A Randomized, Multi-centric, Placebo-controlled, Participant and Investigator-blinded Study to Evaluate the Safety, Tolerability and Efficacy of TIN816 in Adult Patients at Risk for Acute Kidney Injury Following Cardiac Surgery.
Phase: PHASE2
Conditions: Acute Kidney Injury Following Cardiac Surgery
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
Clinical Trial Protocol Title
A randomized, multi-centric, placebo-controlled, participant 
and investigator-blinded study to evaluate the safety, 
tolerability and efficacy of TIN816 in adult patients at risk 
for acute kidney injury following cardiac surgery
NCT05524051
Clinical Trial Protocol Number: CTIN816A12201
Version Number: v02 (Clean)
Compound: TIN816
Brief Title: A multi-center study to evaluate the safety, tolerability and efficacy of 
TIN816 in patients at risk for acute kidney injury following a cardiac surgery
Study Phase: IIa
Sponsor Name: Novartis
Regulatory Agency Identifier Number(s): EudraCT 2022-000794-47
Approval Date: 25-Jan-2024 (content final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022

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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................7
Amendment 2 (January 2024)..............................................................................................8
Amendment 1 (April 2023)................................................................................................14
1
Protocol summary..............................................................................................................17
1.1
Summary................................................................................................................17
1.2
Schema...................................................................................................................23
1.3
Schedule of activities (SoA) ..................................................................................23
2
Introduction........................................................................................................................29
2.1
Study rationale .......................................................................................................29
2.2
Background............................................................................................................29
2.3
Benefit/Risk assessment.........................................................................................31
2.3.1
.32
2.3.2
.33
2.3.3
Infusion and hypersensitivity reactions.................................................33
2.3.4
Anti-drug antibody mediated reactions (immunogenicity) ...................34
2.3.5
COVID-19.............................................................................................34
2.3.6
Drug-drug interactions at pharmacodynamic level ...............................34
2.3.7
Blood sample volume............................................................................35
2.4
Prevention of pregnancy ........................................................................................35
3
Objectives, endpoints, and estimands................................................................................36
3.1
Primary estimands..................................................................................................39
3.2
Secondary estimands..............................................................................................39
4
Study design.......................................................................................................................40
4.1
Overall design ........................................................................................................40
4.2
Scientific rationale for study design.......................................................................41
4.2.1
Participant input into design..................................................................43
4.3
Justification for dose..............................................................................................44
4.3.1
Rationale for choice of background therapy .........................................45
4.4
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................45
4.5
Rationale for public health emergency mitigation procedures ..............................46
4.6
Purpose and timing of interim analyses/design adaptations ..................................46
4.7
End of study definition...........................................................................................47
5
Study population................................................................................................................47
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5.1
Inclusion criteria ....................................................................................................47
5.2
Exclusion criteria ...................................................................................................48
5.3
Lifestyle considerations .........................................................................................51
5.3.1
Recreational drugs.................................................................................51
5.3.2
Activity..................................................................................................51
5.4
Screen failures........................................................................................................52
5.4.1
Replacement policy ...............................................................................52
5.4.2
Participant numbering ...........................................................................52
6
Study treatment(s) and concomitant therapy .....................................................................52
6.1
Study treatment(s)..................................................................................................53
6.1.1
Additional study treatments...................................................................53
6.1.2
Treatment arms/group ...........................................................................53
6.2
Preparation, handling, storage, and accountability ................................................53
6.2.1
Handling of study treatment..................................................................54
6.2.2
Handling of other treatment...................................................................54
6.2.3
Instruction for prescribing and taking study treatment..........................54
6.3
Measures to minimize bias: randomization and blinding ......................................55
6.3.1
Treatment assignment, randomization...................................................55
6.3.2
Treatment blinding ................................................................................55
6.3.3
Emergency breaking of assigned treatment code ..................................56
6.4
Study treatment compliance...................................................................................57
6.4.1
Recommended treatment of adverse events ..........................................57
6.5
Dose modification..................................................................................................58
6.6
Continued access to study treatment after the end of the study.............................58
6.6.1
Post-trial access .....................................................................................58
6.7
Treatment of overdose ...........................................................................................58
6.7.1
Reporting of study treatment errors including misuse/abuse ................58
6.8
Concomitant and other therapy..............................................................................59
6.8.1
Concomitant therapy .............................................................................59
6.8.2
Prohibited medication............................................................................60
6.8.3
Rescue medicine....................................................................................61
7
Discontinuation of study treatment and participant discontinuation/withdrawal ..............62
7.1
Discontinuation of study treatment........................................................................62
7.2
Participant discontinuation from the study ............................................................63
7.3
Withdrawal of informed consent and exercise of participants’ data privacy 
rights.......................................................................................................................63

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7.4
Lost to follow-up....................................................................................................64
7.5
Study stopping rules...............................................................................................64
7.6
Early study termination by the Sponsor.................................................................65
8
Study Assessments and Procedures ...................................................................................65
8.1
Screening................................................................................................................65
8.1.1
Eligibility screening...............................................................................66
8.1.2
Information to be collected on screening failures .................................66
8.2
Participant demographics/other baseline characteristics........................................66
8.2.1
67
8.3
Efficacy assessments..............................................................................................67
8.3.1
Serum Creatinine...................................................................................67
8.3.2
AKI incidence and severity ...................................................................67
8.3.3
Major Adverse Kidney Event (MAKE) ................................................69
8.3.4
Estimated glomerular filtration rate (eGFR) .........................................69
8.3.5
Appropriateness of efficacy assessments ..............................................70
8.4
Safety assessments.................................................................................................70
8.4.1
Physical examinations ...........................................................................70
8.4.2
Vital signs..............................................................................................70
8.4.3
Electrocardiograms................................................................................71
8.4.4
Oxygen saturation..................................................................................71
8.4.5
Clinical safety laboratory tests ..............................................................71
8.4.6
Pregnancy testing...................................................................................73
8.4.7
Appropriateness of safety measurements ..............................................74
8.5
Additional assessments ..........................................................................................74
8.5.1
Clinical Outcome Assessments (COAs)................................................74
8.5.2
Surgery related information...................................................................75
8.5.3
Collection of mechanical ventilation information.................................75
8.5.4
Information on renal replacement therapy ............................................75
8.5.5
Information on hospitalization ..............................................................75
8.5.6
...................................................................................75
8.5.7
Fluid Balance, urine output, blood loss.................................................76
8.5.8
........................................................................76
8.6
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting.................................................................................................................76
8.6.1
Adverse events.......................................................................................77
8.6.2
Serious adverse events...........................................................................78
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8.6.3
SAE reporting........................................................................................79
8.6.4
Pregnancy ..............................................................................................80
8.6.5
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs....................................................................81
8.6.6
Adverse events of special interest .........................................................81
8.7
..82
..82
8.8
..83
8.9
Immunogenicity assessments.................................................................................84
8.9.1
Immunogenicity blood sample collection and handling........................85
8.9.2
Immunogenicity analytical method(s)...................................................85
8.10
Health economics OR Medical resource utilization and health economics...........85
9
Statistical considerations....................................................................................................85
9.1
Analysis sets...........................................................................................................85
9.2
Statistical analyses .................................................................................................86
9.2.1
General considerations ..........................................................................86
9.2.2
Participant demographics and other baseline characteristics ................86
9.2.3
Treatments.............................................................................................86
9.3
Primary endpoint(s)/estimand(s) analysis..............................................................86
9.3.1
Definition of primary endpoint(s) .........................................................87
9.3.2
Statistical model, hypothesis, and method of analysis ..........................87
9.3.3
Handling of intercurrent events of primary estimand............................87
9.3.4
Handling of missing values not related to intercurrent event................87
9.3.5
Sensitivity analyses ...............................................................................87
9.3.6
Supplementary analysis.........................................................................87
9.4
Secondary endpoint(s)/estimand(s) analysis..........................................................88
9.4.1
Safety endpoints ....................................................................................88
9.4.2
Acute Kidney Injury Network (AKIN) criteria.....................................89
9.4.3
Immunogenicity.....................................................................................89
9.4.4
Acute Kidney Disease (AKD)...............................................................89
9.5
Exploratory endpoint(s)/estimand(s) analysis........................................................90
90
90
90
9.6
(Other) Safety analyses..........................................................................................91
9.7
Other analyses........................................................................................................92
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9.8
Interim analysis......................................................................................................92
9.9
Sample size determination .....................................................................................92
9.9.1
Primary endpoint(s)...............................................................................92
10 Supporting documentation and operational considerations...............................................93
10.1
Appendix 1: Regulatory, ethical, and study oversight considerations...................93
10.1.1
Regulatory and ethical considerations...................................................93
10.1.2
Informed consent process......................................................................94
10.1.3
Data protection ......................................................................................95
10.1.4
Committees structure.............................................................................96
10.1.5
Data quality assurance...........................................................................96
10.1.6
Source documents..................................................................................97
10.1.7
Publication policy..................................................................................98
10.1.8
Protocol adherence and protocol amendments......................................98
10.2
Appendix 2: Abbreviations and definitions .........................................................100
10.2.1
List of abbreviations............................................................................100
10.2.2
Definitions...........................................................................................104
10.3
Appendix 3: Clinical laboratory tests...................................................................108
10.3.1
Clinically notable laboratory values and vital signs............................108
10.4
Appendix 4: Participant Engagement ..................................................................110
10.5
Appendix 5: Liver safety monitoring...................................................................111
10.5.1
Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................112
10.6
Appendix 6: 
 
..............................................................................................................115
11 References........................................................................................................................116
List of tables
Table 1-1
Objectives and related endpoints...........................................................17
Table 1-2
Assessment Schedule.............................................................................25
Table 3-1
Objectives and related endpoints...........................................................36
Table 4-1
Rationale for study design.....................................................................41
Table 6-1
Investigational and control drug............................................................53
Table 6-2
Blinding and unblinding plan................................................................56
Table 6-3
Prohibited medication/procedures.........................................................60
Table 7-1
.64
Table 7-2
.65
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Table 8-1
The modified AKIN classification system of acute kidney injury........68
Table 8-2
The kidney disease improving global outcomes (KDIGO) 
classification..........................................................................................68
Table 8-3
The RIFLE (Risk, Injury, Failure, Loss of kidney function, and 
End-stage kidney disease) classification ...............................................69
Table 8-4
Local Laboratory evaluations................................................................72
Table 9-1
91
Table 10-1
Clinically notable laboratory values....................................................108
Table 10-2
Liver event and laboratory trigger definitions.....................................112
Table 10-3
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL......................................................................................................113
Table 10-4
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia..............................................................................114
Table 10-5
115
List of figures
Figure 1-1
Study design ..........................................................................................23
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Amendment 2 (January 2024)
Amendment rationale 
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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval of a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 1 (April 2023)
Amendment rationale 
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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval of a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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1
Protocol summary
1.1
Summary
Protocol Title:
A randomized, multi-centric, placebo-controlled, participant and investigator-blinded study to 
evaluate the safety, tolerability and efficacy of TIN816 in adult patients at risk for acute kidney 
injury following cardiac surgery.
Brief Title:
A multi-center study to evaluate the safety, tolerability and efficacy of TIN816 in patients at 
risk for acute kidney injury following cardiac surgery.
Purpose
This is a phase IIa study to evaluate the safety, tolerability and efficacy of TIN816 in patients 
at risk for acute kidney injury (AKI) following major cardio-vascular surgery, versus placebo.
Study indication /Medical Condition:
Patients at risk of developing acute kidney injury following cardiac surgery.
Treatment type
A
 dose of investigational study treatment TIN816 will be administered via an i.v. infusion 
over 
.
Study type
Interventional phase IIa study to evaluate the safety, tolerability and efficacy of TIN816
Objectives, Endpoints, and Estimands:
Table 1-1
Objectives and related endpoints
Objectives
Endpoints
Primary
To assess the effect of TIN816 on serum 
creatinine levels in patients at high risk for AKI 
and undergoing major cardio-vascular surgery, 
versus placebo
Ratio of the highest serum creatinine value (up 
to and including Study Day 6) versus baseline
Secondary
To evaluate the safety and tolerability of TIN816
Safety based on vital signs, physical 
examination, ECGs, laboratory assessments 
and collection of AEs assessed from baseline 
until the end of the study visit
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Objectives
Endpoints
To assess the effect of TIN816 on the incidence 
and severity of AKI in patients at high risk for 
AKI and undergoing major cardio-vascular 
surgery, versus placebo.
AKI stages 1, 2 and 3 as defined 
by modified AKI Network (AKIN) criteria for 
serum creatinine
To assess immunogenicity of TIN816
Anti-drug antibodies against TIN816
To assess the effect of TIN816 on the incidence 
of acute kidney disease (AKD) in high-risk 
patients undergoing major cardio-vascular 
surgery, versus placebo
Occurrence of major adverse kidney events at 
day 30 (MAKE30) and day 90 (MAKE90)
Occurrence of individual components of the 
MAKE criteria at Days 30 or 90.
Trial Design:
This is a non-confirmatory, randomized, multi-centric, placebo-controlled, participant and 
investigator-blinded study. Approximatively 120 adult patients at risk for acute kidney injury 
(AKI) following non-emergent cardiac surgery will be enrolled in the study.
The study consists of a pre-operative period (screening visit), a treatment period (Day 1) and a 
follow-up period (Day 2 to Day 90). Participants will be followed up daily in the hospital from 
Day 2 to Day 8 (or at home/nearby accommodation/in a rehabilitation unit if discharged earlier 
than Day 8), and then as an out-patient until the end of study (Day 30 and Day 90 visits). 
Participants will receive a 
 i.v. infusion of TIN816 or placebo on Day 1, after wound 
closure.
 
 
 
 
 
 
 
 
Brief Summary:
AKI is a frequent and serious complication of cardiopulmonary bypass surgery (CPBS), 
however, there are no effective therapies to prevent or treat AKI. Depending on the definition, 
AKI occurs in up to 15-40% of adults after CPBS. Of those patients who experience AKI as a 
complication of cardiac surgery, the odds of death increase from four‑fold for mild cases, to 
greater than fifteen-fold for severe AKI. Severe AKI requires renal replacement therapy in 1-5% 
of cases and is associated with a mortality rate of up to 70%.
Perioperative organ injury is caused by ischemia and concomitant hypoxia‑induced 
inflammation. During hypoxic or inflammatory disease states, many cells release ATP from 
their intracellular space toward the extracellular compartment. In the extracellular space, ATP 
can activate P2 receptors, which have been shown to cause inflammatory activation and organ 
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injury. 
 
. In addition, extracellular ATP is a potent inducer of 
vasoconstriction which can lead to lack of perfusion and no-reflow phenomenon. In conjunction 
with the activation of P2Y12 via extracellular ADP leading to platelet activation and thrombosis, 
microvascular occlusions and long-lasting damage can occur. Specifically, the kidney is largely 
dependent on maximal perfusion, oxygenation, and nutrition. In addition, the unique 
microvascular system of the kidney and the high demand in the proximal tubular cells makes 
this organ highly vulnerable to the described pathomechanisms.
 
 
 
 
 
Data generated in non-clinical pharmacokinetics, pharmacology, and toxicology studies as well 
as in the first in human (FIH) clinical study support further testing of TIN816 in patients. 
The current study will be the first clinical trial in which TIN816 is tested in patients.
This study is designed to assess the safety, tolerability and efficacy of TIN816 in patients at risk 
of cardiac surgery associated AKI (CSA-AKI). A total of approximately 120 participants will 
be randomized to TIN816 or placebo.
Participants enrolling into this study will be managed according to current medical and surgical 
standard of care and as per standard institutional procedures. The study will consist of a 
pre-operative period (screening visit), a treatment period (Day 1) and a follow-up  period (Day 2 
to Day 90). Participants will be monitored daily in the hospital from Day 2 to Day 8 (or at home, 
in a nearby accommodation (e.g., hotel) or in a rehabilitation center if discharged earlier than 
Day 8), and then as an out-patient until the end of study (Day 30 and Day 90 visits). 
On Day 1, the participant will undergo on-pump cardiac surgery. Randomization will be 
performed at start of surgery based on the leading surgeon or delegate’s expectation of a CPB 
time of at least 60 min. However, TIN816 or placebo will only be administered after the main 
surgery has been completed and actual CPB time has been confirmed as ≥ 60 min, and also only 
after the leading surgeon has confirmed that there is no ongoing or active bleeding. 
 
 
 
 
Efficacy endpoints include assessments of renal function and Major 
Adverse Kidney Events (MAKE).
Safety assessments, 
 immunogenicity (IG) and 
 will be 
assessed starting pre-surgery and up to end of study. Safety assessments will include physical 
examinations, ECG, vital signs, standard clinical laboratory evaluations (hematology, blood 
chemistry, coagulation parameters, and urinalysis), adverse event and serious adverse event 
monitoring.
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Treatment of interest
TIN816 (human recombinant 
 enzyme).
Number of Participants:
Approximately 120 patients aged 45 years or older with risk factors for acute kidney injury. 
These patients will be randomly assigned to study intervention or placebo.
Key Inclusion criteria
•
Signed informed consent must be obtained prior to participation in the study.
Article I.
Participants must be able to communicate well with the investigator and to 
understand and comply with the requirements of the study.
Article II.
Male and female patients ≥45 years at screening
Article III.
Participants must weigh at least 50 kg and maximum 150 kg to participate 
in the study and must have a body mass index (BMI) below 40. BMI = Body weight (kg) / 
[Height (m)]2
•
At screening, vital signs should be assessed in the sitting or supine position and be within 
the following ranges:
a. body temperature between 35.0-37.5 °C
b. blood pressure (systolic 100-160 mmHg, diastolic < 100 mmHg)
c. pulse rate (50-100/min) stable with or without medication(s) as per Investigator‘s 
assessment.
If vital signs are outside these ranges, the Investigator may obtain two additional readings, 
so that up to three consecutive assessments are made. At least the last reading must be 
within the ranges provided above for the participant to qualify. 
•
Stable renal function with no known increase in SCr of ≥25% at screening visit compared 
to a previous value obtained within the last 6 months as documented by a local laboratory 
using standard assay methodology, and no AKI present (any stage) at pre-surgery baseline 
at discretion of the investigator. 
•
Non-emergent open chest cavity major cardiopulmonary bypass (CPB) surgery with 
expected CPB time ≥1 hour, defined by any of the following options:
 
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Key Exclusion criteria
•
eGFR at screening <15 mL/min/1.73 m2 (calculated using CKD-EPI 2021 equation)
•
Receiving renal replacement therapy (RRT) currently or at any time within 3 months prior 
to screening, or scheduled to start RRT shortly after cardiac surgery.
•
Patients with bleeding risk at screening, or identified as such pre-surgery if screening was 
performed earlier than Day -1. The Investigator should make this determination in 
consideration of the participant's medical history and/or clinical or laboratory evidence of 
any of the following:
•
History of bleeding with suspected or confirmed bleeding disorder or any other high 
risk for bleeding in the opinion of the investigator
•
Thrombocytopenia: platelet count <100x109/L
•
History of platelet dysfunction e.g., ADP induced platelet aggregation lower than 
60%
•
History of coagulation factor deficiencies, including but not limited to fibrinogen ≤ 
2.5 g/L or Von Willebrand factor (vWF) ≤ 50 IU/dL.
•
Duration of cardiopulmonary bypass (CPB) <60 minutes
•
Patient with active bleeding at the end of the surgery as per assessment of the leading 
surgeon
•
Donation or loss of >450 mL of blood or > 200 mL of plasma within four weeks prior to 
dosing, or longer if required by local regulation
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•
Scheduled to undergo cardiac surgery off CPB or with hypothermic circulatory arrest or 
scheduled to undergo TAVI or TAVR only or single vessel, minimally invasive direct 
coronary artery bypass (MIDCAB) off-pump surgeries or left ventricular assist device 
(LVAD) implantation.
Treatment Groups:
Participants will be randomized at visit Day 1 to one of the following treatment arms:
•
For participants enrolled under protocol amendment v00 and v01:
•
 i.v. infusion of TIN816 
mg/kg 
•
 i.v. infusion of placebo
•
For participants enrolling under protocol amendment v02 onwards:
•
 i.v. infusion of TIN816 
mg/kg
•
 i.v. infusion of placebo
For treatment allocation ratio please refer to Section 6.1.2.
Administration of either TIN816 or placebo will occur via 
 intravenous infusion.
Data Monitoring/Other Committee:
Yes, see Section 10.1.4 (Committees Structure)
Key words
Inflammation, 
 acute kidney injury, cardiopulmonary bypass surgery
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1.2
Schema
Figure 1-1
Study design
1.3
Schedule of activities (SoA)
The SoA lists all the assessments when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation. The “X” in the table 
denotes the assessments to be recorded in the clinical database or received electronically from 
a vendor. The “S” in the table denotes the assessments that are only in the participant’s source 
documentation and do not need to be recorded in the clinical database.
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation.
Participants who discontinue from study should be scheduled for a final evaluation visit if they 
agree, as soon as possible, at the time all the assessments listed for the final visit will be 
performed. At this final visit the adverse events and concomitant medications not previously 
reported must be recorded on the CRF.
The preferred sequence of data collection during study visits is ECG collection first, followed 
by vital signs, and blood sampling.
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the Investigator as the situation 
dictates. If allowable by a local health authority, national and local regulations and depending 
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on operational capabilities, phone calls, virtual contacts (e.g., tele consultation) or visits by site 
staff/ off-site healthcare professional(s) staff to the participant´s home, can replace certain 
protocol assessments, for the duration of the disruption until it is safe for the participant to visit 
the site again. If the Investigator delegates tasks to an off-site healthcare professional, the 
Investigator must ensure the individual(s) is/are qualified and appropriately trained to perform 
assigned duties. The Investigator must oversee their conduct and remain responsible for the 
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Table 1-2
Assessment Schedule
Period Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Treatment day 1
Follow-
up 
day 2
Follow-up 
day 3
Follow-
up 
day 4
Follow
-up 
day 5
Follow
-up 
day 6
Follow
-up 
day 7
Follow
-up 
day 8
Follow
-up 
day 30
Follow-
up day 
90 (EOS)
Visit Numbers1
1
100
110
120
130
140
150
160
170
1802
1999
Days
-30 to -1
1
2
3
4
5
6
7
8
30
±3
90
±7
Time
-
Pre-surgery Predose 0H3
20
8h20
24h20
48h20
72h20
-
-
-
-
-
-
Informed consent
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic consent
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria
X
 
X4 
 
 
 
 
 
 
 
 
 
 
 
Demography
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/current medical 
conditions
X
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis and TB screen15
S
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination
S
 
 
 
 
 
 
 
 
 
 
 
 
S
Body Height
X
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight
X
 
 
 
 
 
 
 
 
 
X
X
X
Vital signs10
X
X
X
X
X
X
X
X
X
 
X
X
X
Electrocardiogram (ECG)
X
 
 
 
X
X
X
X
 
 
 
X
X
X
Surgery related information7
 
 
X
 
 
 
 
 
 
 
 
Urine output11
 
 
X9
 
 
 
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Period Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Treatment day 1
Follow-
up 
day 2
Follow-up 
day 3
Follow-
up 
day 4
Follow
-up 
day 5
Follow
-up 
day 6
Follow
-up 
day 7
Follow
-up 
day 8
Follow
-up 
day 30
Follow-
up day 
90 (EOS)
Visit Numbers1
1
100
110
120
130
140
150
160
170
1802
1999
Days
-30 to -1
1
2
3
4
5
6
7
8
30
±3
90
±7
Time
-
Pre-surgery Predose 0H3
20
8h20
24h20
48h20
72h20
-
-
-
-
-
-
Oxygen Saturation)12
Drug administration record
 
 
X3
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick
X13
X
 
X
X
X
X
 
X
X
X
Urine microscopy/sediment
X13
 
X
 
X
 
X
Urine chemistry
X
X13
X
X
X
X
X
X
X
X
X
Full Hematology
X
X13
 
X
X
X
X
Limited Hematology14
X
X
X
X
X
X
Full Clinical Chemistry
X
X13
 
X
X
X
X
X
X
Limited Clinical Chemistry
 
X
 
X
Lipids
X
X
Immunogenicity
 
X13
 
 
 
 
 
 
 
 
X
X
X
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Period Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Treatment day 1
Follow-
up 
day 2
Follow-up 
day 3
Follow-
up 
day 4
Follow
-up 
day 5
Follow
-up 
day 6
Follow
-up 
day 7
Follow
-up 
day 8
Follow
-up 
day 30
Follow-
up day 
90 (EOS)
Visit Numbers1
1
100
110
120
130
140
150
160
170
1802
1999
Days
-30 to -1
1
2
3
4
5
6
7
8
30
±3
90
±7
Time
-
Pre-surgery Predose 0H3
20
8h20
24h20
48h20
72h20
-
-
-
-
-
-
Concomitant medications
as required
Information on renal 
replacement therapy
as required
Information on hospitalization23
as required
Adverse Events
as required
Serious Adverse Events
as required
Study completion information
 
 
 
 
 
 
 
 
 
 
 
 
 
X
Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only. 
2 If the patient is in rehabilitation, this visit can be performed remotely
3 
4 Check exclusion criterion # 11 (time on CPB pump) and #12 (active bleeding) before proceeding to study drug administration 
5 
6 
 
7 Date of surgery, type of surgery, start/end time of surgical intervention, start/end time of cardio-pulmonary bypass, concomitant vasopressor medication and dose, any 
surgical re-assessment for bleeding
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9 Blood loss, urine output and fluid balance from beginning to end of surgery (before start of TIN816/placebo administration)
10 Vital signs will include the collection of body temperature (recorded in °C), blood pressure (BP) and pulse measurements. 
11 From collection bag if urine catheter still in place
12 
. 
13 This pre-surgery assessment can be performed on Day-1. If Screening assessment  has been done on Day -1, no need to perform a new pre-surgery collection.
14 Only platelets count, leucocytes, erythrocyte count, hemoglobin, HCT need to be tested  
15 To be performed only if clinically indicated to rule out active infection 
16 
 
17 
18 
19 
20 Time post TIN816/placebo infusion start; 
 
21 
22 
23 Duration of ICU stay, duration of overall hospital stay after cardiac surgery (from Day 1 to day of discharge), occurrence/date of any rehospitalization 
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2
Introduction
2.1
Study rationale
The purpose of this study is to assess the safety, tolerability and efficacy of TIN816 in patients 
at risk for AKI following cardiac surgery.
2.2
Background
Despite remarkable progress, acute organ injury remains one of the leading causes for morbidity 
and mortality in surgical and intensive care patients.
Advancements in modern medicine, in emergency and intensive care have led to significant 
improvements in monitoring capabilities, in safer drugs, and somewhat improved outcomes. 
Patients who require major surgical interventions - such as cardiothoracic, vascular, general 
surgery, or solid organ transplantation - may often experience perioperative acute organ injury. 
For example, acute kidney injury (AKI), Delayed Graft Function (DGF), acute myocardial 
infarction (AMI), acute ischemic stroke (AIS), intestinal ischemia, reperfusion injury, or lung 
injury are some of the complications that are among the leading causes of perioperative 
morbidity and mortality (Eltzschig, Carmeliet 2011, Eltzschig, Eckle 2011). Acute organ 
injuries represent major cost drivers in the intensive care setting and their prevention is a 
significant unmet medical need.
AKI is a frequent and serious complication of cardiopulmonary bypass surgery (CPBS), 
however, there are no effective therapies to prevent or treat AKI. AKI is new or worsened renal 
insufficiency characterized by a relatively abrupt decrease in glomerular filtration rate (GFR), 
often accompanied by a reduction in urine output (Mehta, Clarke 2007). AKI usually occurs 
within the first 7 days after an initial insult, most commonly following an episode of transient 
hypotension of any cause, but may also occur in response to nephrotoxins or radio-contrast 
media (Waikar et al 2008, Kellum et al 2013). The clinical incidence of AKI is found in 3-18% 
of all hospitalized adult patients worldwide, (Hoste et al 2018) and is more common in the 
context of complex surgery. Depending on the definition, AKI occurs in up to 15-40% of adults 
after CPBS, (Zanardo et al 1994, Rosner, Okusa 2006). Of those patients who experience AKI 
as a complication of cardiac surgery, the odds of death increase from four‑fold for mild cases, 
to greater than fifteen-fold for severe AKI (Chertow et al 1998). Severe AKI requires renal 
replacement therapy in 1–5% of cases and is associated with a mortality rate of up to 70% 
(Khosla et al 2009).
In many instances, perioperative organ injury is caused by ischemia and concomitant 
hypoxia‑induced inflammation. Hypoxia and inflammation share an interdependent 
relationship, where inflammatory diseases such as intestinal inflammation or acute lung injury 
can cause inflamed areas to become severely hypoxic. This typically occurs because of 
increased metabolic demand of resident and inflammatory cells while metabolic supply is 
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During hypoxic or inflammatory disease states, many cells release ATP from their intracellular 
space toward the extracellular compartment. In the extracellular space, ATP can activate 
extracellular ATP receptors, which are classified as P2 receptors. They function as G-protein 
coupled receptors (P2Y receptors) or as ligand-gated ion channels (P2X receptors). Activation 
of P2 receptors has been shown to cause inflammatory activation and organ injury during 
ischemia or inflammation, and therapeutic strategies to reduce ATP receptor activation have 
been hypothesized for the treatment of inflammatory diseases (Idzko et al 2007, 
Colgan, Eltzschig 2012, Gulbransen et al 2012).
 
In addition, extracellular ATP is a potent inducer of vasoconstriction 
which can lead to lack of perfusion and no-reflow phenomenon. In conjunction with the 
activation of P2Y12 via extracellular ADP leading to platelet activation and thrombosis, 
microvascular occlusions and long-lasting damage can occur. Specifically, the kidney is largely 
dependent on maximal perfusion, oxygenation, and nutrition. In addition, the unique 
microvascular system of the kidney and the high demand in the proximal tubular cells makes 
this organ highly vulnerable to the described pathomechanisms.
In contrast to the pro-inflammatory functions of ATP receptors, adenosine receptors have been 
shown to attenuate hypoxic inflammation (Rosenberger et al 2009), provide metabolic tissue 
adaptation to increase ischemia tolerance (Eckle et al 2012), and to promote injury resolution 
(Eckle et al 2008, Grenz et al 2008).
Conversion of extracellular ATP to adenosine is controlled by a two-step enzymatic system. 
The first step, which is rate limiting, is the conversion of extracellular ATP to adenosine 
monophosphate 
 
The subsequent second step in the extracellular generation of adenosine from AMP is catalyzed 
by the ecto-5’‑nucleotidase CD73. 
 
 
 
 
 
 
 
 
 
 has been proven beneficial in preclinical models of 
acute organ injuries, including mouse models of ischemia-reperfusion induced AKI where 
TIN816 was dose dependently preserving kidney function. The protection could be shown in 
terms of kidney structure, kidney inflammation, and acute tubular necrosis, which are also 
hallmarks of human AKI pathophysiology (Basile et al 2012). In addition, the common 
biomarkers of kidney injury and repair in the kidney tissue and in the urine of animals 
undergoing AKI were normalized with TIN816 treatment. 
 
 
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Data generated in non-clinical pharmacokinetics, pharmacology, and toxicology studies as well 
as in the first in human (FIH) clinical study supported further testing of TIN816 in patients. 
The current phase 2 study (CTIN816A12201) is the first clinical trial in which TIN816 is tested 
in CS-AKI patients.
 
 
 
 
2.3
Benefit/Risk assessment
TIN816 has not been previously administered with therapeutic intent to patients undergoing 
cardiac surgery. No statement can therefore be made at this time regarding the actual clinical 
benefit of TIN816 in this population. 
 
 
 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures as well as close clinical monitoring and periodic review of safety data by 
an independent DMC.
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Please refer to the Investigator’s Brochure (Section 7) for a full review of potential risks.
2.3.1
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2.3.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.3
Infusion and hypersensitivity reactions
Injection of a foreign protein into humans may trigger an immune response with or without 
inflammatory signs and symptoms. Such reactions, if they occur, may be immediate or delayed 
up to several weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3.4
Anti-drug antibody mediated reactions (immunogenicity)
There is a possibility of TIN816 inducing an immune response in human subjects. 
 
 
The primary consequence of 
immunogenicity may be altered 
, leading to a potential loss in 
efficacy. There is also a theoretical possibility of immune-mediated reactions. During the 
non-clinical studies, presence of anti-drug antibodies (ADA) was noted in one cynomolgus 
monkey and in some rats and minipigs treated with TIN816 (see Investigator Brochure) but 
these ADA were not correlated with any safety findings. 
 
, the occurrence of ADA in either species was in the range 
expected for a human recombinant protein. It is important to note that the occurrence of ADA 
and resulting ADA-mediated immune reactions in animals are generally not considered 
predictive of the same response in humans and that severe responses to monoclonal antibodies 
in humans are rare (Bugelski, Treacy 2004). 
 
 
 
 
 
 
 
2.3.5
COVID-19
It is not known whether TIN816 
 can influence the clinical course of an 
infection with coronavirus SARS-CoV-2 (COVID-19). TIN816 is designed to treat acute organ 
injuries (Peters et al 2016). Novartis is committed to supporting the safety and well-being of 
our study participants, investigators, and site staff. All local regulations and site requirements 
are being applied in the countries that are affected by the COVID-19 pandemic, including 
COVID-19 testing of participants if applicable. As the COVID-19 situation evolves, 
investigators must use their best judgement to minimize risk to participants during the conduct 
of the study.
2.3.6
Drug-drug interactions at pharmacodynamic level
 
 
 
 
 
 
 
 
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2.3.7
Blood sample volume
A volume of approximatively 450 mL is planned to be collected over a period of 4 months from 
each participant as part of the study. Samples collected as part of standard of care will not need 
to be repeated for the study. The approximate volumes are mentioned in the ICF. 
Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the schedule of activities in Section 1.3.
2.4
Prevention of pregnancy
Since TIN816 has not been tested in reproductive toxicity studies to date, the teratogenicity 
potential of TIN816 is not known. It is known that monoclonal antibodies can actively cross the 
placenta and are detectable in the fetus; however, this requires receptor-mediated transcytosis 
by binding to the neonatal Fc receptor. Proteins for which no specific transport system exists, 
are not expected to cross the placenta due to their high molecular weight (Tetro et al 2018).
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any possibility that the participant will not reliably comply, they 
should not be entered or continue in the study.
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3
Objectives, endpoints, and estimands
Table 3-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
To assess the effect of TIN816 on serum 
creatinine level in patients at high risk for AKI 
and undergoing major cardio-vascular 
surgery, versus placebo
•
Ratio of the highest serum creatinine value 
up to and including Study Day 6 versus 
baseline
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
To evaluate the safety and tolerability of 
TIN816
•
Assessment of safety based on vital signs, 
physical examination, ECGs, laboratory 
assessments, and collection of AEs 
assessed from baseline until the end of the 
study visit
•
To assess the effect of TIN816 on the 
incidence and severity of AKI inpatients at 
high risk for AKI and undergoing major 
cardio-vascular surgery, versus placebo
•
AKI stages 1, 2 and 3 as defined 
by modified AKI Network (AKIN) criteria
•
To assess immunogenicity (IG) of TIN816
•
Anti-drug antibodies (ADA) against TIN816
•
To assess the effect of TIN816 on the 
incidence of AKD in high-risk patients 
undergoing major cardio-vascular surgery, 
versus placebo
•
Occurrence of major adverse kidney event 
at Day 90 (MAKE90)
•
Occurrence of MAKE30
•
Occurrence of individual components of the 
MAKE criteria at Days 30 or 90.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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Objective(s)
Endpoint(s)
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Objective(s)
Endpoint(s)
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Objective(s)
Endpoint(s)
3.1
Primary estimands
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results.
The primary clinical question of interest is: what is the effect of treatment with TIN816 on 
serum creatinine levels (up to and including Study Day 6) in adult patients at high risk of 
developing AKI after undergoing non-emergent CPB surgery regardless of the use of any 
concomitant medications (such as vasopressors), and factors potentially associated with 
changes in serum creatinine levels, such as fluid overload and oxygen saturation.
The justification for the primary estimand is that it will capture both the effect of the study 
treatment and the effect of additional medications/AKI-associated factors, mirroring the 
conditions in clinical practice.
3.2
Secondary estimands
Not applicable.
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4
Study design
4.1
Overall design
This is a non-confirmatory, randomized, multi-centric, placebo-controlled, participant and 
investigator-blinded study. Approximatively 120 adult patients at risk for acute kidney injury 
following non-emergent cardiac surgery will be enrolled in the study.
There will be 3 groups in the study:
•
Placebo
•
TIN816 
mg/kg; subjects enrolling under original protocol and amendment 1
•
TIN816 
mg/kg from protocol amendment 2 onwards
Participants enrolling into this study will be managed according to current medical and surgical 
standard of care and as per standard institutional procedures. The study will consist of a 
pre-operative period (screening visit), a treatment period (Day 1) and a post-treatment follow 
up period (Day 2 to Day 90). 
Participants will be followed up daily in the hospital from Day 2 to Day 8 (or at home, in a 
nearby accommodation (e.g., hotel) or in a rehabilitation center if discharged earlier than Day 
8), and then as an out-patient until the end of study (Day 30 and Day 90 visits).
Patients, who are scheduled to undergo non-emergent open chest cavity or minimally invasive 
cardiac surgeries with cardio-pulmonary bypass (CPBS), will be informed about the study 
purpose and provided with study-specific participant information and informed consent.
Participants who have agreed to participate will be asked to sign a study-specific written 
informed consent and attend a screening visit to determine their eligibility, within 30 days prior 
to the surgery. The visit will assess the participant's suitability to participate in the study based 
on study inclusion and exclusion criteria.
During the pre-operative period, eligible participants will have blood and urine collected for 
safety lab and 
. The pre-operative values will be considered baseline 
values.
On Day 1, the participant will undergo cardiac surgery. Randomization will be performed at 
start of surgery based on the leading surgeon or delegate’s expectation of a CPB time of at least 
60 min. However, actual administration of TIN816 or placebo will only be administered once 
the main surgery has been completed and preparations are ongoing to close the wound, and the 
leading surgeon has confirmed that there is no active bleeding, and it is safe to proceed with 
wound closure. 
 
 
 
 
 
Safety assessments, 
, immunogenicity (IG) and 
 will be done 
for up to end of study visit (see Assessment schedules Section 1.3). Blood and urine samples 
will be collected for these assessments.
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During each visit, basic demographic, clinical information and adverse events (AE) will be 
collected and entered in a Case Report Form (CRF). The collected samples and clinical 
information will be provided to Novartis in coded form.
Safety assessments will include physical examinations, ECG, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, coagulation parameters, and urinalysis), 
adverse event and serious adverse event monitoring.
Remote procedures
At the Investigator's discretion and based on benefit-risk considerations of the participant's 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures according to Section 1.3 Schedule of Activities performed at a remote location.
Procedures will be performed remotely under the oversight of the Investigator, who retains 
accountability for the oversight. The Investigator retains accountability for all efficacy and 
safety decisions with delegation of tasks to an off-site healthcare professional.
The remote procedures will be utilized in certain countries and sites as determined by protocol 
needs and based on national and local/site regulations.
The off-site healthcare professionals will be provided by the site, or a third-party vendor sourced 
by Novartis. Where a site wishes to use off-site healthcare professionals from a third-party 
vendor that is not provided by Novartis this must be agreed with Novartis before use.
In addition to procedures performed by the off-site healthcare professional, the on-site staff may 
perform certain procedures remotely using tele-visits.
4.2
Scientific rationale for study design
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Targeted study population
The inclusion criteria for this study were chosen 
following current knowledge on clinical and 
demographic factors associated with AKI and 
with a goal to enroll patients at highest risk for 
developing AKI after cardiac surgery. According 
to literature, subjects undergoing complex 
surgeries with long CPB times and patients with 
pre-existing kidney disease and other 
comorbidities as well as older individuals in 
general have a higher risk to develop AKI after 
the surgery. 
 
 
 
 
 
 (Delanaye et al 2019).
 
 
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Study Design Aspect
Rationale
(Pottel et al 2017, 
 
 
 
 
 
 
 
 
 
 
 
 
.
Randomization (strata, allocation ratio)
Randomization decreases the chance of 
imbalance of participant characteristics between 
groups, thereby facilitating an unbiased 
assessment of safety, tolerability and efficacy. 
In addition, randomization prevents selection 
bias.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinding
The study is participant- and investigator-blinded 
until final database lock (except where indicated 
in Section 6.3) to reduce potential bias in the 
assessment of readouts.
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Study Design Aspect
Rationale
Duration of study periods
The study follow-up duration is 90 days to allow 
for a meaningful assessment of the safety, 
tolerability and efficacy of TIN816 in AKI. 
The incidence and severity of AKI will be 
assessed through the first week after surgery 
and the MAKE criteria will be evaluated at 
Day 30 and 90.
 
 
 
 
Treatment groups
The control group is placebo on top of standard 
of care because there is no approved treatment 
for AKI
4.2.1
Participant input into design
Acute kidney injury (AKI) is a silent condition, characterized by a sudden deterioration of 
kidney function, sometimes with reduced or even complete loss of urine output. Most patients 
will experience this syndrome during a hospital stay, especially critically ill patients and patients 
undergoing major surgeries. Recovery from AKI is possible, however, in some patients, kidney 
function will continue to decline further and remain chronically impaired. Some patients will 
need at least short-term dialysis or will be left with severe renal impairment and remain dialysis 
-dependent with the need for a kidney transplant.
Based on an internal review of social information mining data conducted by Novartis in 2021, 
acute kidney injury patients reported being admitted to the hospital for around 7 days to restore 
their kidney function. In some cases, patients had to stay longer and required hemodialysis 
treatment, besides other minor interventions. After the acute kidney injury episode, patients 
reported feeling exhausted and drained after the hospital stay. Other points of concern were the 
financial strain from the treatment and the fear of acquiring another unexpected medical 
emergency/complication.
Many patients described how much their lives changed because of dialysis or transplantation. 
For instance, they said they had to stop travelling because of dialysis or transplant. Some of 
them even lost partners or the job they loved because of the many hours they had to spend 
attached to the dialysis machine. Some of them were also discouraged from becoming pregnant 
or continuing with a pregnancy because of the high risks involved.
Many patients need to relocate to live close to a hospital where they can undergo dialysis.
Most patients would simply like to avoid dialysis. The most important drug they would like to 
have is the one that would prevent AKI from progressing into severe AKI or severe kidney 
dysfunction, and even better, prevent any AKI from developing to begin with.
Since severe AKI is also associated with a high mortality rate in the more severe cases, and no 
treatment is currently available, all preventive measures should be taken to avoid the heavy 
burden of this common, but usually overlooked, clinical entity.
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4.3
Justification for dose
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In this study, patients will be administered placebo or the study drug at a dose of 
 mg/kg (for 
patients enrolled under the original protocol and protocol amendment 1) or 
mg/kg (from 
protocol amendment 2 onwards) via a 
 intravenous infusion in a double-blinded fashion. 
Due to the acute nature of AKI and 
 
 it is believed that 
 at 
mg/kg should result 
in a pharmacologically relevant systemic and tissue TIN816 exposure which is 
 
. This is based on in vitro and ex vivo PD assessments in human whole 
blood and the assumption that close to full inhibition of 
 pathways are 
required to provide efficacy. 
 
 
 
 
 
 
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Dose administration 
 provides time to react if unexpected safety related 
reactions occur during dosing. 
 
 
 
 
 
 
 
 
Patients will be followed up for a total duration of 90 days, 
 and safety data 
used to adapt the dose level at interim analysis and to support the dosing strategy for subsequent 
studies in this indication.
4.3.1
Rationale for choice of background therapy
Patients undergoing cardiac surgery are sedated and ventilated, and hence medicated with 
sedatives, anesthetics and analgesics. Moreover, cardiac patients receive anti-platelet therapies 
due to a generally increased risk of thromboembolic events, plus heparin to prevent clotting 
within the cardiopulmonary bypass circuits. Caution is required when TIN816 is 
 
 adequate monitoring of respective 
 is required as per protocol (see Section 8.4.5). There are no specific 
medicines currently approved or available for the prevention or treatment of acute kidney injury 
(AKI), and standard interventions usually consist of fluid management and hemodynamic 
support. These standards will be followed in this trial for both treatment groups (TIN816 and 
placebo) as deemed necessary by the study physician and medical team in charge as per local 
procedures.
4.4
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The comparator treatment in the study will be placebo, in order to provide objective control for 
the evaluation of safety, clinical efficacy and PD parameters. Since there is no approved 
treatment for AKI, the use of placebo as comparator is considered justified. Standard 
background interventions for the prevention as well as treatment of AKI include fluid 
management and hemodynamic stabilization. These will be applied to both study cohorts, 
TIN816 and placebo, as part of standard therapy during and after surgery.
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4.5
Rationale for public health emergency mitigation procedures
During a public health emergency as declared by local or regional authorities (i.e., pandemic, 
epidemic or natural disaster), mitigation procedures to ensure participant safety and trial 
integrity may be implemented: such procedures are listed in the relevant sections. The principal 
investigator should notify and discuss the public health emergency as declared by local or 
regional authorities with Novartis before implementation of any such procedures. All 
procedures adapted to the situation must be submitted, if required as per local regulations, 
through a protocol amendment (see Section 10.1.8.1) to the competent authorities and ethics 
committees prior to implementation of mitigation procedures. 
4.6
Purpose and timing of interim analyses/design adaptations
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the Sponsor’s clinical development projects in general, or in case of any 
safety concerns.
Additional information is presented in the interim analysis Section 9.8.
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4.7
End of study definition
The end of the study is defined as the date of the last visit of the last participant in the study.
Study completion is defined as when the last participant finishes their last study visit and any 
repeat assessments associated with this visit have been documented and followed -up 
appropriately by the Investigator.
5
Study population
The study population will be comprised of approximately 120 patients who are scheduled to 
undergo non-emergent CPB surgery and are at risk of developing AKI.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Participants must be able to communicate well with the investigator and to understand and 
comply with the requirements of the study.
3. Male and female patients ≥45 years at screening.
4. Participants must weigh at least 50 kg and maximum 150 kg to participate in the study and 
must have a body mass index (BMI) below 40. BMI = Body weight (kg) / [Height (m)]2.
5. At screening, vital signs should be assessed in the sitting or supine position and be within 
the following ranges:
a. body temperature between 35.0-37.5 °C
b. blood pressure (systolic 100-160 mmHg, diastolic < 100 mmHg)
c. pulse rate (50-100/min) stable with or without medication(s) as per Investigator 
assessment
 
6. Stable renal function with no known increase in SCr of ≥25% at screening visit compared 
to a previous value obtained within the last 6 months as documented by a local laboratory 
using standard assay methodology, and no AKI present (any stage) at pre-surgery baseline 
at discretion of the investigator.
7.
 
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8. Non-emergent open chest cavity major cardiopulmonary bypass (CPB) surgery with 
expected CPB time ≥1 hour, defined by any of the following options:
 
 
 
 
 
 
 
 
 
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. eGFR at screening <15 mL/min/1.73m2 (calculated using CKD-EPI 2021 equation).
2. Receiving renal replacement therapy (RRT) currently or at any time within 3 months prior 
to screening or scheduled to start RRT shortly after cardiac surgery.
3. Patients with bleeding risk at screening (or identified pre-surgery if screening was 
performed earlier than Day -1). The Investigator should make this determination in 
consideration of the participant's medical history and/or clinical or laboratory evidence of 
any of the following:
•
History of bleeding with suspected or confirmed bleeding disorder or any other high 
risk for bleeding in the opinion of the investigator
•
Thrombocytopenia: platelet count <100x109/L
•
History of platelet dysfunction e.g., ADP induced platelet aggregation lower than 
60 %
•
History of coagulation factor deficiencies: including, but not limited to fibrinogen 
≤ 2.5 g/L or Von Willebrand factor (vWF) ≤50 IU/dL
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4. Any emergency surgeries performed less than 30 days before screening, including aortic 
dissection, and/or major congenital heart defects.
5. Scheduled to undergo cardiac surgery off CPB or with hypothermic circulatory arrest.
6. Scheduled to undergo TAVI or TAVR only or single vessel, minimally invasive direct 
coronary artery bypass (MIDCAB) off-pump surgeries or left ventricular assist device 
(LVAD) implantation (Note: See Inclusion Criterion #8).
7. Cardiogenic shock or hemodynamic instability within four weeks prior to surgery, 
requiring inotropes or vasopressors or mechanical devices such as intra-aortic balloon 
counter-pulsation (IABP). Current or within four weeks prior to surgery, clinically 
significant arrhythmias associated with syncope, dyspnea or hemodynamic instability
8. Have required any of the following within four weeks prior to cardiac surgery: 
defibrillator, mechanical (invasive) ventilation, IABP, LVAD, other forms of mechanical 
circulatory support (MCS).
9. Have received cardiopulmonary resuscitation (CPR) within 30 days prior to cardiac 
surgery.
10.
 
11. Duration of cardiopulmonary bypass (CPB) <60 minutes.
12. Patient with active bleeding at the end of surgery as per assessment of the leading surgeon.
13. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations.
14. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes.
16. Patients who are post-nephrectomy.
17. Any significant QT prolongation as per PI judgment and/or concomitant use of agents 
known to prolong the QT interval unless they can be discontinued or replaced by safe 
alternative for the duration of study (at the discretion of the investigator).
18. Taking medications prohibited by the protocol (see Table 6-3 (Prohibited medications)).
19. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.
20. Donation or loss of >450 mL of blood or > 200 mL of plasma within four weeks prior to 
dosing, or longer if required by local regulation.
21. Have a history of any organ or cellular transplant which requires active 
immunosuppressive treatment which can interfere with kidney function (e.g., calcineurin 
inhibitors).
22. Have ongoing sepsis or history of sepsis within the past 8 weeks or untreated diagnosed 
infection prior to screening visit. Sepsis is defined as presence of a confirmed pathogen, 
along with fever or hypothermia, and hypoperfusion or hypotension.
23. Heart failure stage IV as defined by the New York Heart Association (NYHA) Functional 
Classification.
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24. Left ventricular ejection fraction of < 30% as per most recent echocardiography available.
25. Recent (within the last three years) and/or recurrent history of autonomic dysfunction 
(e.g., recurrent episodes of fainting, palpitations, etc.).
26. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the participant in 
case of participation in the study. The Investigator should make this determination in 
consideration of the participant's medical history and/or clinical or laboratory evidence of 
any of the following:
•
Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding;
•
Pancreatic injury or pancreatitis;
•
Liver disease or liver injury as indicated by abnormal liver function tests: ALT 
(SGPT), AST (SGOT), GGT, alkaline phosphatase and serum bilirubin will be tested.
•
Evidence of significant urinary obstruction or difficulty in voiding at screening.
If necessary, laboratory testing may be repeated on one occasion (as soon as possible) 
prior to randomization, to rule out any laboratory error.
27. History of immunodeficiency diseases or known HIV positive test.
28. Active hepatitis defined as (a) abnormal liver enzymes (Alanine aminotransferase (ALT), 
Gamma-glutamyl transferase (GGT) and ALP > 3x Upper Limit of Normal (ULN)) or (b) 
for active hepatitis B or C infection, a positive Hepatitis B Virus (HBV) or Hepatitis C 
Virus (HCV) serology, as per most recent test available, or patients with advanced chronic 
liver disease, confirmed by a Child-Pugh score of 10–15 (Class C).
29. In patients where medical and travel history, clinical symptoms, or the standard 
pre-operative chest x-ray (not older than 1 month before screening visit) suggest 
possibility for active or latent TB, a QuantiFeron tuberculosis test or a purified protein 
derivative test (PPD, ≥5 mm induration) should be performed, and patient should be 
excluded if the test result is positive or cannot be done. Patients can be included if 
treatment for TB is initiated and completed according to local treatment guidelines.
30. History of drug abuse or unhealthy alcohol use# within the 12 months prior to dosing, or 
evidence of such abuse per investigator judgement at screening.
#Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined 
as “Five or more drinks on the same occasion on each of 5 or more days in the past 
30 days."
31. Pregnant or nursing (lactating) women.
32. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and until the end of study. Highly effective contraception methods 
include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, sympto-thermal and post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
•
Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
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before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment.
•
Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant.
•
Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
If local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF.
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate 
history of vasomotor symptoms). Women are considered not of child-bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to 
enrollment on study. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment is she 
considered to be not of child-bearing potential.
33. Vulnerable participants, e.g., institutionalized due to regulatory or juridical order, 
dependent on sponsor, site or investigator or not able to consent, respectively.
34. Use of plasma exchange, plasmapheresis, and other extracorporeal filtration techniques 
within last month prior to screening or if planned to be used during or after the surgery.
5.3
Lifestyle considerations
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section.
5.3.1
Recreational drugs
No recreational drug use during study through study completion evaluation (i.e., cocaine, 
marijuana).
5.3.2
Activity
No strenuous physical exercise (e.g., weight training, aerobics, football) from screening until 
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5.4
Screen failures
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not randomized. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
If the participant fails to be randomized, the IRT must be notified within 2 days of the screen 
fail that the participant was not randomized. Data and samples collected from participants prior 
to screen failure may still be analyzed.
Participants who are eligible to be randomized but fail to start treatment (e.g., participants 
randomized in error, with CPB time <60 minutes, or ongoing bleeding at end of surgery), will 
be discontinued and IRT must be notified that no dosing occurred. The reason should be 
recorded on the appropriate Case Report Form.
Individuals who do not meet the criteria for participation in this study (screen failure) typically 
may not be rescreened. In the event of a strong rationale to re-screen a participant, the case must 
be discussed and agreed with Novartis on a case-by-case basis.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the eligibility criteria, the assessment may be repeated once prior to randomization. If the 
repeat value remains outside of the specified range, the participant must be excluded from the 
study.
5.4.1
Replacement policy
Participants will not be replaced on study. However, enrollment of additional participants may 
be considered until at least the minimum number of 120 evaluable participants who have 
reached Day 6 is achieved.
5.4.2
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is rescreened. The Participant No. consists of the Site 
Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
6
Study treatment(s) and concomitant therapy
The investigational drug, TIN816 or placebo, will be manufactured by Novartis and supplied to 
the unblinded pharmacist or unblinded qualified site designee. The unblinded pharmacist/ 
unblinded qualified site designee will prepare the appropriate dosage (detailed instructions will 
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Details on the requirements for storage and management of study treatment, prescribing/ 
dispensing, and administration of study treatment are outlined in the Pharmacy Manual.
6.1
Study treatment(s)
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Treatment Form 
or 
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor (global 
or local)
TIN816 70 mg 
(lyophilizate in 
vial)
Powder for  
Solution for 
infusion
Intravenous use
Open label 
patient specific  
supply; vials
Sponsor (global)
Placebo 1 mL 
(liquid in vial)
Concentrate for 
Solution for 
infusion
Intravenous use
Open label 
patient specific  
supply; vials
Sponsor (global)
Drug will be administered as 
 at the clinical site by the study personnel in 
accordance with the specified study procedures.
6.1.1
Additional study treatments
No other treatment beyond investigational drug and placebo are included in this trial.
6.1.2
Treatment arms/group
For participants enrolled under protocol amendment v00 and v01:
Participants will be randomized at visit Day 1 to one of the following treatment arms in a ratio 
of 
 (TIN816:placebo)
•
i.v. infusion of TIN816 
 mg/kg
•
i.v. infusion of placebo
For participants enrolling under protocol amendment v02 onwards:
Participants will be randomized at visit Day 1 to one of the following treatment arms in a ratio 
of 
 (TIN816:placebo)
•
i.v. infusion of TIN816 
mg/kg
•
i.v. infusion of placebo
 
6.2
Preparation, handling, storage, and accountability
Each study site will be supplied with study treatment in packaging as described under Table 6-1 
Investigational and control drugs section (for details on drug preparation please refer to the 
Pharmacy Manual).
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A 
unique 
medication 
number 
is 
printed 
on 
the 
study 
medication 
label. 
Unblinded pharmacist/unblinded qualified site designee will identify the study medication kit 
to be diluted after Investigator or delegated staff has contacted the IRT and triggered the 
medication number(s) release. The study medication has a 2-part label (base plus tear-off label), 
before diluting, the unblinded pharmacist/unblinded qualified site designee will detach the outer 
part of the label from the packaging and affix it to the source document.
6.2.1
Handling of study treatment
Study treatment must be received by an unblinded pharmacist or a qualified site designee, 
handled and stored safely and properly and kept in a secured location to which only the 
unblinded pharmacist or a qualified site designee have access. Upon receipt, all study treatment 
must be stored according to the instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The unblinded pharmacist or an unblinded qualified site designee must maintain an accurate 
record of the shipment and dispensing of study treatment in a drug accountability log. 
Monitoring of drug accountability will be performed by field monitors during site or remote 
monitoring visits, and at the completion of the trial. The unblinded pharmacist or an unblinded 
qualified site designee need to make sure all the materials required for IMP preparation are 
available at the site and at enough quantities to be used in the trial.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the Investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to 
the Novartis monitor or to the Novartis address provided in the Investigator folder at each site.
6.2.2
Handling of other treatment
Not applicable
6.2.3
Instruction for prescribing and taking study treatment
TIN816 or corresponding placebo will be administered to the participant at the study site via 
i.v. infusion over 
 (see details in the Pharmacy Manual). There should be a period 
of at least 1 hour after the infusion during which the participant requires close observation. 
Patient care should be managed as per local medical practice.
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6.3
Measures to minimize bias: randomization and blinding
6.3.1
Treatment assignment, randomization
At visit Day 1, all eligible participants for whom the PI expects a CPB time of at least 60 minutes 
will be randomized via Interactive Response Technology (IRT) to one of the treatment arms at 
start of the surgery. The IRT will assign a randomization number to the participant, which will 
be used to link the participant to a treatment arm and will specify a unique medication number 
for the first package of study treatment to be dispensed to the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. 
A participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment.
 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.3.2
Treatment blinding
Participants, Investigator staff (except unblinded pharmacist/unblinded qualified site designee) 
and persons performing the assessments will remain blinded to the identity of the treatment 
from the time of randomization until database lock.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site.
Open label supply (TIN816 and placebo) will be provided at sites to the unblinded 
pharmacist/unblinded qualified site designee in order to prepare study treatment and to conceal 
treatment code from participants and the Investigators staff performing the assessment.
The following unblinded sponsor roles are required for this study:
•
Statistician, programmers or delegates who need to prepare safety reports for the DMC 
and
•
Bioanalysts 
Both will receive a copy of the randomization schedule (via request to the Randomization 
Office), to facilitate analysis of the samples. They will provide the sample data to the study 
team under blinded conditions unless otherwise allowed. The study statistician will be able to 
access the randomization list for interim analyses and is allowed to share unblinded information 
with the rest of the clinical team as appropriate for internal decision purposes, as outlined 
in Table 6-2. For example, unblinded summaries and unblinded individual data can be shared 
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with the team for interim analyses. Statistical programmers and other personnel involved in 
study data analysis (e.g., drug supply manager) are allowed to access treatment assignment 
information for the purpose of data analysis. The clinical trial team is allowed to share unblinded 
results with other sponsor staff (e.g., decision boards) as required for internal decision making 
on the study or the project at the time of IAs while the study is ongoing. All unblinded personnel 
will otherwise keep randomization lists and data or information that could unblind other study 
team members confidential and secure except as described above. The DMC will be provided 
with unblinded results to facilitate the review of safety information (Table 6-2). More details 
will be provided in the DMC charter about the unblinding plan and data flow. Following final 
database lock all roles may be considered unblinded. See Table 6-2 for an overview of the 
blinding/unblinding plan.
Table 6-2
Blinding and unblinding plan
Time or Event
Role
Randomization 
list generated
Treatment 
allocation 
& dosing
Safety event 
(single 
subject 
unblinded)
Interim 
Analysis/ dose 
escalation/ 
safety review
Participants
B
B
UI
B
Site Staff
B
B
UI
B
Unblinded site staff, e.g., 
pharmacy staff
B
UI
UI
B
Randomization Office
UI
UI
UI
UI
Unblinded Sponsor staff, e.g., 
for study treatment re-supply, 
unblinded monitor(s), sample 
analyst(s)
B
UI
UI
UI
Independent committees used 
for assessing interim results, if 
required (e.g., DMC)
UI
UI
UI
UI
All other Sponsor staff not 
identified above (i.e., project 
team, management & decision 
boards, support functions)
B
B
UI
UI
Statistician/statistical 
programmer/ data analysts 
B
UI
UI
UI
B Complete blinded
UI Unblinded to individual participant treatment codes
6.3.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to treat the participant 
safely.
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the Investigator contacts 
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the system to break a treatment code for a participant, he/she must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for 
the participant. The Investigator will then receive details of the investigational drug treatment 
for the specified participant and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide:
•
protocol number
•
participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
A participant can continue participation in the study in the event of an unblinding incident.
6.4
Study treatment compliance
A one-time intravenous infusion will be administered in the clinic. This information must be 
captured in the source document, the appropriate CRF/s and in the Drug Accountability Log. 
The site personnel should reflect the total dose administered as well as date and time of 
administration start and end in the eCRF page. Any reason for dose interruption of the IV 
infusion will also be captured in the source document and the eCRF.
 
6.4.1
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of AEs. There is also no specific antidote to the IMP. Investigators should use their 
best clinical judgement and follow local treatment guidelines in treating adverse events.
Medication used to treat AEs must be recorded on the appropriate CRF.
Treatment of acute infusion and/or hypersensitivity reactions
As with most biologic compounds, administration of TIN816 carries the risk of anaphylaxis 
and/or hypersensitivity-type reactions. In the event of such a reaction, investigators should 
consider study-specific criteria for treatment interruption (Section 7.1), and the participant 
should be treated with antihistamines and glucocorticoids. Depending on severity, participants 
may also require supplemental oxygen, volume expansion, catecholamine administration and 
transfer to an intensive care setting. Plasmapheresis to decrease the systemic concentration of 
TIN816 may be considered dependent on the participant’s condition. Participants should be 
observed for at least four hours after resolution of signs and symptoms, and those who have 
experienced severe infusion reactions should be closely observed for 24 hours after resolution 
because of the risk for a biphasic episode.
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6.5
Dose modification
Investigational treatment dose adjustments are not permitted. Administration could be 
interrupted in case of adverse reaction (see Section 6.4.1).
6.6
Continued access to study treatment after the end of the study
There will be no treatment following the end of the study.
6.6.1
Post-trial access
Not applicable
6.7
Treatment of overdose
There is no experience with TIN816 overdose. Should an overdose occur, the participant should 
be carefully monitored for any potential symptoms and changes in laboratory parameters 
(including coagulation parameters), and if necessary, appropriate supportive care should be 
provided until the participant has recovered. The use of plasmapheresis may be considered to 
facilitate more rapid elimination of TIN816 from the peripheral circulation in the case of 
overdose.
In the event of an overdose, the Investigator should:
•
Contact the medical monitor immediately.
•
Evaluate the participant to determine, in consultation with the medical monitor, whether 
study treatment should be interrupted or whether the dose should be reduced.
•
Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
TIN816 can no longer be detected systemically.
•
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of 
study treatment if requested by the medical monitor (determined on a case-by-case basis).
•
Document the quantity of the excess dose as well as the duration of the overdose.
6.7.1
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Study treatment 
errors and uses outside of what is foreseen in the protocol, misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 

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24 hours of Investigator’s awareness. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections.
6.8
Concomitant and other therapy
6.8.1
Concomitant therapy
All concomitant therapies (medications, procedures and non-drug therapies, including physical 
therapy) administered from the day the participant was enrolled into the study until the end of 
study must be recorded on the appropriate Case Report Forms.
Note:
Volatile anesthetics are not required to be documented in the CRF, all other anesthetics and 
analgesics should be documented in the CRF for the intra-operative period but can be omitted 
if given post-operatively. One exception are NSAIDs (non-steroidal anti-inflammatory drugs), 
which should always be documented in the CRF (including topical use).
Intravenous fluids (crystalloid and colloidal) should be documented in the CRF for the intra-
operative period but are not required to be documented in the CRF for the post-operative period.
 
 
Significant procedures applied prior to trial enrollment (e.g., previous cardiac surgeries or 
cancer-related procedures) must be documented in the CRF as appropriate. 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before randomizing a participant or allowing a new medication to be started. If the participant 
is already enrolled, contact Novartis to determine if the participant should continue 
participation in the study.
6.8.1.1
Permitted concomitant therapy requiring caution and/or action
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Refer to Section 2.3.1 and Investigator Brochure for more details.
6.8.2
Prohibited medication
Use of the treatments displayed in the table below are not allowed during the indicated period:
Table 6-3
Prohibited medication/procedures
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Medication
Prohibition period
Action taken
6.8.3
Rescue medicine
 As with most biologic compounds, 
administration of TIN816 carries the risk of anaphylaxis and/or hypersensitivity-type reactions. 
In the event of such a reaction, investigators should consider study-specific criteria for treatment 
interruption (Section 7.1), and the participant should be treated with antihistamines and 
glucocorticoids. Depending on severity, participants may also require supplemental oxygen, 
volume expansion, catecholamine administration and transfer to an intensive care setting. 
Plasmapheresis to decrease the systemic concentration of TIN816 may be considered dependent 
on the participant’s condition. Participants should be observed for at least four hours after 
resolution of signs and symptoms, and those who have experienced severe infusion reactions 
should be closely observed for 24 hours after resolution because of the risk for a biphasic 
episode. Blood products (packed red blood cells, platelets, plasma, etc.) should be ordered by 
the site as is standard of care for surgical patients and stored for trial participants to allow for 
immediate transfusion in case of major bleeding events, if indicated as per Principal 
Investigator's evaluation and local procedure.
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7
Discontinuation of study treatment and participant 
discontinuation/withdrawal
7.1
Discontinuation of study treatment
The treatment involves 
 i.v. infusion over 
, and therefore the infusion can be 
interrupted at any time for the reasons described below.
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and can be initiated by either the participant or the Investigator.
The Investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being.
Discontinuation from study treatment is required under the following circumstances:
•
Participant/guardian decision
•
Use of prohibited treatment as per recommendations in the prohibited treatment section
•
Any situation in which continued study participation might result in a safety risk to the 
participant
•
Following emergency unblinding
•
Any laboratory abnormalities that in the judgment of the Investigator, prevents the 
participant from continuing participation in the study
•
Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, 
fever, chills, urticaria, dyspnea, headache, myalgia, hypotension. Immediate interruption 
of the infusion to administer study treatment is required in such cases.
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information.
Participants who discontinue from study treatment are asked to return for the follow-up visits 
indicated in Section 1.3 Schedule of Activities.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be performed according to the study visit schedule.
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact:
•
New/concomitant treatments
•
Adverse Events/Serious Adverse Events
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
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7.2
Participant discontinuation from the study
Discontinuation from study is when the participant prematurely stops receiving the study 
treatment infusion, and/or further protocol-required assessments or follow-up, for any reason.
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in Section 1.3 Schedule of Activities.
7.3
Withdrawal of informed consent and exercise of participants’ 
data privacy rights
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant:
•
Explicitly requests to stop use of their data
and
•
No longer wishes to receive study treatment
and
•
Does not want any further visits or assessments (including further study-related contacts)
This request should be as per local regulations (e.g., in writing) and recorded in the source 
documentation.
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms.
In this situation, the Investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation.
No further assessments must be conducted, and the data that would have been collected at 
subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3 Schedule of 
Activities.
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
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7.4
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g., dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed or until the end of the study.
7.5
Study stopping rules
Sponsor will review emergent safety reports on an ongoing basis to react as soon as there is a 
possibility that a stopping rule could apply. The sponsor will review all SAE as individual cases 
and will also be able to review summaries of non-serious adverse events for patterns and trends 
and will first exclude any events determined to be clearly unrelated to study treatments 
(e.g., SAE which occurred during the pre-treatment screening period, or disease-related SAE 
expected in the population under study). 
 
Table 7-1
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Table 7-2
 
7.6
Early study termination by the Sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination (but not limited to):
•
Unexpected, significant, or unacceptable safety risk to participants enrolled in the study
•
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data
•
Discontinuation of study treatment development in this indication
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from the study: the participant should come for a final End of 
Study (EOS) visit. The Investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the participant’s 
interests. The Investigator or Novartis depending on local regulation will be responsible for 
informing IRBs/IECs of the early termination of the trial.
8
Study Assessments and Procedures
Study procedures and their timing are summarized in Section 1.3 Schedule of Activities. 
Protocol waivers or exemptions are not allowed.
•
Immediate safety concerns should be discussed with Novartis upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.
•
Adherence to the study design requirements, including those specified in Section 1.3 
Schedule of Activities, is essential and required for study conduct.
•
Safety/laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Screening
Procedures conducted as part of the participant’s routine clinical management/standard of care 
(e.g., clinical chemistry, hematology, urinalysis) and obtained before signing of the ICF may 
be utilized for screening or baseline purposes provided the procedures met the 
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protocol-specified criteria and were performed within the timeframe defined in Section 1.3 
Schedule of Activities.
8.1.1
Eligibility screening
Results of below screening evaluation will be available as source data at the study site and will 
not be recorded within the eCRF.
8.1.1.1
Hepatitis screen, HIV screen, Tuberculosis screen
All participants will be evaluated for active hepatitis (refer to exclusion criterion 28).
Evaluation of history of immunodeficiency diseases or known positive HIV test documented in 
source data. Notification of state and federal authorities, as required by law, will be the 
responsibility of the Investigator.
Determination of TB status will be required before administration of study treatment and should 
be performed as defined by local guidelines (refer to exclusion criterion 29).
8.1.1.2
Alcohol test, drug screen
Participants will be assessed by the Investigator at screening for history of drug abuse and 
unhealthy alcohol use as described in Exclusion criterion 30. A positive evaluation will lead to 
the exclusion of the participant.
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and are subsequently found to be ineligible 
(either pre-surgery, or during or shortly after surgery but prior to IMP infusion) will be 
considered a screen failure. 
The reason for screen failure should be entered on the applicable Case Report Form. The 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event during the screening phase (see Section 8.6 Serious adverse events for reporting details).
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form. 
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Participant demographics: age (in years), sex, race/predominant ethnicity (if permitted) and 
relevant medical history/current medical conditions (until date of signature of informed consent) 
will be recorded in the eCRF. Participant race/ethnicity data are collected and analyzed to 
identify any differences in the safety and/or efficacy profile of the treatment due to these 
characteristics. In addition, these data are necessary to assess the diversity of the study 
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All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented up to 6 months before the study. See also the protocol 
Section 6.8.1 Concomitant Therapy for further details on what information must be recorded 
on the appropriate page of the eCRF.
To determine the eligibility for inclusion in the study, serum creatinine, eGFR and surgery 
information will be collected and recorded in the eCRF.
8.2.1
8.3
Efficacy assessments
Planned time points for all efficacy assessments are provided in Section 1.3 Schedule of 
Activities.
Pharmacodynamic (PD) samples will be collected at the time points defined in Section 1.3 
Schedule of Activities. Follow instructions outlined in the Laboratory manual regarding sample 
collection, numbering, processing, and shipment.
Pharmacodynamic samples will be obtained and evaluated in all participants at all dose levels, 
including the placebo group.
8.3.1
Serum Creatinine
Serum creatinine is a standard marker to assess renal function and diagnose AKI. 
Serum creatinine samples will be collected from participants at all visits from baseline to 
Day 90/EOS.
8.3.2
AKI incidence and severity
AKI incidence over the first week after surgery will be measured using the modified AKIN 
classification system, based on changes in serum creatinine compared to pre-operative value. 
Severity of AKI will be assessed using three stages, with stage 1 being the less severe and stage 
3 the more severe (see Table 8-1).
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Table 8-1
The modified AKIN classification system of acute kidney injury
Stage
Serum Creatinine/RRT 
1
Serum creatinine (SCr) ≥1.5 - <2.0 x baseline within 7 days post-surgery
Or
↑ SCr by ≥26.5 μmol/L (≥0.3 mg/dL) within 2 days post-surgery
2
SCr ≥2.0 - <3.0 x baseline within 7 days post-surgery
3
SCr ≥3.0x baseline within 7 days post-surgery 
Or
↑ SCr to ≥353.6 μmol/L (4.0 mg/dL) AND by ≥44.2 μmol/L (0.5 mg/dL) within 7 days 
post-surgery
Or
aInitiation of RRT within 7 days post-surgery
↑ Increase from baseline
aStage 3 includes patients requiring RRT independent of the AKI stage they are in at the moment of 
RRT initiation.
Adapted from (Barry, James 2015)
Table 8-2
The kidney disease improving global outcomes (KDIGO) classification
Stage
Serum Creatinine/RRT
1
SCr 1.5-1.9 x baseline within 7 days post-surgery
Or
↑ SCr by ≥0.3 mg/dL (≥26.5 μmol/L) within 2 days post-surgery
2
SCr 2.0-2.9 x baseline within 7 days post-surgery
3
SCr ≥3.0 x baseline within 7 days post-surgery
Or
↑ SCr to ≥4.0 mg/dL (≥353.6 μmol/L) AND by ≥0.5 mg/dL within 7 days post-
surgery
Or
Initiation of RRT
↑ Increase from baseline
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Table 8-3
The RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-
stage kidney disease) classification
Class
Serum Creatinine/GFR
Risk
SCr 1.5 x baseline or ↓ eGFR >25% 
Injury
SCr 2 x baseline or ↓ eGFR >50%
Failure
SCr 3 x baseline or ↓ eGFR >75% 
Or
↑ SCr to ≥353.6 μmol/L (≥4 mg/dL) AND by >44.2 μmol/L(>0.5 mg/dL)
Loss of kidney function
Complete loss of kidney function >4 weeks
End-stage kidney disease
Complete loss of kidney function >3 months
SCr = serum creatinine, eGFR = estimated glomerular filtration rate 
↑ Increase from baseline, ↓ decrease from baseline
8.3.3
Major Adverse Kidney Event (MAKE)
The proportion of participants having major adverse kidney event at Day 30 (MAKE30) and 90 
(MAKE90) will be assessed using the following components: 1) death, 2) initiation of renal 
replacement therapy, 3) ≥25% reduction in eGFR.
Information on death such as date of occurrence and cause will be captured in the eCRF.
In case a participant needs to receive renal replacement therapy, information will be collected 
in the eCRF, such as date, duration, method of dialysis and number of sessions.
eGFR will be calculated as described in Section 8.3.4.
8.3.4
Estimated glomerular filtration rate (eGFR)
The eGFR 2021 CKD EPI creatinine equation that estimates kidney function without a race 
variable should be used for eGFR calculations during this study. A taskforce of members from 
the National Kidney Foundation NKF and American Society of Nephrology ASN assessed the 
accuracy of a new eGFR equation that incorporates creatinine but omits race, and concluded 
the new equation to be more accurate. Immediate implementation in all US labs was 
recommended in November 2021.
eGFR = 142 × min (SCr /κ, 1)α × max (SCr /κ, 1)-1.200 × 0.9938Age × 1.012 [if female]
where: SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.241 for 
females and -0.302 for males, min indicates the minimum of SCr /κ or 1, and max indicates the 
maximum of SCr /κ or 1.
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area.

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8.3.5
Appropriateness of efficacy assessments
Serum creatinine is a standard marker used to assess renal function and diagnose AKI 
(Ronco et al 2019).
MAKE is a composite endpoint including death, need for RRT and worsening renal 
function (eGFR> 25% reduction from baseline). It can be assessed at defined intervals/ 
timepoints and is increasingly being recognized as an important patient centered outcome from 
studies in patients who are critically unwell (Billings, Shaw 2014).
8.4
Safety assessments
Safety assessments are specified below with Section 1.3 Schedule of Activities detailing when 
each assessment is to be performed.
For details on AE collection and reporting, refer to Section 8.6.
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again.
8.4.1
Physical examinations
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured.
Body mass index (BMI) will be calculated using the following formula:
•
BMI = Body weight (kg) / [Height (m)]2
The Screening Visit height measurement will be used for BMI calculations throughout the study.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be recorded on the appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse Event must be recorded 
as an adverse event.
8.4.2
Vital signs
Vital signs will include the collection of body temperature (recorded in °C), blood pressure (BP) 
and pulse measurements.
Vital signs should be measured in sitting position whenever possible and measured in supine 
position if this is not possible especially early after surgery. After the participant has been sitting 

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for 3 minutes, with back supported and both feet placed on the floor, or just in supine position, 
systolic and diastolic BP will be measured using an automated validated device, with an 
appropriately sized cuff. In case the cuff sizes available are not large enough for the participant's 
arm circumference, a sphygmomanometer with an appropriately sized cuff may be used.
If vital signs are at screening (see Inclusion Criteria  of the protocol for details), two additional 
readings can be obtained, so that up to three consecutive assessments are made, with the 
participant seated quietly for approximately five minutes preceding each repeat assessment. The 
last reading must be within the ranges provided in the eligibility criteria in order for the 
participant to qualify.
In case of repeated vital assessments, the eCRF should contain the qualifying results.
8.4.3
Electrocardiograms
The Fridericia QT correction formula (QTcF) must be used for clinical decisions, e.g., at the 
Screening visit to assess eligibility. The Investigator must calculate QTcF if it is not auto-
-calculated by the ECG machine.
ECGs will be locally collected and evaluated. Interpretation of the tracing must be made by a 
qualified physician and documented on the appropriate CRF. Each ECG tracing should be 
labeled with the study number, participant initials (where regulations permit), participant 
number, date, and kept in the source documents at the study site. Clinically significant 
abnormalities present at screening should be reported on the appropriate CRF. 
Clinically significant findings must be discussed with Novartis prior to enrolling the participant 
in the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded as adverse events. 
The original ECGs and a certified copy on non-heat sensitive paper, appropriately signed, must 
be archived at the study site.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding.
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.4
Oxygen saturation
 
 
8.4.5
Clinical safety laboratory tests
Local laboratories will be used for analysis of all safety specimens collected (see Table 8-4). 
As per Section 4.5, during a public health emergency as declared by local or regional 
authorities' i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol-specified safety lab assessments, an 
alternative lab (local) collection site may be used.
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Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening and, a decision regarding whether the result is of 
clinical significance or not shall be made by the Investigator (in consultation with Novartis) and 
shall be based, in part, upon the nature and degree of the observed abnormality. The assessment 
may be repeated once prior to randomization.
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e. result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study.
Fresh spot urine should be collected for urine assessments, e.g., urinalysis,
. 
For patients with a urine catheter in place, the fresh urine should be obtained from the catheter 
sampling port. For patients without a catheter, a mid-stream (spot) urine should be collected for 
the sample (first morning void should be avoided). 
Table 8-4
Local Laboratory evaluations
Test Category
Test Name
Full Hematology
Erythrocytes, Erythrocyte indices (MCH - Mean Corpuscular 
Hemoglobin, MCHC - Mean Corpuscular Hemoglobin 
Concentration, MCV - Mean Corpuscular Volume, 
Erythrocyte Morphology*), Hematocrit, Hemoglobin, Free 
Heme*, Platelets, Platelet indices (Platelet clumps count*, 
MPV - Mean Platelet Volume*), Leukocytes, Leukocyte 
Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Band Neutrophils)
Limited Hematology
Leucocytes, Erythrocytes, Platelets, Hematocrit, 
Hemoglobin
Full Clinical Chemistry
Albumin, Alkaline phosphatase (ALP), Alanine 
Transaminase (ALT), Amylase (total), Aspartate 
Transaminase (AST), Bicarbonate (from venous blood), 
Total Bilirubin, Direct Bilirubin (conjugated), Indirect Bilirubin 
(unconjugated), Calcium, Chloride, Creatine Kinase (CK), 
Gamma-glutamyl-transferase (GGT), *Glutamate-
dehydrogenase (GLDH), Glucose (fasting or non-fasting**), 
Lactate dehydrogenase (LDH), Lipase, Magnesium, 
Phosphate, Potassium, Sodium, Total Protein, Urea 
Nitrogen (BUN or Urea), Uric Acid, N-terminal pro b-type 
natriuretic peptide (NT-proBNP#, High-sensitivity C-reactive 
Protein (hs-CRP) #, high-sensitivity cardiac troponin# 
(preferentially I (hs-cTnI), but T can be performed if I is not 
available)
Limited Clinical Chemistry
ALT, AST, Bilirubin total, BUN, hs-CRP#, hs-CTnI (hf-
CTnT)#, LDH, NT-proBNP#
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Test Category
Test Name
Lipid Panel
HDL Cholesterol, LDL Cholesterol, Total Cholesterol, 
Triglycerides
Urine Chemistry
Urine albumin, urine creatinine, urine protein, urine albumin-
creatinine ratio (UACR), urine albumin-protein ratio (UPCR)
*Urine microscopy/sediment 
(automatic or manual)
Bacteria, Casts (RTEC - Renal Epithelial Cell Casts, GC – 
Granular Casts, HC – Hyaline Casts, Erythrocyte Casts, - 
Leucocyte Casts)
Urine dipstick 
Macroscopic Panel: Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes (leucocyte esterase), Nitrite, pH, 
Protein, Specific Gravity, Urobilinogen
Hepatitis testing 
HBV or HBC serology tests
Liver Event Testing and Liver Follow-
Up Testing
Albumin, ALP, ALT, AST, CK, GGT, GLDH, INR, PT, and 
Total Bilirubin (TBIL), Test for hemolysis (haptoglobin, 
reticulocytes, unconjugated [indirect] bilirubin.
These tests are in addition to routine testing, to be 
performed only in follow-up to safety events when indicated 
in Section 10.5 Liver safety monitoring
Pregnancy Test
Serum pregnancy test
Urine pregnancy test
Confirmatory serum pregnancy required in case of positive 
urine pregnancy test
*To be performed if the test is available at the local lab.
** Type (fasting/non-fasting) to remain consistent throughout study
# In case tests are not available at the local lab, discuss with Novartis regarding analysis of these 
safety BM parameters by Central Lab.
8.4.6
Pregnancy testing
All pre-menopausal women who are not surgically sterile will have pregnancy testing 
performed at the timepoint specified in the assessment schedule (see Section 1.3). 
Additional pregnancy testing might be performed if requested by local requirements.
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Assessments of fertility
A woman is considered of childbearing potential from menarche and until becoming 
post-menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Medical documentation of 
oophorectomy, hysterectomy, or tubal ligation must be retained as source documents.
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile.
In absence of the medical documentation confirming permanent sterilization, or if the 
post-menopausal status is not clear, the investigator should use their medical judgment to 
appropriately evaluate the fertility state of the woman and document it in the source document.
8.4.7
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
Most patients planned for cardiac surgery are at higher risk for thrombotic events and are 
therefore already under treatment with 
 
. As per guidance of professional societies, anti-platelets are either continued 
during surgery (aspirin) or discontinued and quickly re-started after surgery (P2Y12 inhibitors). 
In addition, anti-coagulants are frequently switched to heparin for the peri-operative period, and 
heparin is used to prevent clots in circuits during CPB use. Bleeding/Coagulation parameters 
will be assessed frequently before, during, and after surgery to ensure monitoring of bleeding 
risk and to allow timely intervention with protamine sulfate, blood or thrombocytes.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Clinician reported outcomes (ClinRO)
 
 
 
 
 
 
 
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8.5.2
Surgery related information
Collection of surgery parameters
Date of surgery, type of surgery, start/end time of surgical intervention on Day 1 will be 
collected.
Cardiopulmonary bypass information
 
Vasoactive agents during surgery
 
8.5.3
Collection of mechanical ventilation information
 
8.5.4
Information on renal replacement therapy
In case a subject receives renal replacement therapy, information will be collected in the CRF, 
such as date, duration, method of dialysis and number of sessions.
8.5.5
Information on hospitalization
The following information will be collected on hospitalization:
•
Duration of ICU stay after the cardiac surgery in days (date of admission to ICU and date 
of  transfer to regular hospital floor)
•
Duration of overall hospitalization after cardiac surgery in days (date of cardiac surgery 
and date of discharge from the hospital)
•
Rehospitalization: record date of any new admission (occurring up to Day 90) and date of 
discharge
8.5.6
 
 
 
 
 
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8.5.7
Fluid Balance, urine output, blood loss
Collection intervals for urine output, fluid balance and blood loss are outlined in the assessment 
schedule (see Table 1-2) and in Table 10-5.
Fluid balance
Fluid balance is the difference between the overall fluid input, e.g., oral liquid foods, beverages 
and i.v. fluids (including blood transfusions and i.v. medications), and the sum of all bodily 
fluid losses (e.g., perspiration, urination, loose stools, vomitus, drainage from surgical tubes, 
blood), and will be recorded for the intervals outlined in the assessment schedule.
Urine output
Urine output as also necessary for fluid balance will be calculated from collection bag(s) if urine 
catheter still in place, and by measured collections following removal of the catheter.
Blood loss
Estimated blood loss (e.g., from open wounds, drainage, wound dressings) is to be recorded and 
reported in the CRF.
Please consider if any blood loss meets the definition of an adverse event and report accordingly, 
as outlined in Section 8.6.
8.5.8
 
 
8.6
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found 
in Section 8.6.
AEs will be reported by the participant.
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 7).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 8.6.3.
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8.6.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The Investigator has the responsibility for managing the safety of individual participants and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer 
to Section 8.6.2):
1.
 (version 5 or higher).
If 
 grading does not exist for an adverse event, use 1=mild; 2=moderate, 3=severe; and 
4=life threatening. 
grade 5 (death) is not used, but is collected in other eCRF 
(e.g., Study Completion, Death/Survival).
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates or ongoing) and the outcome must be reported
4. Whether it constitutes a SAE (see Section 8.6.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:
•
Dose not changed
•
Dose Reduced/increased
•
Drug interrupted/permanently discontinued
6. Its outcome 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
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Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until last study visit.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be not recovered/not resolved (e.g., continuing at the end of the study), and assessment must be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
•
they induce clinical signs or symptoms
•
they are considered clinically significant
•
they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.
8.6.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:
•
fatal
•
life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).
•
results in persistent or significant disability/incapacity
•
constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or 
birth defect
•
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
•
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
•
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
•
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•
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
•
is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective of whether a clinical event has occurred.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
8.6.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until last study visit must be reported to Novartis safety 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
obtaining knowledge of the events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the Investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the Electronic Serious Adverse Event (eSAE) or Serious 
Adverse Event Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report. SAEs occurring after the participant has provided informed 
consent until the time the participant is deemed a Screen Failure must be reported to Novartis.
Event common in the participant population under study: Investigators will report AEs or 
SAEs that are commonly seen in the study population, but they will not be unblinded and will 
not be reported as Suspected Unexpected Serious Adverse Reaction (SUSAR) to regulatory 
agencies, ECs, or investigators during the study. In clinical trials evaluating treatments for high 
morbidity and/or high mortality disease states, SAEs that are known consequences of the 
underlying disease or condition under investigation, or events common in the study population, 
are anticipated to occur with some frequency during the course of the study, regardless of drug 
exposure. While the investigator must still report all SAEs, SUSARS considered consistent with 
the following SAE Preferred Terms (PT) will not be unblinded and reported in an expedited 
timeframe to regulatory agencies, ECs or investigators during the course of the study. 
These events will be presented in the clinical study report at the end of the study: acute kidney 
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If specifically requested by a local Health Authority (HA), pre-specified SAEs that also meet 
the criteria for SUSARs will be expedited to this HA as blinded reports. Investigator 
Notification (IN) will not be issued for these events.
OR
Pre-specified SAEs commonly observed in the study population that occur in patients under the 
jurisdiction of the requesting Health Authority will be expedited to the Health Authority as 
unblinded reports; INs will be issued for these events.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the Investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
Investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the last study visit should only be reported to Novartis Safety if 
the Investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations.
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP <2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law). 
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 
understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data.
8.6.4
Pregnancy
Since TIN816 has not been tested in reproductive toxicity studies to date, the teratogenicity 
potential of TIN816 is not known. Therefore, if a female trial participant becomes pregnant, the 
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presented to the trial participant. The participant must be given adequate time to read, review 
and sign the pregnancy consent form. This consent form is necessary to allow the Investigator 
to collect and report information regarding the pregnancy. To ensure participant safety, each 
pregnancy occurring after signing the informed consent must be reported to Novartis within 
24 hours of learning of its occurrence.
Details of all pregnancies in female participants will be collected after the start of study 
treatment and until the Day 90 visit.
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.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.
Any post study pregnancy-related SAE considered reasonably related to the study treatment by 
the Investigator will be reported to Novartis as described in Section 8.6.3. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
8.6.5
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs
Not applicable.
8.6.6
Adverse events of special interest
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8.7
8.7.1
 
 
 
 
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8.8
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8.9
Immunogenicity assessments
Immunogenicity (IG, production of anti-TIN816 antibodies) serum samples will be obtained 
and evaluated in all participants at all dose levels including the placebo group as defined in the 
assessment schedule (Section 1.3). Unscheduled ADA samples may be collected in case of a 
safety event (Section 8.4) that is potentially immunogenicity related. In case of suspected 
allergic hypersensitivity, the participant should return to the site and a sample to assess 
immunogenicity will be collected. Additionally, serum samples should be collected at the final 
visit from participants who discontinued study treatment or were withdrawn from the study. 
Details on immunogenicity serum sample collection, numbering, processing and shipment are 
provided in the Laboratory Manual.
Immunogenicity will be evaluated in serum by a validated three-tiered ligand binding assay 
approach (MSD bridging assay), details will be outlined in the method validation report. 
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All samples will be screened for potential anti-TIN816 antibodies. Any positive screen result is 
confirmed using a confirmatory assay where sample screening signal suppression upon addition 
of drug in excess is investigated. If a sample is confirmed positive for the presence of 
anti-TIN816 antibodies it will be further analyzed using a titration assay.
 
 
 
8.9.1
Immunogenicity blood sample collection and handling
Follow instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing, and shipment.
8.9.2
Immunogenicity analytical method(s)
A validated ligand binding assay will be used for the detection of anti-TIN816 antibodies, 
thereby applying a 3-tired approach. All samples collected for detection of anti-TIN816 
antibodies will also be evaluated for TIN816 serum concentration to enable interpretation of the 
antibody data. Confirmed immunogenicity positive samples will be titrated
 
The detailed methods for immunogenicity assessment will be described in the Bioanalytical 
Data Report.
8.10
Health economics OR Medical resource utilization and health 
economics
Health economics OR Medical resource utilization and health economics parameters are not 
evaluated in this study.
9
Statistical considerations
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
9.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
The safety analysis set will include all participants that received any study treatment.
 will include all participants with at least one available valid (i.e. not flagged 
for exclusion) 
, who received TIN816 treatment and with no 
protocol deviations that impact 
.
The PD analysis set will include all participants that received any study treatment and had no 
protocol deviations with relevant impact on PD data.
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The IG analysis set will include all participants with at least one available valid (i.e. not flagged 
for exclusion) IG concentration measurement, who received any study treatment and with no 
protocol deviations that impact on IG data.
9.2
Statistical analyses
9.2.1
General considerations
Data from TIN816 treatment groups (
 mg/kg and 
mg/kg) will not be pooled for the 
analyses and will be reported separately. 
All inferential analyses will use 1-sided tests, 0.1 significance level and 90% confidence 
intervals.
 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
9.2.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the Safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term by treatment group.
9.2.3
Treatments
The Safety set will be used for the analyses below. Data for study drug administration and 
concomitant medications and significant non-drug therapies will be listed by treatment group 
and subject.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system and by treatment group.
Additionally, rescue therapy as well as concomitant anti-histamines and glucocorticoids will be 
summarized by treatment group.
9.3
Primary endpoint(s)/estimand(s) analysis
The primary aim of the study is to assess the effect of TIN816 on serum creatinine level in 
high-risk patients undergoing major cardio-vascular surgery, versus placebo. This will be 
evaluated by comparing the serum creatinine level up to and including Study Day 6 vs baseline. 
This analysis will be performed on the PD analysis set.
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9.3.1
Definition of primary endpoint(s)
The primary endpoint of the study is the ratio of the highest serum creatinine value up to and 
including Study Day 6 versus baseline.
9.3.2
Statistical model, hypothesis, and method of analysis
The log-transformed ratio of the highest serum creatinine value up to and including Study Day 
6 vs baseline will be analyzed by a linear model, including log-transformed baseline serum 
creatinine value, treatment group, age and baseline eGFR as covariates. The estimated mean 
and 90% confidence interval of the difference in log-transformed ratios vs baseline between 
each TIN816 treatment group and placebo will be back-transformed to obtain the geometric 
mean ratio and corresponding 90% confidence interval, which will be reported along with the 
corresponding 1-sided p-value.
 
 
9.3.3
Handling of intercurrent events of primary estimand
 
 
 
 
 
 
 
9.3.4
Handling of missing values not related to intercurrent event
 
 
9.3.5
Sensitivity analyses
Not Applicable
9.3.6
Supplementary analysis
Not Applicable
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9.4
Secondary endpoint(s)/estimand(s) analysis
The secondary objectives of the study are provided in Table 3-1.
9.4.1
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 90 days 
(EOS) after the date of actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events 
(events started after the first dose of study medication or events present prior to start of blinded 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:
•
by treatment, primary system organ class and preferred term.
•
by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, and other significant adverse events leading to discontinuation.
The number (and proportion) of participants with adverse events of special interest will be 
summarized by treatment group.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be summarized by treatment group and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment group and visit/time for raw and change from baseline.
12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
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Categorical analysis of QT/QTc interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced by treatment group.
All ECG data will be listed by treatment group, participant, and visit/time; abnormalities will 
be flagged. All ECG data will be summarized by treatment group and visit/time.
Clinical laboratory evaluations
All laboratory data will be summarized by treatment group, and visit/time.
All laboratory data parameters (hematology, biochemistry and Urinalysis) will be listed by 
treatment group, participant, and visit/time and if normal ranges are available abnormalities will 
be flagged.
9.4.2
Acute Kidney Injury Network (AKIN) criteria
Proportion of patients developing AKI as defined by the AKIN (Acute Kidney Injury Network) 
criteria within 7 days post dose using SCr will be summarized by treatment groups and listed 
by visit, participant and by treatment group.
9.4.3
Immunogenicity
Immunogenicity results will be listed by treatment group, participant and visit/time. The listing 
will contain ADA status (negative or positive) and for ADA-positive samples a titer and 
 
. Participants with one or more 
treatment emergent ADAs are counted as ADA-positive participants and they will be 
summarized by treatment group to derive an ADA incidence. 
 
 Visualizations overlaying ADA status including 
characterizations, 
 and potentially efficacy read-outs, may be 
presented.
9.4.4
Acute Kidney Disease (AKD)
MAKE30 is defined as the proportion of patients developing at least one of the following:
1. death through day 30,
2. initiation for renal replacement therapy through day 30, or
3. ≥25% reduction in eGFR from baseline to 30 days after surgery.
MAKE90 is defined as the proportion of patients developing at least one of the following:
1. death through day 90,
2. initiation for renal replacement therapy through day 90, or
3. ≥25% reduction in eGFR from baseline to 90 days after surgery.
Proportion of patients developing the MAKE90 will be summarized by treatment and listened 
by participant and treatment.
Proportion of patients developing the MAKE30 will be summarized by treatment and listened 
by participant and treatment.
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Similarly, the proportion of patients with occurrence of individual components of MAKE90 
and MAKE30 mentioned above will be summarized by treatment and listed by participant and 
treatment.
9.5
Exploratory endpoint(s)/estimand(s) analysis
9.5.1
 
 
 
 
 
 
 
 
 
 
 
9.5.2
 
 
 
 
 
 
 
9.5.3
 
 
 
 
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Summary statistics will include mean (arithmetic and geometric), standard deviation (SD), CV 
 
 
 
 
 
 
 
 
 
 
 
 
Table 9-1
9.6
(Other) Safety analyses
Not applicable.
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9.7
Other analyses
Other exploratory endpoints will be presented as appropriately. More details will be provided 
in the study Statistical Analysis Plan.
9.8
Interim analysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.9
Sample size determination
9.9.1
Primary endpoint(s)
 
 
 
 
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10
Supporting documentation and operational considerations
10.1
Appendix 1: Regulatory, ethical, and study oversight 
considerations
10.1.1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines
•
Applicable ICH Good Clinical Practice (GCP) guidelines
•
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator’s Brochure, [IDFU], and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants.
The Investigator will be responsible for the following:
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
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This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC or European Clinical Trial 
Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the Declaration 
of Helsinki.
10.1.2
Informed consent process
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be required 
to sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, and 
the IRB/IEC or study center.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents.
The medical record must include a statement that written informed consent was obtained before 
the participant 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 participant.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The Investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this.
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant upon obtaining consent and also 
during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate, 
for example, via an Investigator notification or an aggregate safety finding. New information 
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The following informed consents are included in this study:
•
Main study consent, which also included:
•
A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
•
As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment 
•
The study includes 
 component which requires a separate signature 
if the participant agrees to participate. It is required as part of this protocol that the Investigator 
presents this option to the participants, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed 
consent.
Declining to participate in these 
 will in no way affect 
the participant’s ability to join the main research study.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site, for which a separate 
signature is required if the participant agrees. It is required as part of this protocol that the 
Investigator presents this option to the participant, as permitted by national and local governing 
regulations. The process for obtaining consent should be exactly the same as described above 
for the main informed consent.
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local health authority.
Guidance issued by local regulatory bodies on this aspect prevails and must be implemented 
and appropriately documented (e.g. the presence of an impartial witness, sign/dating separate 
ICFs by trial participant and person obtaining informed consent, etc.).
10.1.3
Data protection
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent
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The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws.
10.1.4
Committees structure
10.1.4.1 Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
Investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial and safety data, and recommend to Novartis whether to continue, modify, or 
terminate a trial.
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between Novartis and the DMC.
10.1.5
Data quality assurance
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan, contracts.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis.
10.1.5.1 Data collection
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the Investigator staff.
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the Investigator will receive copies of the participant data for 
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All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
10.1.5.2 Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures, as well as randomization codes and data 
about all study treatments dispensed to the participant and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request 
of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded to those who 
are blinded in the trial setting and made available for data analysis. Any changes to the database 
after that time can only be made after written agreement by Novartis development management.
10.1.6
Source documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. 
The Investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 
informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in the monitoring 
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The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 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 participants 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.
Key study personnel must be available to assist the field monitor during these visits. 
Continuous remote monitoring of each site’s data may be performed by a centralized Novartis / 
delegated CRO /CRA organization. Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters and provide reports 
to Novartis clinical teams to assist with trial oversight.
10.1.7
Publication policy
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT or CTIS public website. In addition, after study completion (defined as 
last participant last visit) and finalization of the study report the results of this trial will be 
submitted for publication and posted in a publicly accessible database of clinical trial results, 
such as the Novartis clinical trial results website and all required health authority websites 
(e.g. Clinicaltrials.gov, EudraCT or CTIS public website, etc.).
For details on the Novartis publication policy including authorship criteria, please refer to 
the Novartis publication policy training materials that were provided to you at the trial 
Investigator meetings.
Any data analysis carried out independently by the Investigator should be submitted 
to Novartis before publication or presentation.
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV.
10.1.8
Protocol adherence and protocol amendments
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it 
to Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
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10.1.8.1 Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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10.2
Appendix 2: Abbreviations and definitions
10.2.1
List of abbreviations
ACCM
American College of Critical Care Medicine
ADA
Anti-Drug Antibodies
ADP
Adenosine diphosphate
AE
Adverse Event
AESI
Adverse Events of Special Interest
AF
Arterial fibrillation
AKD
Acute kidney disease
AKI
Acute kidney injury
AKIN
Acute Kidney Injury Network
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AMP
Adenosine monophosphate
aPTT
Activated partial thromboplastin time
ARDS
Acute Respiratory Distress Syndrome
ASA
Acetylsalicylic acid
AST
Aspartate Aminotransferase
ATP
Adenosine triphosphate
AUC
Area under the curve
BMI
Body Mass Index
CDS
Core Data Sheet
CHMP
Committee on Human Medicinal Products
CK
Creatine Kinase
ClinRO
Clinician Reported Outcomes
CLR
Renal clearance
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
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COA
Clinical Outcome Assessment
CPB
Cardiopulmonary bypass
CPR
Cardiopulmonary resuscitation
CQA
Clinical Quality Assurance
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSA
Cardiac Surgery Associated
CS-AKI
Cardiac Surgery-Associated Acute Kidney Injury 
CSR
Clinical study report
CTA
Clinical trial application
CTC
Common Terminology Criteria
CTT
Clinical Trial Team
DBP
Diastolic Blood Pressure
DGF
Delayed Graft Function
DIN
Drug Inducted Nephrotoxicity
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DQF
Data Query Form
DRES
Disease-related events
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
EDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate
ELISA
Enzyme-linked immunosorbent assay
EOI
End of infusion
EOS
End of study
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
EU
European Union
FDA
Food and Drug Administration
FFP
Fresh frozen plasma
FIH
First in Human
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GLDH
Glutamate Dehydrogenase
GLP
Good laboratory practice
h
Hour
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus

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HCP
Host Cell Protein
HCV
Hepatitis C Virus
HED
Human Equivalent Dose
HEOR
Health Economics & Outcomes Research 
HIV
Human immunodeficiency virus
HV
Healthy volunteer(s)
IA
Interim analysis
i.v.
intravenous
IABP
Intra-aortic balloon counter-pulsation
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
Intensive care unit
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
LDH
lactate dehydrogenase
LFT
Liver function test 
LPLV
Last patient last visit
LVAD
Left ventricular assist device
MAKE
Major adverse kidney event
MCS
Mechanical circulatory support
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
MIDCAB
minimally invasive direct coronary artery bypass
mL
milliliter(s)
MRSD
Standard deviation
NCDS
Novartis Clinical Data Standards
NOEL
No Observed Adverse Effect Level
NYHA
New York Heart Association
oHCP
off-site Healthcare Professional
PD
Pharmacodynamic(s)
PerfO
Performance Outcomes
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PoC
Proof of Concept
PPoS
Predictive probability of success
PRO
Patient Reported Outcomes
PSD
Premature Subject Discontinuation
PT
Prothrombin Time
PTT
Partial thromboplastin time
QD
Once a day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RAP
The Report and Analysis Plan 
RBC
Red blood cells
REB
Research Ethics Board
RIFLE
Risk, Injury, Failure, Loss of kidney function, and End-stage kidney 
disease
RRT
Renal Replacement Therapy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCr
Serum Creatinine
SD
standard deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SoC
Standard of Care
Society of Critical Care 
Medicine
SCCM
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAVI
Transcatheter aortic valve implantation
TAVR
Transcatheter aortic valve replacement
TB
Tuberculosis
ULN
upper limit of normal
ULOQ
Upper limit of quantification
WHO
World Health Organization 
WoC
Withdrawal of Consent
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10.2.2
Definitions
Acute kidney disease
Subchronic kidney injury longer than 7 days but less than 3 months 
after AKI with a glomerular filtration rate (GFR) <60 mL/min/1.73m2, or 
GFR decrease ≥35% from baseline, or SCr increase ≥1.5 times from 
baseline
Acute kidney injury
Serum creatinine (SCr) increase ≥1.5 times from baseline within 
7 days, or >0.3 mg/dL (25.5 umol/L) increase within 48 hours
Additional treatment
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g. any background therapy)
Adverse event
An unexpected medical problem that happens during treatment with a 
drug or other therapy. Adverse events may be mild, moderate, or 
severe, and may be caused by something other than the drug or 
therapy being given.
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant 
Cardiopulmonary Bypass 
(CBP)
CBP is used to temporarily perform the functions of the heart 
(circulation of blood) and lungs (gas exchange) during surgical 
procedures on the heart and great vessels.
Chronic kidney disease
Chronic kidney damage beyond 3 months with a glomerular filtration 
rate (GFR) <60 mL/min/1.73m2, or structural kidney 
damage >3 months
Clinical Trial Team
A group of people responsible for the planning, execution and 
reporting of all clinical trial activities. Examples of team members 
include the Study Lead, Medical Monitor, Trial Statistician etc.
Coded Data
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code.
Cohort
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time
Concomitant drug
Concomitant drugs are two or more drugs used or given at or almost 
at the same time.
Control drug
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug
Discontinuation from study
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of their 
samples or data.
Discontinuation from study 
treatment
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop 
the use of their samples or data.
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
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applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last 
participant
Endpoint
An outcome or event used to objectively measure the effect of a drug 
or other intervention being studied.
Enrollment
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
combines source documents and case report forms (eCRFs) into one 
application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise 
description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same participants under different treatment 
conditions being compared. Attributes of an estimand include the 
population, variable (or endpoint) and treatment of interest, as well as 
the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable.
Glomerular Filtration Rate 
(GFR)
GFR is a measure of how well the kidneys are able to filter waste 
products
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
In vitro
Describes processes or tests performed or taking place in a test tube, 
culture dish, or elsewhere outside a living organism.
Intercurrent events
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with 
the clinical question of interest.
Investigational drug/ 
treatment
The drug whose properties are being tested in the study
Investigational Product/ 
Investigational Medicinal 
product
A pharmaceutical form of an active ingredient or placebo being tested 
or used as a reference (such as an active comparator) in a clinical 
trial, including a product with a marketing authorization when used or 
assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use.
Kidney disease improving 
global outcomes criteria 
(KDIGO)
Increased creatinine level greater than or equal to 1.5 times the 
baseline (historical or measured), which is known or presumed to have 
occurred within the prior seven days.
Stage 1: Serum creatinine 1.5–1.9 times baseline or ≥0.3 mg/dl 
(≥26.5 mmol/l) increase or Urine output <0.5 ml/kg/h for 6–12 hours
Stage 2: Serum creatinine 2.0–2.9 times baseline or <0.5 ml/kg/h for 
≥12 hours
Stage3: Serum creatinine 3.0 times baseline or increase in serum 
creatinine to ≥4.0 mg/dl (≥353.6 mmol/l) or Initiation of renal 
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<35 ml/min per 1.73 m² or Urine output <0.3 ml/kg/h for ≥24 hours or 
anuria for ≥12 hours
Major adverse kidney 
event (MAKE)
Clinical outcome defined using the following components: 1) death, 
2) initiation of renal replacement therapy, 3) ≥25% reduction in GFR. 
MAKE is assessed 30 or 90 days after AKI (MAKE30 and MAKE90, 
respectively)
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study or the participant allocated to 
an invalid stratification factor
Off-site
Describes trial activities that are performed at remote location by an 
off-site healthcare professional, such as procedures performed at the 
participant's home.
Off-site healthcare 
Professional (OHP)
A qualified healthcare professional, such as include those used in the 
study e.g., Nurse, Phlebotomist, Physician, who performs certain 
protocol procedures for the participant in an off-site location such as a 
participant's home.
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(i.e., concomitant or rescue therapy)
Overdose
An excessive and dangerous dose of a drug
Part 
A sub-division of a study used to evaluate specific objectives or 
contain different populations. For example, one study could contain a 
single dose part and a multiple dose part, or a part in participants with 
established disease and in those with newly-diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient). 
"Participant" terminology is used in the protocol whereas term 
"Subject" is used in data collection
Participant number
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for 
the participant and should be used to identify the participant 
throughout the study for all data collected, sample labels, etc.
Patient
An individual with the condition of interest for the study
Patient-Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples.
Placebo
S substance that has no active ingredient which could cause a 
therapeutic effect, used as a control in testing new drugs
Randomization
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
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Randomization number
A unique identifier assigned to each randomized participant
Re-screening
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol
Remote
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location
Risk, Injury, Failure, Loss 
and End-stage kidney 
classification (RIFLE)
RIFLE is an international consensus classification for acute kidney 
injury. RIFLE defines three grades of increasing severity of acute 
kidney injury – risk (class R), injury (class I) and failure (class F) – and 
two outcome classes (loss and end-stage kidney disease)
Screen Failure
A participant who did not meet one or more criteria that were required 
for participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded data, such as paper or 
eSource
Standard of Care (SOC)
Treatment that is accepted by medical experts as a proper treatment 
for a certain type of disease and that is widely used by healthcare 
professionals
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant
Study treatment
Any drug or combination of drugs or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the 
combination, and may consist of 1 or more cohorts.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event.
Withdrawal of consent
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and/or biological samples 
AND no longer wishes to receive study treatment, AND does not agree 
to further protocol required assessments. This request should be in 
writing (depending on local regulations) and recorded in the source 
documentation.
This request should be distinguished from a request to discontinue the 
study. Other study participant's privacy rights are described in the 
corresponding informed consent form.
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending 
on local regulations) and recorded in the source documentation.
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
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10.3
Appendix 3: Clinical laboratory tests
10.3.1
Clinically notable laboratory values and vital signs
Table 10-1
Clinically notable laboratory values
Parameter
Conventional 
Alert Value
Conventional 
Units
SI Alert Value
SI Units
Hematology
Red Blood Cell 
Count
>50% increase,
>30% decrease
×10E6/μL
>50% 
increase, >30% 
decrease
×10E12/L
Hemoglobin
>50% increase,
30% decrease, or 
any value <7
g/dL
>50% 
increase, >30% 
decrease, or any 
value <70
g/L
Hematocrit
>50% 
increase, >30% 
decrease
%
>50% 
increase, >30% 
decrease
L/L
White Blood Cell 
Count
>50% 
increase, >50% 
decrease
×10E3/μL
>50% 
increase, >50% 
decrease
×10E9/L
Platelet Count
>75% 
increase, >50% 
decrease
×10E3/μL
>75% 
increase, >50% 
decrease
×10E9/L
Chemistry
BUN
>50% increase
mg/dL
>50% increase
mmol/L
Creatinine
>50% increase
mg/dL
>50% increase
μmol/L
Albumin
<2
g/dL
<20
g/L
Glucose
>50% 
increase, >50% 
decrease, or any 
value <60
mg/dL
>50% 
increase, >50% 
decrease, or any 
value <3.3
mmol/L
Total Bilirubin
>100% increase
mg/dL
>100% increase
μmol/L
CPK
>300% increase
U/L
>300% increase
U/L
AST (SGOT)
>150% increase
U/L
>150% increase
U/L
ALT (SGPT)
>150% increase
U/L
>150% increase
U/L
Alkaline 
phosphatase
>100% increase
U/L
>100% increase
U/L
Sodium
>5% increase, or
any value >150
mEq/L
>5% increase, or
any value >150
mmol/L
Potassium
>20% 
increase, >20% 
decrease, or any 
value >5.3
mEq/L
>20% 
increase, >20% 
decrease, or any 
value >5.3
mmol/L

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Parameter
Conventional 
Alert Value
Conventional 
Units
SI Alert Value
SI Units
Chloride
>10% 
increase, >10% 
decrease
mEq/L
>10% 
increase, >10% 
decrease
mmol/L
Calcium
>10% 
increase, >10% 
decrease
mg/dL
>10% 
increase, >10% 
decrease
mmol/L
Uric Acid
>50% increase
mg/dL
>50% increase
mmol/L

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10.4
Appendix 4: Participant Engagement
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis.
•
Study infographic: AKI Infographic 
•
Study start and study end Thank You Cards
•
Plain language trial summary - after CSR publication
•
Individual study results - after CSR publication

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10.5
Appendix 5: Liver safety monitoring
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 10-2 in Appendix 5 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 10-2 should 
be followed up by the Investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 10-3 and 
Table 10-4. Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation.
•
These liver chemistry repeats should be performed using the local laboratory used by the 
site. Repeated laboratory test results must be reported as appropriate.
•
If the initial elevation is confirmed, close observation of the participant will be initiated.
•
Hospitalization of the participant if appropriate.
•
Causality assessment of the liver event.
•
Thorough follow-up of the liver event should include.
•
These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease.
•
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
•
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.
•
Exclusion of underlying liver disease, as specified in Table 10-2.
•
Imaging such as abdominal US, CT or MRI, as appropriate.
•
Obtaining a history of exposure to environmental chemical agents.
•
Considering gastroenterology or hepatology consultations.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.

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10.5.1
Liver event and laboratory trigger definitions & follow-up requirements
Table 10-2
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers:
 If ALT, AST and total bilirubin 
normal at baseline:
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
Total bilirubin > 3 × ULN (in the absence of known Gilbert 
syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and Total bilirubin > 2 × ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia
Any adverse event potentially indicative of a liver toxicity
If ALT or AST abnormal at 
baseline:
ALT or AST > 3x baseline AND > 5x ULN 

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Table 10-3
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 5 x ULN for more than 
two weeks
OR
ALT > 8 x ULN
If elevated at baseline:
ALT > 3 x baseline
AND > 5x ULN for more than 
two weeks
OR
ALT ≥ 5x baseline
AND ≥ 8x ULN
Normal
For 
participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
If elevated at baseline:
ALT > 2 x baseline
AND >3x ULN
TBL > 2 x ULN (or 
INR > 1.5)
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin
None
If normal at baseline:
ALT > 3 x ULN
If elevated at baseline:
ALT > 2 x baseline
 AND > 3x ULN 
Normal or 
elevated*
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain*
•
No change to 
study treatment
•
Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin and CK in 
48-72 hours.
•
Follow-up for 
symptoms.
•
Initiate close 
monitoring and 
workup for 
competing 
etiologies.
* This situation suggests liver injury based on (i) elevation of ALT, and (ii) the presence of 
symptoms of liver injury. Even if bilirubin is normal, the presence of liver symptoms indicates 
potentially severe liver injury.

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Table 10-4
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
>1.5 – 3.0 ULN
•
Repeat LFTs within 48-72 hours
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in 
the absence of 
known Gilbert 
syndrome)
•
Repeat LFT within 48-72 hours
•
Hospitalize if clinically appropriate
•
Establish causality
•
Record the AE and contributing 
factors (e.g. concomittant 
medication, medical history, 
laboratory and imaging 
investigations) in the appropriate 
CRF
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 10 x ULN
•
Hospitalize the participant
•
Establish causality
•
Record the AE and contributing 
factors(e.g. concomittant 
medication, medical history, 
laboratory and imaging 
investigations) in the appropriate 
CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion)
Any AE potentially 
indicative of a 
liver toxicity
•
Hospitalization if clinically 
appropriate
•
Establish causality
•
Record the AE and contributing 
factors (e.g. concomittant 
medication, medical history, 
laboratory and imaging 
investigations) in the appropriate 
CRF
Investigator discretion
Based on Investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.

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10.6
Appendix 6: 
 
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11
References
References are available upon request
 
 
 
 
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