration of AKI defined as the number of days meeting the definition of AKI (KDIGO 
definition) starting within 72 hours after first dose of IMP until resolution  
2.2.3 
Other Secondary Endpoints 
The other secondary endpoints of the study are:  
• Post-baseline changes in renal function  
• SCr, cystatin C, and eGFR (both calculated using SCr and cystatin C) at 12, 24, 48, 
and 72 hours, respectively, and at Day 7/discharge, Day 30 and Day 90 
• Change from baseline, up to Day 7/discharge, of peak SCr and cystatin C 
• Time-corrected AUC of Cystatin C for Day 1 to Day 4 (72 hours after first dose of 
IMP) 
• Need for renal replacement therapy 
• Dialysis treatment (for any reason) within 72 hours and within 7 days after end of 
surgery  
• Dialysis-free days from end of surgery to Day 30 and Day 90, respectively  
• MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of estimated 
glomerular filtration rate (eGFR) compared to baseline using the Chronic Kidney Disease-
Epidemiology Collaboration (CKD-EPI) equations (with SCr, cystatin C, and both) 
• AKI Characteristics 
• AKI within 72 hours after first dose of IMP based on cystatin C and/or UO (AKI of 
any stage/severity defined as cystatin C ≥1.5 baseline, OR UO <0.5 mL/kg/h for ≥6 
hours) 
• AKI within 7 days after first dose of IMP (based on SCr and/or UO criteria, or 
cystatin C and/or UO criteria)  
• AKI persistence, defined as an AKI (KDIGO definition) developing within 72 hours 
after first dose of IMP and with a duration of ≥72 hours. Persistence will also be 
assessed per AKI severity stage*   
• AKI severity stage* within 72 hours and within 7 days after first dose of IMP  
 *Severity of AKI defined as the following:  
• Stage 1: SCr 1.5 to 1.9 times baseline within 7 days, OR ≥0.3 mg/dL 
(≥26.5 µmol/L) OR urine output <0.5 mL/kg/h for 6 to <12 hours 
• Stage 2: SCr 2.0-2.9 times baseline within 7 days OR urine output 
<0.5 mL/kg/h for ≥12 hours 


 
 
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• Stage 3: SCr 3.0 times baseline within 7 days, OR increase in SCr 4.0 
mg/dL (≥353.6 µmol/L), OR initiation of renal replacement therapy 
OR urine output <0.3 mL/kg/h for ≥24 hours OR anuria for ≥12 hours 
• Post-baseline changes in urine albumin to creatinine ratio (UACR) and urine protein to 
creatinine ratio (UPCR) at Day 4, Day 30, and Day 90 
• Pharmacokinetics of RMC-035 in plasma (AUC and Cmax) 
• Presence and titers of ADA at Day 1 (pre-surgery), Day 30, and Day 90 
• Characteristics of ADA developed at Day 30 and Day 90 with regards to isotype, neutralizing 
capacity, and cross-reactivity with endogenous alpha-1-microglobulin (A1M) 
2.2.4 
 Exploratory Endpoints 
The exploratory endpoints for post-baseline changes in kidney and cardiac biomarkers are: 
• Kidney Biomarkers: Urine kidney injury molecule 1 (KIM-1), neutrophil gelatinase-
associated lipocalin (NGAL), tissue inhibitor of metalloproteinase 2 (TIMP2), insulin-like 
growth binding factor protein 7 (IGFBP7), chemokine ligand 14 (CCL-14), interleukin-18 
(IL-18), liver fatty acid binding protein (LFABP) and 8-hydroxy-2'-deoxyguanosine (8-
OHdG) 
• Cardiac Biomarkers: Plasma N-terminal-pro-hormone BNP (NT-pro-BNP) and cardiac 
troponin I and T (cTnI, cTnT) 
 
The exploratory endpoint for changes in immunologic biomarkers is: 
• Immunologic biomarkers to explore the background and mechanism of potential IRRs 
including, but not limited to, markers of complement activation, cytokine release, and mast 
cell activation.  
 
The exploratory endpoints for hospitalization time and discharge facility are: 
• Length of index ICU stay and index hospital stay 
• 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  
• Index hospital stay (in Days) is defined as the duration of stay in the hospital from the 
day of surgery to hospital discharge for the index surgery  
• Nature of subject discharge facility (e.g., home, skilled nursing facility, rehabilitation center) 
 
The exploratory endpoints for health-related Quality of Life assessments are: 
• Change from baseline to Day 90 in the following Patient Reported Outcomes (PROs): 
• Medical Outcomes Study (MOS) 36-Item Short Form Survey Instrument (SF-36) 
• European Quality of Life 5 Domain 5-Level Score (EQ-5D-5L) 


 
 
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3. INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a Phase 2, randomized, double-blind, adaptive, parallel group clinical study that will 
evaluate RMC-035 compared to placebo in approximately 268 subjects at high risk for AKI 
following open-chest cardiac surgery (based on predefined risk factors). An interim sample-size 
re-assessment will be performed, during which subject enrollment will continue. The study 
consists of 8 visits for each subject with four study periods: 
• Screening Period: 30 days (Day-30 to -1)  
• Treatment Period: 3 days (Day 1-3)  
• Follow-Up Period: 27 days (Day 4-30)  
• Extended Follow-Up Period: 60 days (Day 31-90) 
 
A short overview for study schedule is in Figure 1. 
Figure 1: Study Flow Chart 
V1 (Rx)
(D-1)
V2 
(D1)
V3
(D2)
V4 (EOT)
(D3)
V5
(D4)
V6 (hospital discharge)
(D7)
V7 
(D30)
SCREENING
TREATMENT
FOLLOW-UP (87 days)
V8 (EOS)
(D90)
ICU stay 
Hospital stay  
AE Collection  
SAE Collection   
Study visit 
PK and/or laboratory assessments
EOS = end of study 
EOT = end of treatment 
Rx = randomization 
RMC-035 administration
Cardiac surgery
Primary endpoint evaluation
 
Eligible subjects who comply with all inclusion criteria and none of the exclusion criteria (refer 
to study protocol for details) will be randomized on Day -1, Visit 1 to receive either RMC-035 or 
placebo in a 1:1 randomization ratio. Both region (North America and Europe) and Day -1 eGFR 
calculated using local laboratory results (≥60 and <60 mL/min/1.73m2) will be used as 
stratification factors to ensure a balanced randomization within these groups. 


 
 
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Surgery will occur on Day 1 (Visit 2). The first administration of IMP will be given during 
surgery, to be started approximately 10 minutes before the expected initiation of 
cardiopulmonary bypass (CPB), as an IV infusion. The start time of the first infusion is time 0, 
the reference point for further dose administrations and protocol-mandated assessments. In total, 
5 doses of RMC-035 or matching placebo will be administered during the treatment period. 
Administration of subsequent IV infusions start at 6, 12, 24 and 48 hours, respectively, after the 
start of the first dose administration.  
IMP will be administered per the schedule below:  
• The first (0h) and second (6h) doses are administered as IV infusions over 60 minutes 
• The third (12h), fourth (24h) and fifth (48h) doses are administered as IV infusions 
over 30 minutes 
At a minimum, all subjects will remain hospitalized for the first 72 hours post-surgery (until 
completion of Visit 5). Subjects will initially be followed up for one month after surgery until the 
next study visit (Day 30, Visit 7). A final study visit will be conducted at 3 months (Day 90) 
after surgery (Visit 8, End of Study [EOS]). Upon completion of all EOS visit procedures, 
subjects will have completed the study. 
See Appendix A for the Schedule of Assessments. 
3.2 
Treatment 
The IMPs for this study are RMC-035 or matching placebo. RMC-035 6.0 mg/mL Concentrate 
for Solution for Infusion (RMC-035) contains the pharmacologically active protein RMC-035, a 
recombinant variant of endogenous human A1M. The formulation of the matching placebo is 
identical to RMC-035 except that it contains no active ingredient. 
Dose levels of IMP will be predefined based on renal function (eGFR calculated using the CKD-
EPI equation with SCr) at screening (Day -1): 
• Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the 
first and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth, and 
fifth dose  
• Subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) 
for all 5 doses 
The start time of the first infusion of IMP is time 0, the reference point for further dose 
administrations. In total, 5 doses of IMP or matching placebo will be administered during the 
treatment period. Administration of subsequent IV infusions will start at 6, 12, 24, and 48 hours, 
respectively, after the start of the first dose administration.  
The first (0h) and second (6h) dose are administered as IV infusions over 60 minutes. The third 
(12h), fourth (24h) and fifth (48h) doses are administered as IV infusions over 30 minutes.  


 
 
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3.2.1 
Randomization Scheme and Treatment Arm Assignment 
Each subject who enters the screening period, which starts when the subject signs the ICF, will 
receive a unique subject identification number. This number will be used to identify the subject 
throughout the study and must be used on all study documentation related to the subject.  
Eligible subjects will be randomized prior to surgery to receive either RMC-035 or placebo  
in a 1:1 randomization ratio using a centralized randomization process. Both region (North 
America and Europe) and Day -1 eGFR calculated using local laboratory results (≥60 and 
<60 mL/min/1.73m2) will be used as stratification factors to ensure a balanced randomization 
within these groups. 
Approximately 30 centers located in North America and Europe will participate in this study. 
During the conduct of the study, additional regions, countries, or sites may be added, as 
necessary. 
A central randomization system, Medidata Rave Randomization & Trial Supply Management 
(RTSM)®, will be used for this study. 
3.2.2 
Replacement of Subjects 
Subjects who are randomized but do not receive the first dose of IMP may be replaced; these 
subjects (randomized but not dosed) will be followed for safety and for the following endpoints: 
• AKI within 72 hours after the first dose of IMP (Visit 4, EOT) 
• Time-corrected AUC of SCr for Day 1 to Day 4 (72 hours after first dose of IMP) 
• MAKE at Day 30 (Visit 7) and Day 90 (Visit 8, EOS) 
Additional assessments are not required to be collected. 
Subjects included to replace others will be randomized (i.e., may not be automatically allocated 
to the same arm to the replaced subject). 
Any subject receiving at minimum the first dose of IMP will not be replaced. 
3.2.3 
Blinding 
RMC-035 Concentrate for Solution for Infusion and placebo are filled in glass vials and 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. 
The Investigator, study personnel, and subject will be blinded to the identity of the IMP  
(RMC-035 or placebo). The investigational pharmacist will be responsible for the preparation  
of IMP for each subject and will be unblinded to the randomization assignment. 
The treatment code for a given randomized subject will be provided in the event of a medical 
emergency requiring knowledge of the treatment assigned to the subject. The time, date, subject 
number and reason for obtaining any of these codes, and therefore breaking the blind, must be 
documented in the study file. The treatment code can only be requested by the Investigator or 
other persons designated as sub-investigators. No subjects or other study personnel will be made 
aware of the treatment given unless a medical emergency necessitates such disclosure. 


 
 
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Except for determining whether a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
requires expedited reporting to regulatory authorities, unblinding of the study medication should 
only be considered for subject safety or when critical therapeutic decisions are contingent upon 
knowing the blinded IMP assignment. Any unblinding by the investigational staff must be 
reported immediately to the Sponsor or designee and must include an explanation of why the 
study medication was unblinded. If possible, the Sponsor and/or designee should be contacted 
prior to unblinding of the study medication. 
3.2.4 
Dosing Schedule 
Surgery will occur on Day 1 (Visit 2). The first administration of Investigational Medicinal 
Product (IMP: RMC-035 or Placebo) will be given during surgery, approximately 10 minutes 
before the expected initiation of cardiopulmonary bypass (CPB), as an intravenous (IV) infusion. 
The start time of the first infusion is time 0, the reference point for further dose administrations 
and protocol-mandated assessments. In total, 5 doses of IMP will be administered during the 
treatment period. Administration of subsequent IV infusions start at 6, 12, 24, and 48 hours, 
respectively, after time 0 (start of the first dose).  
Administration of RMC-035 or placebo:  
• The first (0h) and second (6h) doses are administered as IV infusions over 60 minutes 
• The third (12h), fourth (24h), and fifth (48h) doses are administered as IV infusions over 
30 minutes  
Due to the pharmacokinetics of RMC-035, the predefined dose levels (prior to surgery), are 
based on renal function (eGFR by CKD-EPI equation with SCr) at screening (Day -1, Visit 1): 
• Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first 
and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth, and fifth dose  
• 
Subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for 
all five doses  
3.2.5 
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 CRF. 
4. GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
Apart from the interim results, the analysis will be done upon study completion and database 
lock.  
All continuous data will be summarized using N, mean, standard deviation (SD), first quartile 
(Q1), median (Q2), third quartile (Q3), minimum, and maximum value. Summary statistics for 
categorical variables will contain count and percentage. For log-normal endpoints, geometric 
mean (GM), geometric standard deviation (GSD), and geometric coefficient of variation (GCV) 
will also be produced. Summary results will be provided for each treatment group. All 


 
 
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tabulations will be based on pooled data across centers. 
All statistical tests will be two-sided and tested at the 10% level of significance. If required, the 
nominal alpha level for the final analysis of the primary endpoint will be adjusted using Equation 
(11) of Mehta and Pocock (2009) as detailed in Section 9.3. 
Analyses will be performed using SAS® software for Windows, version 9.4 or higher (SAS, 
Cary, NC), except where other software may be deemed more appropriate. 
Subject data will be listed, sorted by treatment group, and subject number. When applicable, 
listings will be additionally sorted by visit and assessment date/time. 
CTI Clinical Trial and Consulting Services (Covington, KY) will perform all efficacy and safety 
statistical analyses described in this SAP. Mercodia AB will manage the bioanalysis of 
pharmacokinetic (PK) measurements of the study and descriptive statistics of drug 
concentrations over time will be performed and provided by Clinical Trial Consultants AB. 
4.1 
Analysis Quality Control Procedures 
Once all the source verification is complete, all queries are resolved, and the database has been 
updated appropriately, the database will be locked and made available to CTI Biostatistics for 
final analysis.  
Data may be pulled by CTI Biostatistics for the interim analysis at a time when source 
verification and query resolution is ongoing. 
All SAS programs used to create analysis data sets, tables, and listings are double programmed. 
The SAS outputs will be compared, and the programs will be updated until the outputs match.  
4.2 
Analysis Sets 
The Intent to Treat (ITT) set will consist of all randomized subjects. 
The Modified Intent to Treat (mITT) set will consist of all subjects in the ITT set who received at 
least 1 dose of IMP. The mITT set will be used for the primary analysis of efficacy endpoints. 
Subjects will be included in the efficacy analysis based on randomized treatment group.  
The Safety Analysis (SAF) set will consist of all subjects in the mITT set; however, subjects will 
be included in the analysis based on treatment actually received.  
The Per Protocol (PP) set will consist of all subjects in the mITT set who did not have any major 
protocol deviations or other conditions (e.g., insufficient exposure) that were judged to influence 
the efficacy analysis. Prior to database lock, subjects who had a major protocol deviation will be 
identified in a blinded manner by the study team. 
The PK Analysis (PK) set will be used for the PK evaluation and will consist of all randomized 
subjects with no relevant protocol deviations affecting the evaluation of the PK parameters. 
4.3 
Assessment Windows 
SAP analysis visit windows will be constructed for data collected at protocol specified visits 
after the first dose of IMP administration. The analysis visit windows are wider than the 
protocol-defined visit windows to ensure inclusion of data points in the analysis. The date and 


 
 
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time of data collection will be used to determine the analysis visit window relative to the date 
and time of the first dose of IMP. Table 1 shows the post-baseline analysis visit windows. 
Relative days in the study (ADY) will be calculated according to the following rule: 
• Concerned date < reference date: ADY = concerned date – date of 1st IMP administration 
• Concerned date ≥ reference date: ADY = concerned date – date of 1st IMP administration + 1 
Per parameter and analysis window, the value closest to the target relative day will be used in 
analysis tables, other values will only be listed. If more than one value is located at the same 
distance from the target, then the latest in time will be selected. 
Table 1: Analysis Visit Windows  
Visit 
Target 
Analysis Visit Window 
 
 
Lower limit 
Upper limit 
Day 1 (Pre-dose)1 
Day 1 prior to start of 
1st IMP 
administration 
Day of 1st IMP 
administration at 
00:00 
Day/time prior to 
start of 1st IMP 
administration 
Day 1 (12h) 
12 hours after 1st IMP 
administration 
6 hours after 1st IMP 
administration  
<18 hours after 1st 
IMP administration 
Day 2 (24h) 
ADY = 2 
(24 hours after 1st 
IMP administration) 
18 hours after 1st IMP 
administration 
<36 hours after 1st 
IMP administration 
Day 3 (48h) 
ADY = 3 
(48 hours after 1st 
IMP administration) 
36 hours after 1st IMP 
administration  
<60 hours after 1st 
IMP administration 
Day 4 (72h) 
ADY = 4 
(72 hours after 1st 
IMP administration) 
60 hours after 1st IMP 
administration 
96 hours after 1st 
IMP administration 
Day 7 
ADY = 7 
ADY = 5 
ADY = 9 
Discharge 
No window 
Day 30 
ADY = 30 
ADY = 23 
ADY = 37 
Day 90 
ADY = 90 
ADY = 83 
ADY = 97 
Assessments with a date associated with relative days (ADY) 2, 3, and 4 without a time will also 
be assigned to Day 2, 3 and 4 visits if no other assessment with both date and time have assigned 
 
1 This visit is only to be used in the descriptive analysis of SCr and cystatin C (and corresponding eGFR values) 
over time 


 
 
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to that visit. If there are multiple assessments with the same relative days and no time, the 
average will be used. 
The data collected at the visit “Discharge” will be summarized in two ways. First, the data will 
be summarized with the CRF visit “Discharge”. Second, this visit will be remapped to an 
analysis visit based on the date and time of collection.  
For analysis endpoints with cutoff values (e.g., AKI within 72 hours), the windows will not be 
used at the cutoff value (i.e., AKI within 72 hours, not 96 hours).  
4.4 
Handling of Dropouts or Missing Data 
Missing demographic, baseline information, and safety data will be treated as missing; no 
method for imputation is planned. 
Details of any missing data imputation or sensitivity analyses will be specified in the analysis 
methods for each of the efficacy endpoints, described in Section 6. 
4.5 
Multiple Comparisons 
No adjustment for multiplicity will be performed. 
4.6 
Data Derivations and Transformations 
The following derivations will be used in this study: 
Study Day: date of assessment – date of first dose of IMP (+1 for assessments done on or after 
date of first date of IMP). 
Baseline Observation: the last non-missing value prior to IMP administration.  
Note baseline samples for serum creatinine and cystatin C will be collected at Day -1 (screening) 
for central laboratory analysis which will provide the baseline values for the purpose of relevant 
endpoint assessments. Only if the value at screening is missing, the definition above will be used. 
Change from baseline: assessment result at specific post-dose timepoint – baseline assessment 
result. 
Ideal body weight (IBW): 
• Males: IBW = 50kg + (0.91kg x number of centimeters [cm] over 1.52m) 
• Females: IBW = 45.5kg + (0.91kg x number of centimeters [cm] over 1.52m) 
Time-corrected area under the curve (AUC): the area under the SCr [or cystatin C] concentration 
versus time curve following drug administration will be calculated using timepoints at Day 1 (12 
hour), Day 2 (24 hour), Day 3 (48 hour) and Day 4 (72 hour). The individual log-transformed 
SCr [or cystatin C] values will be determined, and the AUC (utilizing planned times) will be 
calculated using the right Riemann sum. The formula for the right Riemann sum is: 
𝐴𝐴= ෍
∆𝑥𝑥𝑖𝑖𝑓𝑓(𝑥𝑥𝑖𝑖)
𝑛𝑛
𝑖𝑖=1
 
 


 
 
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where ∆𝑥𝑥𝑖𝑖 is the width of each of the 𝑛𝑛 rectangles (0.5, 1, and 1, respectively) and 𝑓𝑓(𝑥𝑥𝑖𝑖) is the 
height at the right endpoint of its base, or  
A = 0.5 x SCr(12h) + 0.5 x SCr(24h) + 1 x SCr(48h) + 1 x SCr(72h) 
The time-corrected AUC (log-scale) is calculated as AUC/3. 
Geometric calculations: 
• Geometric mean (GM) is calculated as exp(m), where m is the arithmetic mean of the log-
transformed data. 
• Geometric standard deviation (GSD) is calculated as exp(s), where s is the standard 
deviation of the log-transformed data. 
• Geometric coefficient of variation (GCV) is calculated as ඥexp(𝑠𝑠2) −1, where s is the 
standard deviation of the log-transformed data. 
 
Estimate glomerular filtration rate (eGFR): this will be calculated utilizing the Chronic Kidney 
Disease-Epidemiology Collaboration (CKD-EPI) equation for SCr, Cystatin C, and SCr, and 
Cystatin C. Refer to Appendix B for further information.  
 
Actual Dose: the actual dose for RMC-035 and placebo will be calculated as a relative dose, as 
well as an absolute dose. Note when all 50 mL are administered, expected dose and actual dose 
will be the same. 
 
• Actual Relative Dose (mg/kg): 
൮
൬𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 (𝑚𝑚𝑚𝑚)
50 𝑚𝑚𝑚𝑚
൰ 𝑥𝑥 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 (𝑚𝑚𝑚𝑚) 𝑥𝑥 6.0 𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 (𝑘𝑘𝑘𝑘)
൲ 
• Actual Absolute Dose  (mg): 
൬𝑣𝑣𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 (𝑚𝑚𝑚𝑚)
50 𝑚𝑚𝑚𝑚
൰ 𝑥𝑥 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼𝐼𝐼 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 (𝑚𝑚𝑚𝑚) 𝑥𝑥 6.0 𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 
 
Due to the pharmacokinetics of RMC-035, the pre-defined dose levels (prior to surgery), are 
based on renal function (eGFR by CKD-EPI equation with SCr) at screening (Day -1, Visit 1): 
• Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first 
and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth, and fifth dose 
• Subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for 
all five doses 
To determine the expected volume of IMP (mL) for each subject at each of the five doses, the 
screening eGFR and weight will be utilized with the same formulas used to dose subjects at the 
beginning of the study (found below), rounding to one decimal place after the calculation has 
been made. 


 
 
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• Subjects with eGFR ≥60 mL/min/1.73m2:  
Expected volume (mL) for first two doses  = (1.3 mg/kg x weight (kg))/6.0 mg/mL 
Expected volume (mL) for last three doses  = (0.65 mg/kg x weight (kg))/6.0 mg/mL  
• Subjects with eGFR >30 and <60 mL/min/1.73m2:  
Expected volume (mL) for all five doses = (0.65 mg/kg x weight (kg))/6.0 mg/mL  
The Dosing Tables containing body weight, dose (mg), volume of IMP (mL), and volume of 
0.9% sodium chloride (mL) used can be found in Appendix C. 
Duration: 
• Duration of surgery (hours): the duration between the beginning of surgery and end of 
surgery (exact date/time of skin closure – exact date/time of initial skin incision)  
• Index ICU stay (days): the duration of stay in the ICU immediately following surgery or 
recovery room post-surgery until ICU discharge (date of ICU discharge – date of ICU 
admission + 1) 
• Index hospital stay (days): the duration of stay in the hospital from the day of surgery to 
hospital discharge for the index surgery (date of hospital discharge for the index surgery 
– beginning date of surgery + 1) 
• Duration of AKI (days): the number of days meeting the definition of AKI starting within 
72 hours after first dose of IMP until resolution (observed resolution date – AKI onset 
date + 1).  
Note that AKI onset should be within 72 hours of first dose of IMP. Duration of AKI will 
be calculated for all subjects. Subjects who do not develop AKI will have a duration of 0 
days. Subjects who die without meeting AKI criteria will have a duration of 0 days. If 
status regarding AKI is not available, the subject will be classified as not having AKI. If 
resolution is not reached by Day 90, it is assumed they are resolved at Day 91. The 
minimum duration of AKI for a subject with AKI is 1. A subject without AKI has a 
duration of 0. 
Acute Kidney Injury (AKI): AKI (yes/no) is defined as a subject meeting any of the AKI severity 
stages, where the AKI Severity Stages are:  
Stage 
Serum Creatinine 
Urine Output 
1 
1.5 to 1.9 times baseline within 7 days 
OR 
≥0.3 mg/dL (≥26.5 µmol/L) 
<0.5 mL/kg/h for 6 to <12 hours 
2 
2.0-2.9 times baseline within 7 days 
<0.5 mL/kg/h for ≥12 hours 
3 
3.0 times baseline within 7 days 
OR  
4.0 mg/dL (≥353.6 µmol/L) 
OR  
initiation of renal replacement therapy 
<0.3 mL/kg/h for ≥24 hours  
OR  
anuria for ≥12 hours 
 


 
 
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Serum Creatinine and Urine Output results are to be rounded to one decimal place before the Stage 
is determined. 
AKI persistence: persistent AKI (yes/no) is defined as an AKI developing within 72 hours after 
first dose of IMP and with a duration of ≥72 hours. Persistence will also be assessed per AKI 
severity stage. 
Fridericia’s formula for QT interval correction (QTcF): 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚) = 𝑄𝑄𝑄𝑄 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚) 𝑥𝑥 ൬𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 (𝑏𝑏𝑏𝑏𝑏𝑏)
60
൰
1/3
 
4.6.1 
Primary Efficacy Endpoint Considerations  
For the primary endpoint of AKI, missing data and untimely assessments will be handled as 
follows: 
• If subject is missing the screening (Day -1) SCr value, the last non-missing value prior to 
the first dose of IMP will be used. 
• Subjects with no SCr and no UO will be classified as not having AKI unless the subject 
has dialysis treatment. 
• Any death within 72 hours after first dose of IMP will be classified as not having AKI 
unless the subject had met the AKI criteria before expiring. 
4.6.2 
Other Efficacy Endpoint Considerations 
For the secondary endpoint dialysis treatment (for any reason) within 72 hours and within 7 days 
after end of surgery, missing data and untimely assessments will be handled as follows: 
• Any death within 72 hours after first dose of IMP will be classified as not having dialysis 
unless the subject had dialysis before expiring. 
For the secondary endpoint dialysis-free days from end of surgery to Day 30 and Day 90, 
missing data and untimely assessments will be handled as follows: 
• Any periods without evidence of dialysis are considered free of dialysis, including 
periods where subjects expire.  
5. STUDY SUBJECTS 
5.1 
Disposition of Subjects 
A table of frequency counts and percentages of all subjects in the ITT, mITT, PP, and Safety sets 
will be provided. Subject disposition including study completion status and reasons for early 
termination will be tabulated by treatment group and overall. A by subject listing will be 
provided.  
Completion of the study is defined as the time at which the last randomized subject completes 
the final follow-up period visit, is considered lost to follow-up, withdraws consent, or dies. 


 
 
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5.2 
Protocol Deviations 
Distribution of the types of protocol deviations and the number of subjects in the mITT set that 
deviate from the protocol will be tabulated by study treatment. A listing of all protocol deviations 
will be provided. 
5.3 
Demographic and Baseline Characteristics 
Demographic data will be collected and will include gender, age, race, and ethnicity. 
Demographic data, risk factors for AKI, and other relevant baseline characteristics will be 
summarized by treatment group and overall using summary statistics for the subjects in the mITT 
set. Surgical details for the cardiac surgery including types and location of surgery, surgical 
duration, CPB details, and vital assessments will be summarized and listed as well. Refer to 
Appendix D for a listing of risk factors.  
5.4 
Medical History 
Medical/surgical history and disease characteristics, a listing of relevant past diseases (within 5 
years prior to Screening) and current diseases (ongoing at the time of Screening), and the details 
of active diseases will be obtained from medical records and recorded in the CRF.  
All medical conditions and surgical procedures will be classified by system organ class (SOC) 
and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percent of subjects with each medical condition and surgical procedure will be 
presented for each SOC and PT for the mITT set for each study treatment and overall. 
5.5 
Prior and Concomitant Medications 
Prior prescription and non-prescription medications (e.g., over-the-counter drugs and herbal 
supplements) taken within 30 days prior to scheduled date of surgery up to the date of consent 
will be obtained and all medications (including anesthesia) given before and during surgery will 
be collected. Medications are classified as prior if the stop date is before or on the day the ICF is 
signed. 
Prior and concomitant medications will be coded using World Health Organization (WHO) drug 
classifications. The number and percent of subjects in the mITT set using concomitant 
medications will be tabulated by Anatomical, Therapeutic, and Chemical (ATC) level 4 and 
preferred name for each study treatment and overall. 
6. EFFICACY ANALYSIS 
Efficacy analyses will be performed in mITT set and will consist of all subjects in the ITT set 
who received at least 1 dose of IMP. Additionally, the primary and each of the key secondary 
endpoints will also be analyzed using the PP set, only if there are differences between the mITT 
and PP sets. 
 
 


 
 
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6.1 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint is AKI within 72 hours after first dose of IMP based on SCr 
and/or UO. If one of the two results (SCr or UO) indicates a subject has AKI (based on the stages 
below) and the other doesn’t, the subject will be considered as having AKI.  
Stage 
Serum Creatinine 
Urine Output 
1 
1.5 to 1.9 times baseline within 7 days 
OR 
≥0.3 mg/dL (≥26.5 µmol/L) 
<0.5 mL/kg/h for 6 to <12 hours 
2 
2.0-2.9 times baseline within 7 days 
<0.5 mL/kg/h for ≥12 hours 
3 
3.0 times baseline within 7 days 
OR  
4.0 mg/dL (≥353.6 µmol/L) 
OR  
initiation of renal replacement therapy 
<0.3 mL/kg/h for ≥24 hours  
OR  
anuria for ≥12 hours 
This endpoint will be analyzed by the Cochran-Mantel-Haenszel estimate of the common relative 
risk (RMC-035 vs. placebo) across the four stratification groups formed by region (North 
America and Europe) and eGFR at Day -1 (≥60 and <60 mL/min/1.73m2). The estimate of the 
common relative risk, 90% confidence interval (CI) utilizing Greenland and Robins, and  
p-value will be reported. In addition, the proportion of subjects with AKI within 72 hours after 
first dose of IMP and its 90% CI will be calculated for each treatment group.  
The hypotheses to be tested are as follows: 
• Null hypothesis: the proportion of subjects developing AKI within 72 hours after first 
dose of IMP is the same for the RMC-035 and the placebo treatment groups  
(pRMC-035 = pplacebo)  
• Alternative hypothesis: the proportion of subjects developing AKI within 72 hours after 
first dose of IMP is different for the RMC-035 and the placebo treatment groups  
(pRMC-035 ≠ pplacebo)  
The frequency and proportion for AKI within 72 hours after first dose of IMP will be reported by 
strata and treatment group, as well as by treatment group (pooling all four strata). 
See Appendix E for the derivation of urine output utilizing disjoint intervals in determining 
whether a subject has AKI. Other imputations for the primary endpoint can be found in Section 
4.6.1. 
6.1.1 
Supplementary Analyses of the Primary Endpoint 
The first supplementary analysis will be performed for AKI within 72 hours after first dose of IMP 
based on SCr ONLY, as described above in Section 6.1.  
The second supplementary analysis will be performed for AKI within 72 hours after first dose of 
IMP as described above in Section 6.1; the only difference being any deaths within 72 hours will 
be counted as having AKI. 


 
 
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The third supplementary analysis will be performed for AKI within 72 hours after first dose of 
IMP as described above in Section 6.1; the only difference being UO is not derived from the actual 
body weight, but from the ideal body weight. 
The fourth supplementary analysis will be performed for AKI within 72 hours after first dose of 
IMP, as described above in Section 6.1; the only difference being UO will be derived from rolling 
6-hour intervals, instead of disjoint intervals. See Appendix E for the derivation of urine output 
utilizing rolling intervals in determining whether a subject has AKI. 
6.1.2 
Sensitivity Analyses of the Primary Endpoint 
The primary endpoint will also be analyzed using the PP set, assuming there are differences 
between the mITT and PP sets. 
6.2 
Key Secondary Efficacy Endpoints and Analyses 
The following key secondary endpoints will be analyzed on the mITT set.  
• Time-corrected area under the curve (AUC) of SCr for Day 1 to Day 4 (72 hours after 
first dose of IMP) 
• Duration of AKI defined as the number of days meeting the definition of AKI starting 
within 72 hours after first does of IMP until resolution 
Time-corrected area under the curve (AUC) of SCr for Day 1 to Day 4 (72 hours after first 
dose of IMP) 
For the key secondary AUC endpoint, Robust regression using Huber weights with a cut-off of 2 
will be utilized on AUC for serum creatine, adjusting for baseline log-transformed SCr and 
region. The geometric weighted least square means of the time-corrected AUC will be obtained 
for each RMC-035 and placebo by transforming the model estimates back to the original scale. 
Between-arms differences of the Robust regression estimates will be transformed back to the 
original scale using 100×(e(statistic)-1) and reported as geometric mean percent changes. The 
estimate of the geometric mean percent change from baseline per arm, 90% confidence interval 
(CI), and p-value will be reported. The relative difference (RMC-035 vs. placebo) and its 90% CI 
will also be reported. 
In order to handle missing data, the analysis will be performed over 3 phases: an imputation 
phase, analysis phase, and pooling phase, as described below.   
Imputation phase 
The first step of the imputation phase will create data with a monotone data structure having 
imputed 20 datasets separately within each treatment arm. The number of burn-in iterations will 
be set to 200, and observations will be sampled every 200 iterations within the same chain for 
each imputed dataset. An autocorrelation plot will be produced to confirm that NITER is long 
enough to ensure imputations are independent and a trace plot also produced to confirm there are 
no systematic trends.   
 
 


 
 
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proc mi data=data nimpute=20 seed=2019301 out=mono; 
 
var BASE VAL1-VAL7; 
 
mcmc chain=single nbiter=200 niter=200 impute=monotone; 
 
by TRT; 
run; 
 
where BASE, and VAL1-VAL7 are the log-transformed SCr values at baseline and at Day 1 (12 
hour), Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour), Day 7, Day 30, and Day 90. 
In the second step of the imputation phase, data will be multiply imputed using a regression 
method sequentially imputing data across successive visits separately by treatment arm from 
each dataset imputed in the first step. This analysis assumes data are missing at random 
conditional on previous SCr recordings, which is the same assumption used in a MMRM model 
and therefore would be expected to give equivalent results (O’Kelly & Ratitch). 
proc mi data=mono nimpute=1 SEED=2019301 OUT=imputed; 
 
class TRT REGION;  
 
var REGION BASE VAL1-VAL7; 
 
monotone regression;    
 
by TRT _imputation_; 
run; 
 
where BASE, and VAL1-VAL7 are the log-transformed SCr values at baseline and at Day 1 (12 
hour), Day 2 (24 hour), Day 3 (48 hour),Day 4 (72 hour), Day 7, Day 30, and Day 90. 
Missing data are therefore multiply imputed conditional on outcomes previously observed for the 
same patient and based on the trajectory of outcomes of other patients in the same treatment arm.  
Analysis phase 
In the analysis phase, the AUC will be calculated for each patient within each imputed dataset. 
Each time point will be given the weight stated in Section 4.6. Then AUC of the log-transformed 
data will be analyzed using Robust Regression with independent variables of treatment and log-
transformed baseline SCr. M-estimation will be used with Huber weights and a cut-off value of 2 
with the median method used to estimate the scale parameter.  
proc robustreg data=auc method=m (wf=huber(c=2) scale=med) outest=est1 
covout; 
 
by _imputation_; 
 
class TRT REGION; 
model AUC = BASE TRT REGION;   
run; 
Pooling phase  
In the pooling phase, estimated treatment effects and associated standard errors from each 
imputation will be combined using Rubin’s rules to provide an overall treatment effect, 
associated 90% confidence interval (CI), and 2-sided p-value. 
 
 


 
 
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proc mianalyze data=est1; 
 
modeleffects estimate; 
 
stderr stderr; 
 
ods output ParameterEstimates=est2; 
run; 
Sensitivity analysis  
A sensitivity analysis will be performed using a mixed model for repeated measurements 
(MMRM) on the log-transformed SCr values. The log-transformed values at Day 1 (12 hour), 
Day 2 (24 hour), Day 3 (48 hour) and Day 4 (72 hour) will be modelled in the response vector. 
An 8-level visit-by-treatment class variable and a 4-level visit-by-baseline covariate will be 
included (i.e., between arm differences will only be allowed at the post-baseline visits). In 
addition, region will be used as a fixed factor. The AUC will be obtained as a function of the 
model parameters utilizing SAS estimate statements.  
Duration of AKI (within 72 hours) defined as the number of days meeting the primary 
endpoint until resolution 
The key secondary AKI duration endpoint will be analyzed using the Wilcoxon Rank-Sum test 
with stratification groups formed by region (North America and Europe) and eGFR at Day -1 
(≥60 and <60 mL/min/1.73m2). The estimate of median difference, 90% confidence interval (CI) 
for the median difference utilizing Hodges-Lehman, and p-value will be reported.  
6.3 
Other Secondary Efficacy Endpoints and Analyses 
SCr, cystatin C, and eGFR at 12, 24, 48, and 72 hours, respectively, and at Day 7/discharge, 
Day 30, and Day 90 
For SCr, cystatin C, and eGFR, descriptive statistics will be produced by analysis visit on the 
raw untransformed data. eGFR values will be calculated from the raw untransformed SCr data 
and cystatin C data. This summary will include all analysis visits including the screening and 
Day 1 (Pre-Operative) visit. Columns for actual values, changes from baseline, and percent 
change from baseline (calculated as 100*(change/baseline)) will be included. Changes from 
baseline will be reported for all visits except screening. 
For SCr, cystatin C, and eGFR, robust regression will be utilized to determine the between-arm 
difference at each visit. The existing 3-phase multiple imputation approach detailed above will 
be re-used for this analysis. After imputation, all observed and imputed log-transformed SCr and 
cystatin C values will be transformed back to the original scale. Imputed eGFR values will be 
calculated from the imputed SCr data, as well as the imputed cystatin C data. In the analysis step, 
AUC (dependent variable) will be replaced by either VAL1, VAL2, VAL3, VAL4, VAL5, 
VAL6, or VAL7 representing the missing-data-free SCr, cystatin C, or eGFR values at Day 1 (12 
hour), Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour), Day 7, Day 30, and Day 90. The 
untransformed baseline values will be subtracted from the resulting values in order to obtain, for 
each subject, absolute changes from baseline to each of the 7 aforementioned timepoints.  
The analysis phase will be therefore slightly different from that done for AUC in the sense that 
the model will be applied to the absolute change from baseline. The untransformed baseline 
values will be used as an independent variable. Robust regression estimates will be averaged 


 
 
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over imputations using Rubin's rules. The estimated mean change from baseline per arm and 
respective 90% CI and p-value will be calculated. Additionally, the estimated between-arm 
difference will be calculated, along with the respective 90% CI and p-value. 
A sensitivity analysis will be performed using a mixed model for repeated measurements 
(MMRM) separately for each of the untransformed SCr, cystatin C, and eGFR values. The 
(untransformed) change from baseline values for Day 1 (12 hour), Day 2 (24 hour), Day 3 (48 
hour), Day 4 (72 hour), Day 7/Discharge, Day 30 & Day 90 will be modelled in the response 
vector. A 14-level visit-by-treatment class variable and a 7-level visit-by-screening and visit-by-
pre-operation covariate will be included. In addition, region will be used as a fixed factor. For 
the sensitivity analysis only, subjects without a screening value will use the Day 1 pre-operative 
value for screening. Additionally for the sensitivity analysis only, subjects without a Day 1 pre-
operative value will use the screening value for Day 1 pre-operative. The estimated mean change 
from baseline per arm and respective 90% CI and p-value will be calculated. Additionally, the 
estimated between-arm difference will be calculated, along with the respective 90% CI and p-
value. 
Change from baseline, up to Day 7/discharge, of peak SCr and cystatin C  
The raw untransformed data will be utilized for this analysis. The dependent variable is peak 
change from baseline (peak value-baseline value). The untransformed baseline values will be 
used as an independent variable, as well as region. The estimated between-arm difference will be 
calculated, along with the respective 90% CI and p-value. 
Time-corrected AUC of Cystatin C for Day 1 to Day 4 (72 hours after first dose of IMP)  
This endpoint will be analyzed as described in Section 6.2 for the key secondary AUC endpoint, 
utilizing cystatin C instead of serum creatinine.  
Dialysis treatment (for any reason) within 72 hours and within 7 days after end of surgery 
This endpoint will be analyzed as described in Section 6.1. 
The frequency and proportion for dialysis treatment within 72 hours and within 7 days after first 
dose of IMP will be reported by strata and treatment group, as well as by treatment group 
(pooling all strata). 
Dialysis-free days from end of surgery to Day 30 and Day 90, respectively  
This endpoint will be analyzed as described in Section 6.2 for the key secondary AKI duration 
endpoint.  
Dialysis-free duration in 30 and 90 days, is the sum of all dialysis-free durations of a subject in 
the time periods, respectively. Number of dialysis-free days will be calculated for all subjects.  
If status regarding dialysis is not available, the subject will be classified as not having undergone 
dialysis.  
Dialysis-free days will be counted when  the subject achieves at least 7 consecutive days without 
dialysis. 
For the Day 30 analysis, subjects who may have become dialysis independent (defined as  


 
 
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7 consecutive dialysis-free days) between Days 24 and 30 will need to be followed for the 
number of additional days to determine whether 7 consecutive dialysis-free days have occurred. 
Therefore, daily dialysis recording for these subjects may need to be extended into the period 
from Day 31 to Day 36). This will be similar for the analysis of Day 90. 
The number and frequency of dialysis-free subjects from end of surgery to Day 30 will be 
provided, as well as for Day 90. 
MAKE by Day 30 and 90 
A subject will be considered as having a MAKE at Day X, where X=30 and 90, if the subject 
experiences: 
• Death through Day X; or  
• Any dialysis through Day X; or 
• A ≥25% reduction of estimated glomerular filtration rate (eGFR) on Day X 
compared to baseline using the Chronic Kidney Disease-Epidemiology 
Collaboration (CKD-EPI) equations (utilizing SCr only) 
The analysis for Day 30 and Day 90 will be examined separately.  
This endpoint will be analyzed as described in Section 6.1. 
Additionally, the number and frequency of subjects who meet each of the three criteria listed 
above will be displayed separately. 
A sensitivity analysis utilizing the alternative definition of MAKE X will be performed as 
described above, where the alternative definition utilizes cystatin C only. A second sensitivity 
analysis utilizing the alternative definition of MAKE X will be performed as described above, 
where the alternative definition utilizes SCr and cystatin C. See Appendix B for the three 
calculations.  
AKI within 72 hours after first dose of IMP based on cystatin C and/or UO (AKI of any 
stage/severity defined as cystatin C ≥1.5 times baseline, OR UO <0.5 mL/kg/h for ≥6 hours) 
This endpoint will be analyzed as described in Section 6.1. 
The frequency and proportion for AKI within 72 hours after first dose of IMP will be reported by 
strata and treatment group, as well as by treatment group (pooling all strata). 
AKI within 7 days after first dose of IMP (based on SCr and/or UO criteria, or cystatin C 
and/or UO criteria) 
This endpoint will be analyzed as described in Section 6.1. The frequency and proportion for 
AKI within 7 days after first dose of IMP will be reported by strata and treatment group, as well 
as by treatment group (pooling all strata). 
 
 


 
 
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AKI persistence, defined as an AKI developing within 72 hours after first dose of IMP and 
with a duration of ≥72 hours.  
This endpoint will be analyzed as described in Section 6.1. The frequency and proportion for 
AKI persistence will be reported by strata and treatment group, as well as by treatment group 
(pooling all strata). 
In addition, persistence will be tabulated by AKI severity and treatment group. 
AKI severity stage within 72 hours and within 7 days after first dose of IMP.  
Descriptive statistics (frequency and proportions) will be displayed by treatment group. The 
highest stage a subject reaches within the respective timeframe will be used. For example, a 
subject developing AKI stage 1 and subsequently stage 2 and/or 3 will counted as 3. 
Post-baseline changes in urine albumin to creatinine ratio (UACR) and urine protein to 
creatinine ratio (UPCR) at Day 4, Day 30, and Day 90  
The data will be reported separately. 
Pharmacokinetics of RMC-035 in plasma (AUC and Cmax)  
Mercodia AB will conduct bioanalysis of PK samples with PK parameters and reporting carried 
out by CTC. Descriptive statistics of drug concentrations over time will be provided by dose 
group and by renal function at baseline. 
Presence and titers of ADA at Day 1 (pre-surgery), Day 30, and Day 90  
Presence and titers of ADA and ADA characterization will be reported separately.  
Characteristics of ADA developed at Day 30 and Day 90 with regards to isotype, 
neutralizing capacity, and cross-reactivity with endogenous alpha-1-microglobulin (A1M)  
If ADAs are present, the presence and further characterization will be reported separately. 
6.4 
Exploratory Efficacy Endpoints and Analyses 
Kidney Biomarkers 
Urine kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), 
tissue inhibitor of metalloproteinase 2 (TIMP2), insulin-like growth binding factor protein 7 
(IGFBP7), chemokine ligand 14 (CCL-14), interleukin-18 (IL-18), liver fatty acid binding 
protein (LFABP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) may be analyzed and reported 
separately.  
Cardiac Biomarkers 
Plasma N-terminal-pro-hormone BNP (NT-proBNP) and cardiac troponin I and T (cTnI, cTnT) 
may be analyzed and reported separately.  
Immunologic Biomarkers 
Biomarkers may be analyzed and reported separately. 
Index ICU stay (in Days)  
Data will be presented separately. 


 
 
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Index hospital stay (in Days) 
Data will be presented separately.  
Nature of subject discharge facility  
Data will be presented separately.  
Change from baseline to Day 90 for Medical Outcomes Study (MOS) 36-Item Short Form 
Survey Instrument (SF-36) 
These parameters will be reported separately.  
Change from baseline to Day 90 for European Quality of Life 5 Domain 5-Level Score (EQ-
5D-5L) 
These parameters will be reported separately.  
The European Quality Visual Analog Scale (VAS)  
These parameters will be reported separately. 
6.5 
Subgroup Analysis 
A subgroup analysis for the primary endpoint will be conducted by Day -1 eGFR (≥60 and <60 
mL/min/1.73m2) and region (North America and Europe). 
7. SAFETY ANALYSIS 
Safety analyses will be conducted on the Safety Analysis Set (SAF), which includes all 
randomized subjects who received at least 1 dose of RMC-035. To characterize the safety 
profile, the number and percentage of subjects with TEAEs and AEs per dose group will be 
tabulated per System Organ Class (SOC) and Preferred Term (PT) according to the Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.1.  
Descriptive statistics will be provided for laboratory tests (hematology, biochemistry, urinalysis) 
and vital signs (pulse rate, respiratory rate and blood pressure) by visit and for the changes from 
baseline to each visit split by dose group. 
All adverse events (AEs) will be collected from initiation of the first IMP administration through 
the Day 30 study visit. All serious adverse events (SAEs) will be collected from the signing of 
the informed consent form (ICF) through the end of study visit. 
7.1 
Extent of Exposure 
The total number of infusions received, the expected total infusion dose, and the actual infusion 
dose administered will be summarized and presented. 
7.2 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject, 
temporally associated with the use of medicinal product, whether or not considered related to this 
IMP. An AE can therefore be any unfavorable and unintended sign (including an abnormal 


 
 
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laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of medicinal product. 
All AEs will be collected from initiation of the first IMP administration through the Day 30 
study visit. 
All SAEs will be collected from the signing of the ICF through the EOS visit. 
7.2.1 
Treatment-emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is any AE that occurs after the initial IMP 
administration through 72 hours (inclusive) after the final IMP administration. 
7.2.2 
Post-treatment Adverse Event 
A post-treatment adverse event (PTAE) is any AE that occurs later than 72 hours after the final 
IMP administration. 
7.2.3 
Adverse Event Severity 
The intensity of an event describes the degree of impact upon the subject and/or the need for, and 
extent of, medical care necessary to treat the event. Intensity will be assessed according to the 
CTCAE scale v5.0, as follows: 
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 Activities of Daily Living (ADL). 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
Grade 4  Life-threatening consequences; urgent intervention indicated 
Grade 5  Death related to AE 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. Self-care ADLs refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 
For events not listed in the CTCAE scale, intensity grading will occur according to the following 
scale: 
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 Activities of Daily Living (ADL). 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 


 
 
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Grade 4  Life-threatening consequences; urgent intervention indicated 
Grade 5  Death related to AE 
An AE of severe intensity may not be considered serious. 
7.2.4 
Adverse Event Relationship to Study Medication 
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: 
• Not related (unlikely) 
o Does not follow a reasonable temporal sequence from drug administration 
o Is readily explained by the subject's clinical state or by alternative etiologies such 
as underlying disease(s), concomitant therapy and other risk factors 
• Related (possible/probable) 
o Follows a reasonable temporal sequence from IMP administration 
o Cannot be reasonably explained by the known characteristics of the subject's 
clinical state 
Alternative etiology should be provided for all AEs assessed as possibly related to IMP. 
The Investigator will use clinical judgment to determine the relationship. 
7.2.5 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that meets at least one of the following 
serious criteria: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent disability/incapacity 
• Is a congenital anomaly/birth defect 
• Other medically important serious event  
7.2.6 
Adverse Events of Special Interest 
Injection Site Reaction (ISR) and 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. The CTCAE grading for ISR and IRR are provided in Table 2 below. 
 
 
 


 
 
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Table 2: CTCAE Grading for Injection Site Reactions (ISR) and Infusion Related 
Reactions (IRR) 
CTCAE 
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Definition 
MedDRA PT: 
Injection site 
reaction 
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. 
MedDRA PT: 
Infusion 
related 
reaction 
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. 
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; MedDRA=Medical 
Dictionary for Regulatory Activities; NSAID=non-steroidal anti-inflammatory drug; SOC=system organ class 
7.2.7 
Adverse Event Summaries 
The number and percentage of subjects with TEAEs and PTAEs per dose group will be tabulated 
per System Organ Class (SOC) and Preferred Term (PT) according to the Medical Dictionary for 
Regulatory Activities (MedDRA) version 24.1.  
For treatment-emergent AEs (TEAEs), the following will be summarized and presented for the 
Safety set: 
i. 
An overall summary of TEAEs, which includes:   
a. the number and percentage of subjects experiencing a TEAE 
b. the number and percentage of subjects experiencing a TEAE by strongest 
relationship to investigational product 
c. the number and percentage of subjects experiencing a TEAE by greatest intensity 


 
 
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d. the number and percentage of subjects experiencing a TEAE leading to permanent 
discontinuation of the IMP 
e. the number and percentage of subjects experiencing a treatment emergent serious 
adverse event (TESAE) 
f. the number and percentage of subjects experiencing a TESAE by strongest 
relationship to investigational medicinal product 
g. the number and percentage of subjects experiencing a TEAE leading to death 
h. the number and percentage of subjects experiencing a TEAE Injection Site 
Reaction (h) of grade 3 or higher 
i. the number and percentage of subjects experiencing a TEAE Infusion Related 
Reaction (IRR) of grade 3 or higher 
j. the number and percentage of subjects experiencing a TEAE suggestive of IRRs 
on days of treatment 
ii. 
the number and percentage of subjects experiencing a TEAE by SOC, PT, and the 
strongest relationship to investigational product 
iii. 
the number and percentage of subjects experiencing a TEAE by SOC, PT, and the 
greatest intensity 
iv. 
the number and percentage of subjects experiencing a TEAE leading to permanent 
discontinuation of the IMP by SOC and PT 
v. 
the number and percentage of subjects experiencing a TESAE by SOC and PT 
vi. 
the number and percentage of subjects experiencing a TESAE by SOC and PT, and 
the strongest relationship to the investigational medicinal product 
vii. 
the number and percentage of subjects experiencing a TEAE leading to death 
viii. 
the number and percentage of subjects experiencing a TEAE Injection Site Reaction 
(ISR) of grade 3 or higher by SOC and PT 
ix. 
the number and percentage of subjects experiencing a TEAE Infusion Related 
Reaction (IRR) of grade 3 or higher by SOC and PT 
x. 
the number and percentage of subjects experiencing a TEAE suggestive of IRRs on 
days of treatment by PT and Site 
The same tables described above will be presented for post-treatment AEs (PTAEs) for the 
Safety set, as applicable. 
In the overall summary of TEAEs and PTAEs tables (i), besides tabulating the number and 
percentage of subjects, the total number of TEAE episodes will also be provided. If a subject has 
repeated episodes of a particular TEAE, all episodes will be counted in the summary table.   
In the remaining summary tables, the incidences of TEAEs and PTAEs will be calculated by 
dividing the number of subjects who have experienced the event by the total number of subjects 
in the SAF set. Thus, the incidence of TEAEs is shown in terms of the total number of subjects 


 
 
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and not in terms of the total number of episodes. If a subject has repeated episodes of a particular 
TEAE or PTAE, only the most severe episode, or the episode with the strongest causal 
relationship to IMP, will be counted in the summary tables.  
A subject with more than one type of TEAE or PTAE in a particular SOC will be counted only 
once in the total of subjects experiencing TEAEs or PTAEs in that particular SOC. Since a 
subject could have more than one type of TEAE/PTAE within a particular SOC, the sum of 
subjects experiencing different TEAEs/PTAEs within the SOC could appear larger than the total 
number of subjects experiencing TEAEs/PTAEs in that SOC. Similarly, a subject who has 
experienced a TEAE/PTAE in more than one SOC will be counted only once in the total number 
of subjects experiencing AEs in all SOCs. 
All occurrences of all AEs will be listed for each subject, grouped by treatment group. The 
listing will contain the following information: treatment group, event verbatim term, SOC, PT, 
maximum intensity, relationship to investigational product, date and day of onset, date and day 
of resolution, treatment given to treat the adverse event, the outcome, whether the event was an 
SAE, and which serious criteria were applicable, whether it led to permanent discontinuation of 
the IMP, whether it is a TEAE, and whether it is a PTAE. Listings will be sorted by subject 
identification number, onset date, SOC, and PT. If the onset date is completely missing, then 
these events will be presented first. If the onset date is missing a month or a day, then these 
events will be presented before any complete dates. 
7.3 
Clinical Laboratory Assessments 
Laboratory assessments will include hematology, clinical chemistry, liver function labs, 
urinalysis, urine albumin and protein creatinine ratio, as well as other screening tests. 
Continuous laboratory parameters will be summarized by parameter, treatment group, and 
analysis visit. Actual values and changes from baseline will be tabulated separately by each visit, 
split by dose group. This tabulation will include the maximum and the minimum post-baseline. 
Shift tables will be produced for laboratory reference ranges using the lowest and highest post-
baseline level. 
Laboratory parameter results from unscheduled visits will be excluded from table summaries but 
will be included in data listings. When there are repeat measurements for a given visit, only the 
last measurement will be used in the table summaries. 
Listings will include flags for values outside of the reference ranges, and clinical significance if a 
laboratory result is deemed abnormal, if available. 
Box plots per analysis visit and treatment arm will be produced for each continuous laboratory 
parameter. One page will be produced for each parameter. This plot will include the reference 
ranges as horizontal lines. 
A frequency table of the number and percent of subjects with potentially clinically significant 
liver value elevations will be provided. 
7.4 
Vital Signs 
Vital signs will include body temperature (°C), systolic and diastolic blood pressure (mmHg), 
heart rate (bpm) and respiratory rate (breaths per min), and oxygen saturation (SpO2). 


 
 
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Continuous vital signs will be summarized by parameter, treatment group and analysis visit. 
Actual values and changes from baseline will be tabulated separately by each visit, split by dose 
group. This tabulation will include the maximum and the minimum post-baseline. Shift tables 
will be produced for potentially clinically significant vital sign values (worst values):  
o Systolic blood pressure (mmHg): ≥ 140, ≥ 160, ≥ 180, < 90, < 60 
o Diastolic blood pressure (mmHg): ≥ 90, ≥ 100, ≥ 120, < 60, < 45 
o Heart rate (bpm): >100, > 115, > 130, < 60, < 50, < 40 
o Body temperature (°C): > 38, < 35 
Unscheduled visits will be excluded from the summaries but will be included in the data listings. 
Box plots per analysis visit and treatment arm will be produced for each continuous vital sign. 
One page will be produced for each parameter. This plot will include the reference ranges as 
horizontal lines. 
7.5 
ECG 
Continuous electrocardiogram interval measurements will be summarized by parameter, 
treatment group and analysis visit. Actual values and changes from baseline will be tabulated 
separately by each visit, split by dose group. This tabulation will include the maximum and the 
minimum post-baseline. Shift tables will be produced for potentially clinically significant ECG 
(worst values):  
o QTcF (ms): > 450, > 480, > 500 
o Change from baseline in QTcF (ms): >30, >60 
Box plots per analysis visit and treatment arm will be produced for each continuous 
electrocardiogram interval measurements. One page will be produced for each parameter. This 
plot will include the reference ranges as horizontal lines. 
7.6 
Physical Examination 
The Investigator or qualified designee will conduct the exams, determine findings, and assess 
any abnormalities as to clinical significance. The physical examination performed at screening 
should be comprehensive; all other physical examinations may be abbreviated and symptom 
driven. 
8. SAMPLE SIZE AND POWER CALCULATIONS 
For the primary endpoint, AKI within 72 hours after first dose of IMP, RMC-035 has been 
assumed to lead to a 30% relative risk reduction vs. placebo. The event rate in the placebo group 
has been assumed to be 50%. A sample size of 268 subjects dosed leads to a test power of 80% 
to show statistically significant results at a two-sided significance level (alpha) of 0.10. An 
interim analysis (IA) of the primary endpoint will be performed when 50% of the planned 
subjects have completed Visit 6. Conditional power (CP) given ‘the current trend’ will be 
calculated. Sample size may be increased to a maximum of 348 subjects dosed. Sample size will 
not be decreased. 


 
 
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It is planned that approximately 380 subjects (approximately 30% screen failure assumed) will 
be enrolled to ensure 268 subjects dosed with either RMC-035 or placebo in a 1:1 ratio. Based on 
results at an interim analysis, up to 348 subjects may be dosed, requiring approximately 500 
subjects to be enrolled. 
9. INTERIM ANALYSIS 
An interim analysis (IA) of the primary endpoint (see Section 6.1) will be performed on the 
mITT set when 50% (n=134) of the planned randomized subjects have completed the study 
through discharge (Visit 6) and data have been reviewed and are available. Serum creatinine and 
urine output collected through Visit 6 will be included in the analysis. Conditional power (CP), 
the probability that the final analysis will be statistically significant, will be calculated. Sample 
size may be increased to a maximum of 348 randomized subjects. Sample size will not be 
decreased. The study may be stopped at the IA for futility reasons. Study eligibility criteria may 
also be modified. 
Given the unblinded nature of this IA, an unblinded Data Monitoring Committee (DMC) of 
independent individuals not involved in any other study activities will be utilized. The Sponsor 
and all other CRO personnel will remain blinded. The unblinded materials, data, and analysis 
results will be stored securely and separately from blinded clinical material and will not be 
accessible by blinded personnel. Results of the IA will not be shared with the Sponsor or blinded 
CRO personnel; only a decision on whether sample size expansion criteria have been met will be 
shared with the blinded team.  
Further details on the dissemination of IA results and rules governing adaptations will be 
provided in the Data Monitoring Committee (DMC) charter. 
The following will be provided at the interim analysis: 
• Table 14.1.3 Summary of Demographics – mITT Set 
• Table 14.1.4 Summary of Baseline Characteristics – mITT Set 
• Table 14.1.7 Summary of Surgical Details – mITT Set 
• Table 14.2.1.1.1 Summary of Primary Endpoint: AKI based on SCr and/or UO, utilizing 
disjoint intervals – mITT Set 
Supplementary Analyses of Primary Endpoint  
o Table 14.1.1.1.6 (AKI based on SCr only) – mITT Set 
o Table 14.1.1.1.7 (AKI based on SCr and/or UO, Counting Deaths as AKI) – mITT 
Set 
o Table 14.1.1.1.8 (AKI based on SCr and/or UO, Using Ideal Body Weight instead 
of Actual Body Weight) – mITT Set 
o Table 14.1.1.1.9 (AKI based on SCr and/or UO, utilizing rolling intervals) – 
mITT Set 
• Table 14.2.2.1.1 Summary of Key Secondary Endpoint: Time-Corrected AUC of Serum 
Creatinine for Day 1 to Day 4 (72 Hours After First Dose of IMP) – mITT Set 
• Table 14.2.3.6 Summary of Key Secondary Endpoint: Time-Corrected AUC of Cystatin 
C for Day 1 to Day 4 (72 Hours After First Dose of IMP) – mITT Set 


 
 
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• Table 14.2.3.1 Summary of Other Secondary Endpoint: Serum Creatinine at Hour 12, 24, 
48, and 72, and Day 7, 30, and 90 – mITT Set  
• Table 14.2.3.2 Summary of Other Secondary Endpoint: Cystatin C at Hour 12, 24, 48, 
and 72, and Day 7, 30, and 90 – mITT Set 
• Table 14.2.3.3 Summary of Other Secondary Endpoint: eGFR (calculated from Serum 
Creatinine) at Hour 12, 24, 48, and 72, and Day 7, 30, and 90 – mITT 
• Table 14.2.3.4 Summary of Other Secondary Endpoint: eGFR (calculated from Cystatin 
C) at Hour 12, 24, 48, and 72, and Day 7, 30, and 90 – mITT Set 
• Table 14.2.3.8 Summary of Other Secondary Endpoint: Dialysis-Free Days from End of 
Surgery to Day 30 and Day 90 – mITT Set 
• Table F: Sample Size Assessment Utilizing Primary Endpoint (AKI) – mITT (see Section 
9.1 and Appendix F) 
• Figure 14.2.3.1 Lineplot of Geometric Means and Standard Errors (Descriptive Statistics) 
of Serum Creatinine – mITT Set 
• Figure 14.2.3.2 Lineplot of Geometric Means and Standard Errors (Descriptive Statistics) 
of Cystatin C – mITT Set 
• Figure 14.2.3.3 Lineplot of Geometric Means and Standard Errors (Descriptive Statistics) 
of eGFR (calculated from Serum Creatinine) – mITT Set  
• Figure 14.2.3.4 Lineplot of Geometric Means and Standard Errors (Descriptive Statistics) 
of eGFR (calculated from Cystatin C) – mITT Set 
 
In addition to the efficacy IA described above, one exploratory interim analysis of cardiac and 
kidney biomarkers is planned in the protocol (as of version 3.0). This biomarker IA is 
independent from the IA of the primary endpoint, and it is not subject to review and decision 
making by the DMC. Further details on the biomarker IA and the associated measures to 
minimize impact on data integrity will be documented separately. 
9.1 
Conditional Power 
The conditional power at the interim analysis will be calculated as follows: 
CP = 1 −Φ ቆ𝑧𝑧𝛼𝛼√𝑛𝑛2 −𝑧𝑧1√𝑛𝑛1
ඥ𝑛𝑛෤2
−𝑧𝑧1ඥ𝑛𝑛෤2
√𝑛𝑛1
ቇ 
where Φ is the CDF for 𝑁𝑁(0,1), 𝛼𝛼 is 0.10, 𝑧𝑧∝ is 1.645, and 𝑧𝑧1 =
𝑙𝑙𝑙𝑙 (𝑅𝑅𝑅𝑅𝑀𝑀𝑀𝑀)
ඥ𝑣𝑣𝑣𝑣𝑣𝑣[𝑙𝑙𝑙𝑙(𝑅𝑅𝑅𝑅𝑀𝑀𝑀𝑀)] is the z-score 
corresponding to the log-transformed relative risk statistic, and 𝑛𝑛෤2 = 𝑛𝑛2 −𝑛𝑛1 is the incremental 
sample size between stage 1 (interim analysis after n1 subjects) and stage 2 (final analysis after n2 
subjects).  
Where the estimate of the common relative risk is computed as: 
𝑅𝑅𝑅𝑅𝑀𝑀𝑀𝑀= (∑𝑛𝑛ℎ11
ℎ
 𝑛𝑛ℎ2./𝑛𝑛ℎ)
(∑𝑛𝑛ℎ21
ℎ
 𝑛𝑛ℎ1./𝑛𝑛ℎ)
൘
 
 
 


 
 
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with 100(1-α/2)% confident limits: 
(𝑅𝑅𝑅𝑅𝑀𝑀𝑀𝑀 𝑥𝑥exp൫−𝑧𝑧𝛿𝛿̂൯,  𝑅𝑅𝑅𝑅𝑀𝑀𝑀𝑀 𝑥𝑥exp൫𝑧𝑧𝛿𝛿̂൯)  
and 
𝛿𝛿̂2 = 𝑉𝑉𝑉𝑉𝑉𝑉
෢(log((𝑅𝑅𝑅𝑅𝑀𝑀𝑀𝑀)) = 
∑(𝑛𝑛ℎ1.
ℎ
 𝑛𝑛ℎ2. 𝑛𝑛ℎ.1− 𝑛𝑛ℎ2./𝑛𝑛ℎ11 𝑛𝑛ℎ21 𝑛𝑛ℎ)/𝑛𝑛ℎ
2
(∑𝑛𝑛ℎ11
ℎ
 𝑛𝑛ℎ2./𝑛𝑛ℎ) (∑𝑛𝑛ℎ21
ℎ
 𝑛𝑛ℎ1./𝑛𝑛ℎ)
 
Appendix F contains the table shell that will be produced at the time of the IA which includes the 
estimated treatment effect, sample size used, and conditional power.  
9.2 
Sample Size Readjustment 
If the conditional power at the interim analysis is ≥80%, it is recommended to proceed with the 
planned original sample size of n=268. 
If the conditional power at the interim analysis is <80%, it is recommended to proceed with 
either the planned original sample size, planned maximum sample size, and/or amend eligibility 
criteria or terminate the study. 
9.3 
Alpha Level 
If required, the nominal alpha level for the final analysis of the primary endpoint will be adjusted 
using Equation (11) of Mehta and Pocock (2009): 
2 ∗(1 −Φ(max (z∝′(𝑛𝑛2
∗)−0.5 ቈ
(𝑛𝑛2
∗−𝑛𝑛1)
(𝑛𝑛2 −𝑛𝑛1) ൫𝑧𝑧∝ඥ𝑛𝑛2 −𝑧𝑧1ඥ𝑛𝑛1൯+ 𝑧𝑧1ඥ𝑛𝑛1቉))) 
where 𝑧𝑧1 is the interim analysis z statistic, 𝑧𝑧∝ is 1.645, 𝑛𝑛2 is equal to 268 (the planned sample 
size), 𝑛𝑛1 is the sample size used at the unblinded interim analysis, and 𝑛𝑛2
∗ is the final sample size 
if it is increased. Applying this equation, the only situations where it will be necessary to use a 2-
sided significance level lower than 10% is when the sample size is increased and Z1, the interim 
standardized normal test statistic associated with the log-transformed relative risk statistic, is less 
than 1.0956 – corresponding to increasing the sample size when the interim conditional power of 
statistical significance at a 268 patient analysis is < 44.6%. Refer to Section 9 for additional 
details regarding the interim analysis. 
9.4 
Conduct of Unblinded Interim Analysis  
This analysis will be conducted by an unblinded programming team which is separate from the 
blinded statistician and study team, and the unblinded statistician will oversee and review the 
programming and unblinded results. 
The unblinded statistician will confirm the interim analysis details included in the study 
protocol/SAP/DMC Charter. 
The unblinded statistician will minimize the risk of communication of interim results and 
maintain the integrity of the trial blinding. 


 
 
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The unblinded statistician will proceed with the unblinding of the interim study database 
according to CTI SOP and produce the outputs outlined in the DMC Charter, unless otherwise 
specified by the Sponsor. 
10. BLINDING AND UNBLINDING 
10.1 
Blinded Statistician 
The blinded statistician will define the eligible subjects to be included in each population based 
on blinded information. 
The blinded statistician and blinded programming team will create and validate data sets using 
dummy randomization data. 
The blinded statistician will confirm database lock with the study data manager so that the 
unblinded final statistical analysis may begin. 
10.2 
Management of Accidental Unblinding 
If a study subject is accidentally unblinded or access to unblinded data is inadvertently granted, 
the team will follow CTI SOP GL-PRJ-009 which includes notification and assessment of impact 
with the Sponsor. 
10.3 
Unblinding for Analysis Purposes at the End of the Trial 
Once the confirmation of database lock has occurred, the study statistician will request the 
production randomization list be exported from RTSM and sent to the blinded statistical team. 
Upon receipt, the blinded statistical team will be considered unblinded and carryout the final 
analysis. The statistical team will continue to keep all analysis and unblinding to themselves, 
only sharing requested information with appropriate members of the sponsor team. The statistical 
team will not share any unblinded information with anyone until informed to do so by the 
sponsor. 
11. REFERENCES 
Gao, P., J. H. Ware and C. Mehta (2008). "Sample size re-estimation for adaptive sequential 
design in clinical trials." J Biopharm Stat 18(6): 1184-1196. 
Mehta, C. R. and S. J. Pocock (2011). "Adaptive increase in sample size when interim results are 
promising: A practical guide with examples." Statistics in Medicine 30(28): 3267-3284. 
Khwaja, A. (2012). "KDIGO clinical practice guidelines for acute kidney injury." Nephron Clin 
Pract 120(4): c179-184. 
 


 
 
 
 
 
 
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12. APPENDICES 
12.1 
APPENDIX A: SCHEDULE OF ASSESSMENTS 
 


 
 
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12.2 
APPENDIX B: CKD-EPI CALCULATIONS 
 
The 2009 CKD-EPI calculation for SCr is:  
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 𝐴𝐴∗൬𝑆𝑆𝑆𝑆𝑆𝑆
𝐵𝐵൰
𝐶𝐶
∗0.993𝑎𝑎𝑎𝑎𝑎𝑎              [𝑖𝑖𝑖𝑖 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴, 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑏𝑏𝑏𝑏 1.159] 
Where A, B, and C are: 
FEMALE 
MALE 
SCr ≤ 0.7 
A = 144 
SCr ≤ 0.9 
A = 141 
B = 0.7 
B = 0.9 
C = -0.329 
C = -0.411 
SCr > 0.7 
A = 144 
SCr > 0.9 
A = 141 
B = 0.7 
B = 0.9 
C = -1.209 
C = -1.209 
 
The 2012 CKD-EPI calculation for Cystatin C is:  
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 133 ∗ቀ
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
0.8 ቁ
𝐴𝐴
∗0.996𝑎𝑎𝑎𝑎𝑎𝑎 𝑥𝑥 𝐵𝐵                
Where A and B: 
 
FEMALE 
MALE 
Scys ≤ 0.8 
A = -0.499 
A = -0.499 
B = 0.932 
B = 1 
Scys > 0.8 
A = -1.328 
A = -1.328 
B = 0.932 
B = 1 
 
 
 


 
 
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The 2012 CKD-EPI calculation for SCr and Cystatin C is:  
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 𝐴𝐴∗൬𝑆𝑆𝑆𝑆𝑆𝑆
𝐵𝐵൰
𝐶𝐶
∗൬𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
0.8 ൰
𝐷𝐷
∗0.995𝑎𝑎𝑎𝑎𝑎𝑎              [𝑖𝑖𝑖𝑖 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴, 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑏𝑏𝑏𝑏 1.08] 
Where A, B, C, and D are: 
FEMALE 
SCr ≤ 0.7 
SCr > 0.7 
Scys ≤ 0.8 
A = 130 
A = 130 
B = 0.7 
B = 0.7 
C = -0.248 
C = -0.601 
D = -0.375 
D = -0.375 
Scys > 0.8 
A = 130 
A = 130 
B = 0.7 
B = 0.7 
C = -0.248 
C = -0.601 
D = -0.711 
D = -0.711 
 
MALE 
SCr ≤ 0.9 
SCr > 0.9 
Scys ≤ 0.8 
A = 135 
A = 135 
B = 0.9 
B = 0.9 
C = -0.207 
C = -0.601 
D = -0.375 
D = -0.375 
Scys > 0.8 
A = 135 
A = 135 
B = 0.9 
B = 0.9 
C = -0.207 
C = -0.601 
D = -0.711 
D = -0.711 
 
 
 
 


 
 
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12.3 
APPENDIX C: DOSING TABLES 
12.3.1 Table C1: Volumes of IMP and diluent for dose level 1.3 mg/kg 
NOTE! This table is used for dilution of  
• 1st and 2nd dose for subjects with eGFR ≥60 mL/min/1.73 m2. 
 
Body Weight 
Dose (mg) 
Volume of IMP 
(mL) 
Volume of 0.9% Sodium 
Chloride (mL)  
50 
65.0 
10.8 
39.2 
51 
66.3 
11.1 
39.0 
52 
67.6 
11.3 
38.7 
53 
68.9 
11.5 
38.5 
54 
70.2 
11.7 
38.3 
55 
71.5 
11.9 
38.1 
56 
72.8 
12.1 
37.9 
57 
74.1 
12.4 
37.7 
58 
75.4 
12.6 
37.4 
59 
76.7 
12.8 
37.2 
60 
78.0 
13.0 
37.0 
61 
79.3 
13.2 
36.8 
62 
80.6 
13.4 
36.6 
63 
81.9 
13.7 
36.4 
64 
83.2 
13.9 
36.1 
65 
84.5 
14.1 
35.9 
66 
85.8 
14.3 
35.7 
67 
87.1 
14.5 
35.5 
68 
88.4 
14.7 
35.3 
69 
89.7 
15.0 
35.1 
70 
91.0 
15.2 
34.8 
71 
92.3 
15.4 
34.6 
72 
93.6 
15.6 
34.4 
73 
94.9 
15.8 
34.2 
74 
96.2 
16.0 
34.0 
75 
97.5 
16.3 
33.8 
76 
98.8 
16.5 
33.5 
77 
100.1 
16.7 
33.3 
78 
101.4 
16.9 
33.1 
79 
102.7 
17.1 
32.9 
80 
104.0 
17.3 
32.7 
81 
105.3 
17.6 
32.5 
82 
106.6 
17.8 
32.2 
83 
107.9 
18.0 
32.0 


 
 
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Body Weight 
Dose (mg) 
Volume of IMP 
(mL) 
Volume of 0.9% Sodium 
Chloride (mL)  
84 
109.2 
18.2 
31.8 
85 
110.5 
18.4 
31.6 
86 
111.8 
18.6 
31.4 
87 
113.1 
18.9 
31.2 
88 
114.4 
19.1 
30.9 
89 
115.7 
19.3 
30.7 
90 
117.0 
19.5 
30.5 
91 
118.3 
19.7 
30.3 
92 
119.6 
19.9 
30.1 
93 
120.9 
20.2 
29.9 
94 
122.2 
20.4 
29.6 
95 
123.5 
20.6 
29.4 
96 
124.8 
20.8 
29.2 
97 
126.1 
21.0 
29.0 
98 
127.4 
21.2 
28.8 
99 
128.7 
21.5 
28.6 
100 
130.0 
21.7 
28.3 
101 
131.3 
21.9 
28.1 
102 
132.6 
22.1 
27.9 
103 
133.9 
22.3 
27.7 
104 
135.2 
22.5 
27.5 
105 
136.5 
22.8 
27.3 
106 
137.8 
23.0 
27.0 
107 
139.1 
23.2 
26.8 
108 
140.4 
23.4 
26.6 
109 
141.7 
23.6 
26.4 
110 
143.0 
23.8 
26.2 
111 
144.3 
24.1 
26.0 
112 
145.6 
24.3 
25.7 
113 
146.9 
24.5 
25.5 
114 
148.2 
24.7 
25.3 
115 
149.5 
24.9 
25.1 
116 
150.8 
25.1 
24.9 
117 
152.1 
25.4 
24.7 
118 
153.4 
25.6 
24.4 
119 
154.7 
25.8 
24.2 
120 
156.0 
26.0 
24.0 
121 
157.3 
26.2 
23.8 
122 
158.6 
26.4 
23.6 
123 
159.9 
26.7 
23.4 


 
 
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Page 60 of 73 
Body Weight 
Dose (mg) 
Volume of IMP 
(mL) 
Volume of 0.9% Sodium 
Chloride (mL)  
124 
161.2 
26.9 
23.1 
125 
162.5 
27.1 
22.9 
126 
163.8 
27.3 
22.7 
127 
165.1 
27.5 
22.5 
128 
166.4 
27.7 
22.3 
129 
167.7 
28.0 
22.1 
130 
169.0 
28.2 
21.8 
131 
170.3 
28.4 
21.6 
132 
171.6 
28.6 
21.4 
133 
172.9 
28.8 
21.2 
134 
174.2 
29.0 
21.0 
135 
175.5 
29.3 
20.8 
136 
176.8 
29.5 
20.5 
137 
178.1 
29.7 
20.3 
138 
179.4 
29.9 
20.1 
139 
180.7 
30.1 
19.9 
140 
182.0 
30.3 
19.7 
141 
183.3 
30.6 
19.5 
142 
184.6 
30.8 
19.2 
143 
185.9 
31.0 
19.0 
144 
187.2 
31.2 
18.8 
145 
188.5 
31.4 
18.6 
146 
189.8 
31.6 
18.4 
147 
191.1 
31.9 
18.2 
148 
192.4 
32.1 
17.9 
149 
193.7 
32.3 
17.7 
150 
195.0 
32.5 
17.5 
151 
196.3 
32.7 
17.3 
152 
197.6 
32.9 
17.1 
153 
198.9 
33.2 
16.9 
154 
200.2 
33.4 
16.6 
155 
201.5 
33.6 
16.4 
156 
202.8 
33.8 
16.2 
157 
204.1 
34.0 
16.0 
 
 
 


 
 
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12.3.2 Table C2: Volumes of IMP and diluent for dose level 0.65 mg/kg 
Note! This table is used for dilution of  
• all doses for subjects with eGFR >30 and <60 mL/min/1.73 m2 and  
• 3rd, 4th, and 5th dose for subjects eGFR ≥60 mL/min/1.73 m2 
 
Body Weight 
Dose (mg) 
(for 0.65 mg/kg) 
Volume of IMP 
(mL) 
Volume of 0.9% Sodium 
Chloride (mL) 
50 
32.5 
5.4 
44.6 
51 
33.2 
5.5 
44.5 
52 
33.8 
5.6 
44.4 
53 
34.5 
5.7 
44.3 
54 
35.1 
5.9 
44.2 
55 
35.8 
6.0 
44.0 
56 
36.4 
6.1 
43.9 
57 
37.1 
6.2 
43.8 
58 
37.7 
6.3 
43.7 
59 
38.4 
6.4 
43.6 
60 
39.0 
6.5 
43.5 
61 
39.7 
6.6 
43.4 
62 
40.3 
6.7 
43.3 
63 
41.0 
6.8 
43.2 
64 
41.6 
6.9 
43.1 
65 
42.3 
7.0 
43.0 
66 
42.9 
7.2 
42.9 
67 
43.6 
7.3 
42.7 
68 
44.2 
7.4 
42.6 
69 
44.9 
7.5 
42.5 
70 
45.5 
7.6 
42.4 
71 
46.2 
7.7 
42.3 
72 
46.8 
7.8 
42.2 
73 
47.5 
7.9 
42.1 
74 
48.1 
8.0 
42.0 
75 
48.8 
8.1 
41.9 
76 
49.4 
8.2 
41.8 
77 
50.1 
8.3 
41.7 
78 
50.7 
8.5 
41.6 
79 
51.4 
8.6 
41.4 
80 
52.0 
8.7 
41.3 
81 
52.7 
8.8 
41.2 
82 
53.3 
8.9 
41.1 
83 
54.0 
9.0 
41.0 


 
 
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Body Weight 
Dose (mg) 
(for 0.65 mg/kg) 
Volume of IMP 
(mL) 
Volume of 0.9% Sodium 
Chloride (mL) 
84 
54.6 
9.1 
40.9 
85 
55.3 
9.2 
40.8 
86 
55.9 
9.3 
40.7 
87 
56.6 
9.4 
40.6 
88 
57.2 
9.5 
40.5 
89 
57.9 
9.6 
40.4 
90 
58.5 
9.8 
40.3 
91 
59.2 
9.9 
40.1 
92 
59.8 
10.0 
40.0 
93 
60.5 
10.1 
39.9 
94 
61.1 
10.2 
39.8 
95 
61.8 
10.3 
39.7 
96 
62.4 
10.4 
39.6 
97 
63.1 
10.5 
39.5 
98 
63.7 
10.6 
39.4 
99 
64.4 
10.7 
39.3 
100 
65.0 
10.8 
39.2 
101 
65.7 
10.9 
39.1 
102 
66.3 
11.1 
39.0 
103 
67.0 
11.2 
38.8 
104 
67.6 
11.3 
38.7 
105 
68.3 
11.4 
38.6 
106 
68.9 
11.5 
38.5 
107 
69.6 
11.6 
38.4 
108 
70.2 
11.7 
38.3 
109 
70.9 
11.8 
38.2 
110 
71.5 
11.9 
38.1 
111 
72.2 
12.0 
38.0 
112 
72.8 
12.1 
37.9 
113 
73.5 
12.2 
37.8 
114 
74.1 
12.4 
37.7 
115 
74.8 
12.5 
37.5 
116 
75.4 
12.6 
37.4 
117 
76.1 
12.7 
37.3 
118 
76.7 
12.8 
37.2 
119 
77.4 
12.9 
37.1 
120 
78.0 
13.0 
37.0 
121 
78.7 
13.1 
36.9 
122 
79.3 
13.2 
36.8 
123 
80.0 
13.3 
36.7 


 
 
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Page 63 of 73 
Body Weight 
Dose (mg) 
(for 0.65 mg/kg) 
Volume of IMP 
(mL) 
Volume of 0.9% Sodium 
Chloride (mL) 
124 
80.6 
13.4 
36.6 
125 
81.3 
13.5 
36.5 
126 
81.9 
13.7 
36.4 
127 
82.6 
13.8 
36.2 
128 
83.2 
13.9 
36.1 
129 
83.9 
14.0 
36.0 
130 
84.5 
14.1 
35.9 
131 
85.2 
14.2 
35.8 
132 
85.8 
14.3 
35.7 
133 
86.5 
14.4 
35.6 
134 
87.1 
14.5 
35.5 
135 
87.8 
14.6 
35.4 
136 
88.4 
14.7 
35.3 
137 
89.1 
14.8 
35.2 
138 
89.7 
15.0 
35.1 
139 
90.4 
15.1 
34.9 
140 
91.0 
15.2 
34.8 
141 
91.7 
15.3 
34.7 
142 
92.3 
15.4 
34.6 
143 
93.0 
15.5 
34.5 
144 
93.6 
15.6 
34.4 
145 
94.3 
15.7 
34.3 
146 
94.9 
15.8 
34.2 
147 
95.6 
15.9 
34.1 
148 
96.2 
16.0 
34.0 
149 
96.9 
16.1 
33.9 
150 
97.5 
16.3 
33.8 
151 
98.2 
16.4 
33.6 
152 
98.8 
16.5 
33.5 
153 
99.5 
16.6 
33.4 
154 
100.1 
16.7 
33.3 
155 
100.8 
16.8 
33.2 
156 
101.4 
16.9 
33.1 
157 
102.1 
17.0 
33.0 
 
 
 


 
 
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Page 64 of 73 
12.4 
APPENDIX D: eCRF DOCUMENTATION 
12.4.1 Table D1: Risk Factors 
AKI Risk Number 
AKI Risk Description 
AKIRISK1  
Left ventricular ejection fraction (LVEF) <35% at any time during the 3-
month period before or at the time of screening  
AKIRISK2 
Repeat surgery/history of previous open chest cavity cardiac surgery with 
or without CPB  
AKIRISK3 
Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months prior to 
screening AND ongoing treatment with an approved anti-diabetic drug  
AKIRISK4  
Age ≥70 years at the time of screening  
AKIRISK5  
Heart failure New York Heart Association (NYHA) class II or higher at 
any time during the 3-month period before or at the time of screening  
AKIRISK6  
Documented history of previous AKI as per KDIGO criteria longer than 3 
months before date of screening  
AKIRISK7  
Anemia with hemoglobin ≤11 g/dL at any time during the 3-month period 
before or at the time of screening  
AKIRISK8  
Albuminuria, defined as urine albumin-to-creatinine ratio (UACR) >100 
mg/g in a spot urine sample or > 100 mg/24 hour in a 24-hour urine 
collection at any time during the 3-month period before or at the time of 
screening.  
AKIRISK9  
Estimated glomerular filtration rate is <60 mL/min/1.73 m2 using the 
CKD-EPI equation with SCr at the time of screening  
 
12.4.2 Table D2: Inclusion/Exclusion Criteria 
Inclusion/Exclusion 
Number 
Inclusion/Exclusion Description 
Inclusion 1 
Institutional Review Board (IRB)-/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 
Inclusion 2 
Subject has the ability to understand and comply with the study 
requirements and is able to provide written informed consent 
Inclusion 3 
Subject age is ≥18 and <85 years 
 
 


 
 
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Inclusion 4 
Estimated glomerular filtration rate (eGFR) is ≥30 mL/min/1.73 m2 (at 
screening) using the Chronic Kidney Disease-Epidemiology 
Collaboration (CKD-EPI) equation with SCr 
Inclusion 5a and 5b 
Subject is scheduled for non-emergent CABG surgery AND/OR valve 
surgery (single or multiple valves) AND/OR ascending aorta aneurysm 
surgery with use of CPB AND AKI risk factors are present (at screening) 
as specified below: 
a. If only one type of surgery is scheduled at least two AKI risk factors  
    should be present OR eGFR should be <60 mL/min/1.73m2 (at  
    screening) with or without additional risk factors 
b. If any combined surgery is scheduled at least one AKI risk factor  
    should be present 
    Risk factors for AKI are defined below: 
• Left ventricular ejection fraction (LVEF) <35% at any time 
during the 3-month period before or at the time of screening as 
assessed by either echocardiography, cardiac magnetic resonance 
imaging (MRI) or nuclear scan. 
• Repeat surgery/history of previous open chest cavity cardiac 
surgery with or without CPB 
• Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months 
prior to screening AND ongoing treatment with an approved anti-
diabetic drug 
• Age ≥70 years at the time of screening 
• Heart failure New York Heart Association (NYHA) class II or 
higher at any time during the 3-month period before or at the time 
of screening 
• Documented history of previous AKI as per KDIGO criteria 
longer than 3 months before date of screening independent of the 
etiology of AKI 
• Anemia with hemoglobin ≤11 g/dL at any time during the 3-
month period before or at the time of screening 
• Albuminuria, defined as urine albumin-to-creatinine ratio 
(UACR) >100 mg/g in a spot urine sample or > 100 mg/24 hour 
in a 24-hour urine collection at any time during the 3-month 
period before or at the time of screening. 
• Estimated glomerular filtration rate is <60 mL/min/1.73 m2 using 
the CKD-EPI equation with SCr at the time of screening 
 
 


 
 
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Inclusion 6a and 6b 
Female subject is either: 
a. 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) 
 
b. Of childbearing potential 
• Agree not to try to become pregnant throughout the treatment 
period, and for 7, days after the final Investigational Medicinal 
Product (IMP) administration 
• Must have a negative serum pregnancy test at screening 
• If sexually active, agree to consistently use a highly effective 
form of birth control (see Appendix 1 of the study protocol) 
starting at screening and throughout the treatment period, for 7 
days after final IMP administration. If required by local law, 2 
highly effective methods of birth control must be used, 1 of which 
must be a barrier method 
Inclusion 7 
Female subject must not be breastfeeding starting at screening, 
throughout the treatment period and for 7 days after the final IMP 
administration 
Inclusion 8 
Female subject must not donate ova starting at screening, throughout the 
treatment period and for 7 days after the final IMP administration 
Inclusion 9 
Male subject and their female spouse/partner(s) who are of childbearing 
potential must be using a condom starting at screening and continue to do 
so throughout the treatment period and for 7 days after final IMP 
administration. If required by local law, 2 highly effective methods of 
birth control must be used, 1 of which must be a barrier method. 
Inclusion 10 
Male subjects must not donate sperm starting from screening, throughout 
the treatment period for up to 7 days after final IMP administration 
Inclusion 11 
Subject agrees not to participate in another interventional study from the 
time of signing the informed consent until the EOS visit 
Exclusion 1 
Subject has any medical condition that in the opinion of the Investigator 
makes the subject unsuitable for study participation 
Exclusion 2 
Subject is scheduled for emergent surgeries (e.g., aortic dissection) 
 
 


 
 
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Exclusion 3 
Subject is scheduled for CABG and/or valve surgery and/or ascending 
aorta aneurysm surgery combined with additional non-emergent cardiac 
surgeries (e.g., congenital heart defects) 
Exclusion 4 
Subject is scheduled to undergo transcatheter aortic valve implantation 
(TAVI) or transcatheter aortic valve replacement (TAVR), or off-pump 
surgeries or left ventricular assist device (LVAD) implantation 
Exclusion 5 
Subject experiences a cardiogenic shock 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 
Exclusion 6 
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) 
Exclusion 7 
Subject has been diagnosed with AKI (as defined by KDIGO criteria) 
within 3 months prior to surgery 
Exclusion 8 
Required cardiopulmonary resuscitation within 14 days prior to cardiac 
surgery 
Exclusion 9 
Ongoing sepsis (as defined by SEPSIS-3, the Third International 
Consensus Definitions for Sepsis and Septic Shock) within the past 2 
weeks or, in the opinion of the Investigator, an untreated diagnosed 
clinically significant infection (viral or bacterial) prior to or at screening 
and before randomization. 
Exclusion 10 
Total bilirubin or alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 2 times the upper limit of normal (ULN) at 
screening 
Exclusion 11 
Subject has a history of solid organ transplantation 
Exclusion 12 
Subject has a history of renal replacement therapy (RRT) 
Exclusion 13 
Subject has a medical condition which requires active 
immunosuppressive treatment 
Exclusion 14 
Subject has severe allergic asthma defined as confirmed diagnosis of 
asthma poorly controlled while receiving high-dose inhaled corticosteroid 
treatment, or with requirement of a high level of treatment to maintain 
control 
Exclusion 15 
Subject has an ongoing chemotherapy or radiation therapy for 
malignancy that may have an impact on kidney function as assessed by 
the medical monitor 
Exclusion 16 
Subject has received an investigational medicinal product within the last 
90 days (or within 5 half-lives of the investigational drug, whichever is 
longer) 


 
 
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Exclusion 17 
Subject has a known allergy to RMC-035 or one of its constituents, or 
has previously received RMC-035 
 
 
 


 
 
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Page 69 of 73 
12.5 
APPENDIX E: DERIVATION OF URINE OUTPUT 
Deriving Records for Analysis 
• For each subject and urine output record, calculate the start time of the collection and the 
stop time of collection in minutes compared to the date and time of the first dose of IMP 
o (Start Date/Time – First Dose of IMP Date/Time)/60 = urine start (min) 
o (End Date/Time – First Dose of IMP Date/Time)/60 = urine stop (min) 
Subject 
Total volume 
(mL) 
Urine Start 
(min) 
Urine Stop 
(min) 
Duration 
(min) 
1001-001 
1100 
-10 
45 
55 
1001-001 
45 
44 
103 
59 
 
• Gaps between urine collection records: 
o ≤30 minute gaps 
 Urine output records with a collection start date/time ≤30 minutes after the 
collection end date/time of the previous record, then the start date/time of 
the record will be equal to the end date/time of the previous record. The 
justification for the transformation is: the accumulated urine in the tubes 
over the time of replacement of the urine drainage bag will appear in the 
output of the subsequent sample. 
Subject 
Total 
volume 
(mL) 
Urine 
Start 
(min) 
Urine 
Stop 
(min) 
Adjusted 
Urine Start 
(min) 
Adjusted 
Urine Stop 
(min) 
Adjusted 
Duration 
(min) 
1001-001 
1100 
-10 
45 
-10 
45 
55 
1001-001 
45 
44 
103 
45 
103 
60 
 
o >30 minute gaps 
 If there is a gap between the start date/time of one record and the end 
date/time of the previous record, then then a record with a missing volume 
will be added from the end date/time of the record prior to the gap to the 
start date/time of the record after the gap.  
Data without empty record: 
Subject 
Total 
volume 
(mL) 
Urine Start 
(min) 
Urine Stop 
(min) 
Adjusted 
Urine Start 
(min) 
Adjusted 
Urine Stop 
(min) 
Adjusted 
Duration 
(min) 
1001-001 
1100 
-10 
45 
-10 
45 
55 
1001-001 
45 
44 
103 
45 
103 
60 
1001-001 
80 
145 
205 
145 
205 
60 
1001-001 
100 
206 
266 
205 
266 
61 
 


 
 
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Page 70 of 73 
Data WITH empty record: 
Subject 
Total 
volume 
(mL) 
Urine Start 
(min) 
Urine Stop 
(min) 
Adjusted 
Urine Start 
(min) 
Adjusted 
Urine Stop 
(min) 
Adjusted 
Duration 
(min) 
1001-001 
1100 
-10 
45 
-10 
45 
55 
1001-001 
45 
44 
103 
45 
103 
60 
1001-001 
 
 
 
103 
145 
42 
1001-001 
80 
145 
205 
145 
205 
60 
1001-001 
100 
206 
266 
205 
266 
61 
 
• Now that the urine output records per subject are derived in minutes and gaps between 
collections are corrected, the urine output records for the analysis of AKI need to be 
defined: 
o For each record, create a urine volume per minute. Thus, there will be a record for 
each minute of the adjusted duration (min): 
𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑚𝑚𝑚𝑚 𝑃𝑃𝑃𝑃𝑃𝑃 1 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚= 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 (𝑚𝑚𝑚𝑚)
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 (𝑚𝑚𝑚𝑚𝑚𝑚) 
For example, the first record for Subject 1001-001 will be transformed to a volume per 
minute as follows: 
 
Subject 
Volume 
per minute 
(mL) 
Minute of 
Adjusted 
Duration 
1001-001 
20 
-10 
1001-001 
20 
-9 
1001-001 
20 
-8 
... 
 
 
1001-001 
20 
42 
1001-001 
20 
43 
1001-001 
20 
44 
1001-001 
20 
45 
 
• Please be aware that a missing result and a total volume of 0 mL are NOT the same. A 
total volume of 0 mL means the subject did not have any urine collected for that time 
frame.  
 
• The primary endpoint specifies that AKI is defined as >First dose of IMP Date/Time and 
≤72 hours (4,320 minutes) after the first dose of IMP. Thus, for each subject, records 
where the minute is <0 or >4,320 should be removed. 


 
 
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Subject 
Volume 
per minute 
(mL) 
Minute of 
Adjusted 
Duration 
1001-001 
20 
1 
1001-001 
20 
2 
1001-001 
20 
3 
... 
 
 
1001-001 
20 
42 
1001-001 
20 
43 
1001-001 
20 
44 
1001-001 
20 
45 
... 
 
 
1001-001 
0.75 
57 
1001-001 
0.75 
58 
1001-001 
0.75 
59 
1001-001 
0.75 
60 
 
• Now, the records need to transformed back into hours. The urine volume per hour will be 
summarized by summing the volume per minute using the sequential records in minutes 
with a maximum of 60 records. For example, the first 60 records per subject will be the 
first hour of urine collection. For Subject 1001-101, the first hour would be derived as 
follows: 
𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑚𝑚𝑚𝑚
= (20 𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚∗45 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚) + (0.75 𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚∗15 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚) 
= 911.25 𝑚𝑚𝑚𝑚 
Subject 
Hour 
Total 
volume 
(mL) 
Missing 
Values 
1001-001 
1 
911.25 
0 
 
• Since there are missing records due to gaps >30 minutes between records, there may not 
be enough records to calculate the urine volume per hour. Thus, use the following 
derivations: 
o If >20 minutes (i.e., 20 records) of the urine volume per minute is missing in a  
1 hour period, then the total volume per hour will be set to missing. 
o Otherwise, impute the total volume per hour as follows: 
𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝 ℎ𝑜𝑜𝑜𝑜𝑜𝑜
= 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑚𝑚𝑚𝑚∗
60
60 −# 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 ,  
0 ≤𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 ≤20 
 


 
 
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o Note: a total volume of 0 mL is NOT considered a missing result.  
 
• Finally, the urine total volume needs to be adjusted for the subject’s weight:  
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝 𝑘𝑘𝑘𝑘= 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑚𝑚𝑚𝑚 𝑝𝑝𝑝𝑝𝑝𝑝 ℎ𝑜𝑜𝑜𝑜𝑜𝑜
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
 
The weight of the subject is collected at Screening, Day 2, Day 3, and Day 4. The 
following weight adjustments will be used for the following intervals: 
 0<Hours≤24: Adjust using weight at Screening 
 24<Hours≤48: Adjust using weight at Day 2 
 48<Hours≤72: Adjust using weight at Day 3 
If weight is missing at Screening, then the weight at Day 2 will be used. If weight is 
missing at any other visit after Screening, then the last non-missing weight will be used.  
Derivation of AKI Utilizing DISJOINT Intervals (Utilized in the Primary Analysis): 
Review the urine volume per hour (mL) in 6 hour intervals (e.g., hours 1-6, 7-12, 13-18, …, 67-
72) for each subject. If within a 6 hour consecutive non-missing interval a subject has all urine 
volumes per hour <0.5 mL/kg/hour, then the subject will be flagged as having AKI. For AKI 
stage, repeat this process using 12 and 24 hour consecutive intervals. 
Derivation of AKI Utilizing ROLLING Intervals (Utilized in a Sensitivity Analysis): 
Review the urine volume per hour (mL) in 6 hour intervals (e.g., hours 1-6, 2-7, 3-8, …, 67-72) 
for each subject. If within a 6 hour consecutive non-missing interval a subject has all urine 
volumes per hour <0.5 mL/kg/hour, then the subject will be flagged as having AKI. For AKI 
stage, repeat this process using 12 and 24 hour consecutive intervals. 
 
 


 
 
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12.6 
APPENDIX F: CONDITIONAL POWER ANALYSIS 
Table F: Sample Size Assessment Utilizing Primary Endpoint (AKI) – mITT Set 
 
Value 
Results used from Cochran-Mantel-Haenszel estimate [1] 
 
   Sample size used at the interim analysis (n1) 
x 
   Estimated RR 
x.xx 
   90 % CI  
x.xx,x.xx 
Log (RR) 
x.xxx 
Variance (Log-RR) 
xx.xxx 
Z1 
x.xxx 
 
 
Computed Values 
   Conditional power (CP) [2] 
xx 
CI, confidence interval; RR, relative risk. 
The Modified Intent to Treat Set (mITT) includes all randomized subjects who  
received at least 1 dose of IMP and is based on randomized treatment group.  
 
[1] Cochran-Mantel-Haenszel estimate with stratification factors of region (North America  
and Europe) and eGFR at Day -1 (≥60 and <60 mL/min/1.73m2) (alpha=0.10). 
 
[2] CP = 1 – Phi([zalpha * sqrt(n2) – z1 * sqrt(n1)]/sqrt(tilden2) –  
(z1 * sqrt(tilden2))/sqrt(n1));  
where Phi is the cumulative density function (CDF) for the standard normal N(0,1),  
alpha is 0.10, zalpha is 1.645, z1 is the z-score corresponding to the Log RR statistic 
z1=-ln(RR)/sqrt[Var{ln(RR)}], n1 is n of interim analysis, n2 is n of final analysis  
(268), tilden2 is n2 - n1 (incremental sample size between interim and final analysis). 
 
NOTE: Conditional Power is not provided as a percentage, but on the 0-1 scale.