A Participant and Investigator-blinded, Randomized, Placebo-controlled Phase 2a Study to Investigate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of TIN816 in Patients With Sepsis-associated Acute Kidney Injury
Phase: PHASE2
Conditions: Acute Kidney Injury Due to Sepsis
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Clinical Trial Protocol Title: 
A multicenter, participant and investigator-blinded, 
randomized, placebo-controlled Phase 2a study to 
investigate the pharmacokinetics, pharmacodynamics, 
safety and tolerability of TIN816 in the treatment of patients 
with sepsis-associated acute kidney injury 
Clinical Trial Protocol Number: CTIN816B12201 / NCT05507437
Version Number: v00 (Original Protocol) 
Compound: TIN816 
Brief Title: A multicenter study to evaluate pharmacokinetics, safety and tolerability 
of TIN816 in patients with sepsis-associated acute kidney injury. 
Study Phase: IIa 
Sponsor Name: Novartis 
Regulatory Agency Identifier Number(s): EUDRACT Number: 2022-000887-23 
Approval Date: 03-Jun-2022 (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 ...................................................................................................................... 6 
1 
Protocol summary ................................................................................................................ 7 
1.1 
Summary .................................................................................................................. 7 
1.2 
Schema ................................................................................................................... 11 
1.3 
Schedule of activities (SoA) .................................................................................. 11 
2 
Introduction ....................................................................................................................... 17 
2.1 
Study rationale ....................................................................................................... 17 
2.2 
Background ............................................................................................................ 17 
2.3 
Benefit/Risk assessment ........................................................................................ 19 
2.3.1 
Benefits ................................................................................................. 19 
2.3.2 
Risks ...................................................................................................... 20 
2.3.3 
COVID-19 ............................................................................................. 21 
2.3.4 
Pregnancy .............................................................................................. 21 
2.3.5 
Drug-drug interactions .......................................................................... 22 
2.3.6 
Blood sample volume ............................................................................ 22 
3 
Objectives, endpoints, and estimands ................................................................................ 22 
3.1 
Primary estimands ................................................................................................. 23 
3.2 
Secondary estimands ............................................................................................. 24 
4 
Study design ...................................................................................................................... 24 
4.1 
Overall design ........................................................................................................ 24 
4.2 
Scientific rationale for study design ...................................................................... 25 
4.3 
Justification for dose .............................................................................................. 26 
4.4 
Rationale for choice of control drugs (comparator/placebo) ................................. 27 
4.5 
Rationale for public health emergency mitigation procedures .............................. 27 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 28 
4.7 
End of study definition .......................................................................................... 28 
5 
Study population ................................................................................................................ 28 
5.1 
Inclusion criteria .................................................................................................... 28 
5.2 
Exclusion criteria ................................................................................................... 29 
5.3 
Screen failures ....................................................................................................... 31 
5.3.1 
Participant numbering ........................................................................... 31 
6 
Study treatment(s) and concomitant therapy ..................................................................... 31 
6.1 
Study treatment(s) .................................................................................................. 32 

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6.1.1 
Additional study treatments .................................................................. 32 
6.1.2 
Treatment arms/group ........................................................................... 32 
6.1.3 
Treatment duration ................................................................................ 33 
6.2 
Preparation, handling, storage, and accountability ................................................ 33 
6.2.1 
Handling of study treatment .................................................................. 33 
6.2.2 
Handling of other treatment .................................................................. 34 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 34 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 34 
6.3.1 
Treatment assignment, randomization .................................................. 34 
6.3.2 
Treatment blinding ................................................................................ 34 
6.3.3 
Emergency breaking of assigned treatment code .................................. 36 
6.4 
Study treatment compliance .................................................................................. 36 
6.4.1 
Recommended treatment of adverse events .......................................... 36 
6.5 
Dose modification .................................................................................................. 36 
6.6 
Continued access to study treatment after the end of the study ............................. 36 
6.6.1 
Post trial access ..................................................................................... 37 
6.7 
Treatment of overdose ........................................................................................... 37 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 37 
6.8 
Concomitant and other therapy .............................................................................. 37 
6.8.1 
Concomitant therapy ............................................................................. 37 
6.8.2 
Prohibited medication ........................................................................... 38 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 38 
7.1 
Discontinuation of study treatment ........................................................................ 38 
7.2 
Participant discontinuation from the study ............................................................ 39 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 39 
7.4 
Lost to follow-up ................................................................................................... 40 
7.5 
Early study termination by the Sponsor................................................................. 40 
8 
Study Assessments and Procedures ................................................................................... 41 
8.1 
Screening ............................................................................................................... 41 
8.1.1 
Eligibility Screening .............................................................................. 41 
8.1.2 
Information to be collected on screening failures ................................. 41 
8.2 
Participant demographics/other baseline characteristics ....................................... 42 
8.2.1 
Demographics and Medical History...................................................... 42 
8.3 
Efficacy assessments ............................................................................................. 43 
8.3.1 
Creatinine clearance (CrCl)................................................................... 43 

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 43 
8.3.3 
Kidney disease improving global outcomes (KDIGO) stage ................ 44 
8.3.4 
Renal replacement therapy (RRT) ........................................................ 44 
8.3.5 
Scoring Systems .................................................................................... 45 
8.3.6 
Appropriateness of efficacy assessments .............................................. 48 
8.3.7 
Serum Creatinine ................................................................................... 48 
8.4 
Safety and tolerability assessments ....................................................................... 48 
8.4.1 
Physical examinations ........................................................................... 49 
8.4.2 
Vital signs.............................................................................................. 50 
8.4.3 
Electrocardiograms ............................................................................... 50 
8.4.4 
Clinical safety laboratory tests .............................................................. 51 
8.4.5 
Pregnancy testing .................................................................................. 52 
8.4.6 
Appropriateness of safety measurements .............................................. 53 
8.5 
Additional assessments .......................................................................................... 53 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 53 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 54 
8.6.1 
Adverse events ...................................................................................... 54 
8.6.2 
Serious adverse events .......................................................................... 55 
8.6.3 
SAE reporting........................................................................................ 56 
8.6.4 
Pregnancy .............................................................................................. 58 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 58 
8.6.6 
Adverse events of special interest ......................................................... 58 
8.7 
Pharmacokinetics ................................................................................................... 60 
 
 61 
 
 61 
8.9 
Immunogenicity assessments................................................................................. 62 
8.10 
Health economics OR Medical resource utilization and health economics .......... 62 
9 
Statistical considerations ................................................................................................... 62 
9.1 
Analysis sets .......................................................................................................... 62 
9.2 
Statistical analyses ................................................................................................. 63 
9.2.1 
General considerations .......................................................................... 63 
9.2.2 
Participant demographics and other baseline characteristics ................ 63 
9.2.3 
Treatments ............................................................................................. 63 
9.3 
Primary endpoint(s)/estimand(s) analysis.............................................................. 64 
9.3.1 
Definition of primary endpoint(s) ......................................................... 64 

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9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 65 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) .... 65 
9.3.4 
Handling of missing values not related to intercurrent event ............... 65 
9.3.5 
Sensitivity analyses ............................................................................... 65 
9.3.6 
Supplementary analysis ......................................................................... 65 
9.4 
Secondary endpoint(s)/estimand(s) analysis.......................................................... 65 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 65 
9.4.2 
Safety endpoints .................................................................................... 66 
9.4.3 
Pharmacokinetics .................................................................................. 67 
 
 67 
 
 67 
 
 67 
9.6 
(Other) Safety analyses .......................................................................................... 68 
9.7 
Other analyses ........................................................................................................ 68 
9.8 
Interim analysis ...................................................................................................... 68 
9.9 
Sample size determination ..................................................................................... 69 
9.9.1 
Primary endpoint(s) ............................................................................... 69 
10 Supporting documentation and operational considerations ............................................... 70 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations................... 70 
10.1.1 
Regulatory and ethical considerations .................................................. 70 
10.1.2 
Informed consent process ...................................................................... 71 
10.1.3 
Data protection ...................................................................................... 72 
10.1.4 
Committees structure ............................................................................ 72 
10.1.5 
Data quality assurance ........................................................................... 72 
10.1.6 
Source documents ................................................................................. 74 
10.1.7 
Publication policy.................................................................................. 74 
10.1.8 
Protocol adherence and protocol amendments ...................................... 75 
10.2 
Appendix 2: Abbreviations and definitions ........................................................... 76 
10.2.1 
List of abbreviations .............................................................................. 76 
10.2.2 
Definitions ............................................................................................. 79 
10.3 
Appendix 3: Clinical laboratory tests .................................................................... 83 
10.3.1 
Clinically notable laboratory values and vital signs ............................. 83 
10.4 
Appendix 4: Participant Engagement .................................................................... 85 
10.5 
Appendix 5: Liver safety monitoring .................................................................... 86 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................... 86 

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10.6 
Appendix 6: Renal safety monitoring .................................................................... 90 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up .......... 90 
11 References ......................................................................................................................... 92 
List of tables 
Table 1-1 
Objectives and related endpoints ............................................................ 7 
Table 1-2 
Assessment Schedule ............................................................................ 13 
Table 3-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Investigational and control drug ............................................................ 32 
Table 6-2 
Blinding and unblinding plan ................................................................ 35 
Table 6-3 
Prohibited medication ........................................................................... 38 
Table 8-1 
Staging of AKI ...................................................................................... 44 
Table 8-2 
Components of the SOFA score ............................................................ 45 
Table 8-3 
Components of the APACHE-II score .................................................. 46 
Table 8-4 
Local Laboratory evaluations ................................................................ 52 
Table 9-1 
Non-compartmental pharmacokinetic parameters ................................ 64 
Table 9-2 
Sensitivity of confidence interval precision to change in 
assumption for GCV rate ...................................................................... 69 
Table 10-1 
Clinically notable laboratory values...................................................... 83 
Table 10-2 
Liver event and laboratory trigger definitions ...................................... 86 
Table 10-3 
Follow-up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 88 
Table 10-4 
Follow-up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 89 
Table 10-5 
Specific renal alert criteria and actions ................................................. 90 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 11 
 

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1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A multicenter, participant and investigator-blinded, randomized, placebo-controlled phase 2a 
study to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of 
TIN816 in the treatment of patients with sepsis-associated acute kidney injury 
Brief Title: 
A multicenter study to evaluate pharmacokinetics, safety and tolerability of TIN816 in patients 
with sepsis-associated acute kidney injury 
Purpose 
This is a phase 2a study to characterize pharmacokinetic (PK)/pharmacodynamic (PD) profile 
and to evaluate safety and efficacy of TIN816 in hospitalized adult participants in an intensive 
care setting with a diagnosis of sepsis-associated acute kidney injury (SA-AKI). 
Study Indication /Medical Condition: 
Sepsis-associated acute kidney injury 
Treatment type 
A single dose of investigational study treatment TIN816 will be administered via an IV infusion. 
Study type 
Interventional phase 2a study to evaluate PK/PD, safety and efficacy of TIN816 
Objectives, Endpoints, and Estimands: 
Table 1-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary 
 
To assess PK of TIN816 with a single dose of IV 
infusion 
TIN816 concentrations in serum 
PK parameters: Cmax, Tmax, T1/2, Cl, Vz, AUClast 
and AUCinf of TIN816 (See Section 10.2.2 for 
definitions) 
Secondary 
 
To assess safety and tolerability of TIN816 vs 
placebo 
Safety evaluations (including adverse 
events/serious adverse events, safety laboratory 
parameters, vital signs and immunogenicity) 

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Trial Design: 
This is a multicenter, participant and investigator-blinded, randomized, placebo-controlled 
study to characterize PK/PD profile and to evaluate the safety and the efficacy of TIN816 in 
hospitalized adult participants with diagnosis of sepsis and acute kidney injury (AKI). 
Approximately 20 participants will be randomized in the study. The study consists of a 
screening period (up to 48 hours), treatment period (Day 1), and post-treatment period (Day 2 
to 90). 
An interim analysis (IA) is planned when approximately 8 participants complete Day 14 visit. 
The study will continue without modification if a similar PK profile of TIN816 compared to the 
one in the healthy volunteers (HV) is confirmed. Otherwise, an adaptive design would be 
implemented with options to add up to two additional arms testing a higher dose, multiple bolus 
doses, extended infusion dosing regimens or combination of bolus dose and extended infusion. 
The adaptive design will be supported by modeling and simulation with data from the 
preclinical studies, first in human (FIH) study and the IA of the current PK/PD study. Patient 
recruitment will continue during the IA to enroll up to a cap of 12 patients. In the circumstance 
that the first IA does not provide sufficient PK data to support phase 2b, an additional IA will 
be added when all 20 patients complete Day 14 visit. 
Brief Summary: 
Approximately 90% of sepsis is caused by bacterial infection and 40-60% of septic patients 
experience sepsis-associated acute kidney injury (SA-AKI). In the recent decades, the growing 
knowledge about the physiopathology of sepsis and AKI has suggested that adenosine 
triphosphate (ATP), adenosine diphosphate (ADP) and adenosine play an essential role as 
extracellular signaling molecules in both sepsis and  AKI. Several lines of evidence have shown 
the potential benefits of the conversion of extracellular ATP to adenosine in treating sepsis and 
the related organ injury. 
TIN816 is an engineered, highly effective, soluble, and stabilized human recombinant CD39 
enzyme. The enzyme hydrolyzes extracellular ATP and ADP to adenosine monophosphate 
(AMP). TIN816 has been proven beneficial in preclinical models of acute organ injuries. 
TIN816 has also been studied in healthy volunteers. To date, 32 healthy participants have 
received either TIN816 (N=24) or placebo (N=8) in the ongoing phase 1 healthy volunteer study 
(CTIN816A02101). The study results showed that TIN816 was safe and well tolerated. Overall, 
based on the existing evidence of potential benefits by conversion of extracellular ATP to 
adenosine in treating sepsis and the related organ injuries, the accumulated data of TIN816 from 
the preclinical studies; as well as, the FIH study, it is anticipated  that therapeutic application of 
TIN816 will have potent anti-inflammatory and tissue-protective activity in patients suffering 
from SA-AKI. 
This study is designed to assess the PK/PD profile of TIN816 in the participants with SA-AKI. 
In addition, this study will evaluate safety, tolerability and efficacy of TIN816. Screening will 
take place during hospitalization in intensive care unit (ICU) or intermediate/high dependency 
unit (HDU) where potential participants will undergo screening to assess the presence of sepsis 
and AKI based on sequential organ failure assessment (SOFA) and kidney disease improving 
global outcomes (KDIGO) scores. A total of approximately 20 participants will be randomized 

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• Receiving renal replacement therapy (RRT) or a decision has been made to initiate RRT 
within 24 hours of admission. 
• Presence of AKI for a period longer than 48 hours prior to study drug administration as 
suggested by clinical manifestations, e.g., prolonged oliguria or severe renal dysfunction 
(eg., serum creatinine > 4 mg/dL) on admission without a history of CKD. 
• Evidence of recovery from AKI based on the investigator’s clinical judgement prior to 
randomization. 
• Documented (biopsy proven) or suspected history of acute or sub-acute kidney diseases 
such as rapidly progressive glomerular nephritis (RPGN) and acute interstitial nephritis 
(AIN). 
• Patients who are on dual antiplatelet therapy. 
• Patients who are thrombocytopenic at screening (Platelet count <100,000 microliter) or 
other high risk for bleeding in the opinion of the investigator. 
Treatment Groups: 
Approximately 20 participants will be assigned to one of the following two treatment 
arms/groups in a ratio of 3:1; TIN816: placebo 
• TIN816: 2 mg/kg; intravenous infusion; one-time administration 
• Placebo: intravenous infusion; one-time administration 
Data Monitoring/Other Committee: No 
Key words 
Sepsis, acute kidney injury, anti-inflammatory, immunosuppression 

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1.2 
Schema 
Figure 1-1 
Study Design 
 
1.3 
Schedule of activities (SoA) 
The SoA lists all of 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. Unscheduled visits may occur at any time for adverse event/serious adverse 
event follow-up and/or to repeat any laboratory assessment due to safety and/or technical 
reasons. 
Participants who discontinue from the study should be scheduled for a final evaluation visit if 
they agree, as soon as possible, at which time all of 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 electronic case report forms  (eCRF). 
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 
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 

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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 
evaluation of the data collected. 

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Period 
Screening 
Treatment 
Post-treatment Visits  
Visit Name 
Screening 
Day 12 
Day 
2 
Day 
3 
Day 
5 
Day 
8  
Day 
11  
Day 
14  
Day 
21  
Day 
30  
Day 
60  
Day 
90/End 
of Study 
(EOS) 
Visit Numbers1 
1 
100 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-2 to -1 
1 
2 
3 
5 
8 
11 
14 
21 
30 
60 
90 
Time (post-dose) 
- 
pre-dose3 
0H 
2 H (END of the infusion)  3 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
local laboratory and results entered in the eCRF 
7 Sample will be shipped and analyzed by the sponsor designated laboratory.  
 
9 During hospitalization, one midpoint serum creatinine sample will be collected during the 6 hour +/-1 urine collection. When participants are discharged from the 
hospital, one serum creatinine sample will be collected at the end of the 24 hour urine collection period. Dedicated blood samples for serum creatinine and Cystatin C 
will be analyzed by the central laboratory.  
10 Sample should be taken at day1 pre-dose before administering the study drug 
12 Study Completion information includes Interactive Response Technology (IRT) completion of last visit 

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2 
Introduction 
2.1 
Study rationale 
The purpose of this study is to assess the pharmacokinetics, pharmacodynamics and safety 
profile of TIN816 in patients with SA-AKI to support future phase 2 clinical drug development. 
2.2 
Background 
During sepsis, a dysregulated host response to infection leads to a life-threatening multi-organ 
dysfunction. Sepsis is a leading cause of death and a major public health problem that affects 
millions of patients worldwide every year (Fleischmann et al., 2016, Rudd et al., 2020). In the 
United States (US) alone, an estimated 1.7 million adults present to hospital each year with 
sepsis with up to 270,000 deaths resulting (Rhee et al., 2017). An aging population and an 
increase in underlying comorbidities have led to continuous growth in the incidence of sepsis 
(Mayr et al., 2014). 
Approximately 90% of sepsis is caused by bacterial infection and 40-60% of septic patients 
experience sepsis-associated acute kidney injury (SA-AKI ) (Liu et al., 2020, Yu et al., 2021). 
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function, resulting in the 
retention of urea and other nitrogenous waste products and in the dysregulation of extracellular 
volume and electrolytes. It is estimated that ~813,000 patients suffer from SA-AKI in the US, 
~793,000 
in 
urban 
China, 
~232,000 
in 
Japan 
and 
~79,000 
in 
Germany 
(Fleischmann-Struzek et al., 2018, Peters et al., 2018, Tian et al., 2019, Imaeda et al., 2021). 
Development of AKI in patients with sepsis is associated with significantly increased mortality 
rate of up to 65%, and survivors are at significantly increased risk of developing chronic kidney 
disease (CKD) and kidney failure, resulting in a significant health and financial burden for both 
patient and society (Peerapornratana et al., 2019, Chua et al., 2020, Liu et al., 2020). 
SA-AKI is a multifactorial syndrome with inflammatory, nephrotoxic, and ischemic insults 
occurring simultaneously with other pathophysiological responses rapidly leading to kidney 
impairment. Over the last 30 years, there were a considerable number of potential drug targets 
and the development of new therapies to treat sepsis and/or AKI. Attempts were primarily 
focusing on improving hemodynamics, reducing oxidative stress, and blocking hyper-
inflammatory 
response; 
however, 
all 
of 
which 
have 
failed 
in 
clinical 
trials 
(Cohen et al., 2015, Kellum et al., 2021). As a result, there are currently no specific 
pharmacological agents available for the treatment of SA-AKI. Management of patients with 
SA-AKI relies mainly on targeted antibiotics and supportive treatment including fluid 
resuscitation, vasoactive agents and renal replacement therapy (RRT). 
In the recent decades, the growing knowledge about the pathophysiology of sepsis and AKI has 
suggested that adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine play 
an essential role as extracellular signaling molecules in sepsis as well as AKI 
(Burnstock and Verkhratsky, 2010, Menzies et al., 2017, Dwyer, Kishore and Robson, 2020). 
Extracellular purines can modulate immune responses, balancing inflammatory processes and 
immunosuppression. Following an infectious insult, immune cells release intracellular ATP 
toward the extracellular compartment through various mechanisms. In addition, purine 

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metabolites released from cell death caused by lytic bacterial or viral toxin or the dysregulated 
host responses further increase extracellular levels of ATP and ADP (Ledderose et al., 2016). 
Increased levels of extracellular ATP have been detected in the plasma and peritoneum of 
animals with sepsis (Sumi et al., 2014, Li et al., 2017). Moreover, extracellular ATP levels 
correlate with lactate levels and APACHE II scores in severely ill patients with burns or multi 
organ dysfunction due to post-cardiac arrest syndrome (Sumi et al., 2014). 
In the extracellular space, ATP and ADP can activate extracellular purine receptors which are 
classified as P2 receptors. They function as G-protein coupled receptors (P2Y receptors) or as 
ligand-gated ion channels (P2X receptors). Extracellular ATP induces activation of P2X7 and 
downstream inflammasome activation, interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) 
secretion and cell death. In addition, extracellular ATP is vasoactive. In the kidney, ATP is 
inducing vasoconstriction which can lead to lack of perfusion and no-reflow phenomenon 
(Guan and Inscho, 2011). In conjunction with the activation of P2Y12 via extracellular ADP 
leading to platelet activation and thrombosis, it will result in microvascular occlusions and long-
lasting damage to the kidney. Specifically, the kidney is largely dependent on maximal 
perfusion, oxygenation, and nutrition. The unique microvascular system of the kidney and the 
high metabolic 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), to 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). In 
summary, treatment approaches to enhance extracellular ATP conversion to adenosine 
represents a therapeutic strategy to mitigate and dampen acute organ injury in general 
(Idzko et al., 2007, Colgan and Eltzschig, 2012, Gulbransen et al., 2012). 
Several lines of evidence have shown the potential benefits by conversion of extracellular ATP 
to adenosine in treating sepsis and the related organ injury. In a septic animal model induced 
by cecal ligation and puncture (CLP), treatment with apyrase, an ATPase that promotes the 
enzymatic breakdown of extracellular ATP, diminished the concentration of extracellular ATP 
in peritoneal lavages and significantly reduced mortality (Li et al., 2017). A clinical study 
conducted with alkaline phosphatase (ALP) in SA-AKI patients showed that AP improved 
kidney function determined by a composite endpoint of creatinine clearance, requirement for 
RRT, and duration of RRT (Pickkers et al., 2012). Alkaline phosphatase is an endogenous 
enzyme that exerts detoxifying effects through dephosphorylation of endotoxins and 
extracellular ATP. In a relatively larger clinical study in patients with SA-AKI (N=301), results 
have suggested a potential mortality benefit with treatment of AP compared to placebo even 
though the study did not meet its primary endpoint in improving short-term kidney function 
measured by area-under-the time corrected endogenous creatinine clearance from Day 1 to Day 
7 (Pickkers et al., 2018). 
TIN816 is an engineered, highly effective, soluble, and stabilized human recombinant CD39 
enzyme. The enzyme hydrolyzes extracellular ATP and ADP to adenosine monophosphate 
(AMP), which is a rate limiting step in conversion of extracellular ATP to adenosine. AMP is 
further catalyzed by the ecto-5’-nucleotidase CD73 to adenosine. The enzymatic activities of 
CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature 
of purinergic signals delivered to immune cells, driving a shift from an ATP-driven pro-

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inflammatory environment to an anti-inflammatory milieu induced by adenosine. It is becoming 
increasingly appreciated that rebalancing this equilibrium could change the course and outcome 
of several pathophysiological events, such as SA-AKI. 
TIN816 has been investigated extensively in preclinical models. In human whole blood TIN816 
dose dependently inhibited ATP/Lipopolysaccharide (LPS)-induced IL-1β secretion as well as 
ADP induced platelet aggregation. TIN816 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, Anderson and Sutton, 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. Biomarkers of target 
engagement and proximal pharmacodynamic extracellular ATP and ADP in the urine of 
animals after AKI were dose-dependently reduced and extracellular AMP and adenosine were 
dose-dependently increased (Investigator Brochure). 
TIN816 has also been studied in healthy volunteers (HV). To date, 32 healthy participants have 
received either TIN816 (N=24) or placebo (N=8) in the ongoing phase 1 FIH healthy volunteer 
study (CTIN816A02101). In this study, single IV doses of TIN816 (0.1, 0.3, 1.0 and 2.0 mg/kg) 
were administered to healthy participants in four cohorts. In each cohort of eight healthy 
participants, six received the investigational drug (TIN816) and two received matching placebo. 
The study results showed that TIN816 was safe and well tolerated. The breakdown of adverse 
events to different doses of TIN816 does not suggest any pattern or increase of the AE incidence 
associated with higher doses. There was no increased bleeding/clotting time beyond the normal 
range compared to placebo; there were no immunogenicity findings. The pharmacokinetic 
results are fully in line with the previously predicted TIN816 serum concentration. The pathway 
engagement markers demonstrate dose-dependent and reversible inhibition of (i) ex vivo ADP-
induced platelet aggregation and (ii) ex vivo LPS/ATP-induced IL‑1β release in TIN816 treated 
participants (Investigator Brochure). 
Overall, based on the existing evidence of potential benefits by conversion of extracellular ATP 
to adenosine in treating sepsis and the related organ injuries, the accumulated data of TIN816 
from the preclinical studies; as well as, the FIH study, it is anticipated that the therapeutic 
application of TIN816 will have potent anti-inflammatory and tissue-protective activity in 
patients suffering from SA-AKI. As a result, a small study of TIN816 is proposed in patients 
with SA-AKI to generate pharmacokinetic (PK) and pharmacodynamic (PD), safety 
 in SA-AKI patients to inform the future phase 2b study. 
2.3 
Benefit/Risk assessment 
An expanded risk-benefit summary is provided in the TIN816 IB. 
2.3.1 
Benefits 
There is currently no approved pharmacological therapy to treat or prevent AKI. Management 
of patients with SA-AKI relies mainly on anti-microbial therapies and supportive treatment 
including fluid resuscitation, vasoactive agents and RRT. The potential benefit of TIN816 in 
SA-AKI to be assessed in this study is anti-inflammation, anti-coagulation and tissue protection 

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that could lead to improvement of renal function and reduction of mortality. However, all 
potential benefits are theoretical and need to be confirmed in a large phase 3 study. 
2.3.2 
Risks 
TIN816 has been tested in HV with doses up to 2 mg/kg via intravenous infusion. Although 
there was no safety signal detected in the FIH study, there are potential risks based on its 
mechanism of action and the findings from the preclinical studies as listed below (refer also to 
the Investigator’s Brochure for details). The risk to participants in this study will be minimized 
by compliance with the eligibility criteria, close clinical monitoring, early stopping rules, 
periodic review of the safety data and guidance for the investigators in the Investigator Brochure 
(IB). 
2.3.2.1 
Bleeding 
TIN816 ability to decrease ADP levels can reduce ADP and thrombin-induced platelet 
aggregation; and therefore, is linked to a potential risk of increase in bleeding (see Investigator's 
Brochure). For this reason, standard coagulation tests (including prothrombin time (PT), 
international normalized ratio (INR), partial thromboplastin time (PTT), activated partial 
thromboplastin time (APTT) will be monitored throughout the acute phase of the study. In 
addition, patients on dual antiplatelet therapy will be excluded from this study given that an 
increased risk of bleeding following concomitant administration of TIN816 and 
antiplatelet/anticoagulant agents cannot be excluded. Caution is required when TIN816 is 
concomitantly administered with anticoagulant agents, and adequate monitoring of respective 
coagulation parameters is required. 
In the ongoing phase 1 study in healthy volunteers, inhibition of ADP-induced platelet 
aggregation was seen in the ex vivo whole blood aggregometry assay, but was not associated 
with any changes in coagulation parameters (such as PT, INR, APTT), and bleeding time nor 
any bleeding AE (see Investigator's Brochure). 
2.3.2.2 
Perivascular/vascular mineralization 
Minimal to mild perivascular/vascular mineralization in kidney, reproductive tract and thyroid 
were seen in 2- and 4-week minipig toxicology studies at ≥15 mg/kg/q4d. 
In the ongoing phase 1 study in healthy volunteers, no changes were observed in kidney function 
markers (e.g., eGFR) and no abnormalities were seen in urine dipstick parameters (protein, 
blood, glucose, ketones, bilirubin, urobilinogen, pH, leukocyte esterase, specific gravity). There 
was no change in cardiovascular parameters (blood pressure, ECG) or joint AE pointing to 
mineralization. There was no change in serum calcium. Measurement of PPi levels in serum in 
cohorts 1-4 from the FIH study (where single doses of 0.1, 0.3, 1 and 2 mg/kg TIN816 were 
given IV) showed a dose dependent and reversible reduction (cleavage) of PPi with maximum 
effect reached within hours post dose. PPi data in cohorts 1-4 suggest a similar effect of TIN816 
on PPi concentrations compared to the ex vivo IL-1ß assay. 
Comparable duration of low PPi levels was observed in minipig at the no observed adverse 
effect level (NOAEL) while mineralization was only seen following low PPi levels for at least 
35 days. Of note, the minipig is considered a highly sensitive species to vascular calcification 

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compared to rats or cynomolgus monkeys. In the absence of effect on phosphorus and calcium, 
this low level of PPi for a duration of 2-3 weeks is unlikely to lead to vascular calcification; 
however, plasma calcium, phosphorus and inorganic pyrophosphate level will be monitored 
(see Investigator's brochure). 
2.3.2.3 
Infusion and hypersensitivity reactions 
Injection of a foreign protein into humans may trigger immune response with or without 
inflammatory signs and symptoms. Such reactions, if they occur, may be immediate or delayed 
up to several weeks. Since TIN816 is a modified version of a naturally occurring human protein, 
immunogenicity may occur. In the ongoing phase 1 study in HVs, no infusion reaction, nor 
hypersensitivity, was observed (see Investigator's Brochure). 
2.3.2.4 
Anti-drug antibody mediated reactions (immunogenicity) 
As with other therapeutic recombinant proteins, there is a possibility of TIN816 inducing an 
immune response in human participants. Presence of host cell proteins in preclinical and clinical 
TIN816 
batches, 
is 
also 
known 
to 
enhance 
the 
risk 
of 
immunogenicity 
(Vanderlaan et al., 2018). The primary consequence of immunogenicity may be altered PK  and 
PD properties of the drug, leading to a potential loss in efficacy. There is also a theoretical 
possibility of immune-mediated reactions. 
In the ongoing phase 1 study in HVs, no anti-drug antibodies (ADA) were observed in cohort 
1-3 until end of study, and in Cohort 4 up to Day 8 (data cut-off). Development of anti-TIN816 
antibodies including their potential to neutralize TIN816 or endogenous CD39 will be 
monitored (see Investigator's Brochure). 
2.3.3 
COVID-19 
It is not known whether TIN816 (recombinant CD39) 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, Pickkers et al., 2018). 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. 
2.3.4 
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 

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to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
Given the very low predicted levels of TIN816 in the semen, the subsequent serum levels of a 
female sexual partner would be negligible (Scialli et al., 2016). Therefore, given that the 
likelihood is low that TIN816 would be carried in the semen and result in teratogenicity, no 
restrictions will be placed on male participants with regard to sexual activity or condom use. 
2.3.5 
Drug-drug interactions 
Concomitant use with antiplatelet agents 
In vitro incubation of human whole blood with TIN816 at ≥ 0.8 μg/mL had a strong effect on 
ADP - and thrombin - (TRAP-6) - induced platelet aggregation. Moreover, an additive PD 
interaction between TIN816 and antiplatelet agents with respect to platelet aggregation is 
anticipated since in vitro incubation of human whole blood with TIN186 in combination with 
P2Y12 inhibitors (e.g., ticagrelor or cangrelor) or acetylsalicylic acid (ASA) resulted in dose-
dependent increased inhibition of platelet aggregation with lower IC50 but no increase in 
maximal inhibitory effect, compared to TIN816 or antiplatelet agents alone. However, an 
increased risk of bleeding following concomitant administration of TIN816 and antiplatelet 
agents cannot be excluded. If concomitant treatment is indicated, adequate monitoring of 
respective coagulation parameters is required. 
Concomitant use with anticoagulant agents 
In vitro incubation of human whole blood with TIN816 at 1.0 μM had only a minimal effect on 
clot formation with delayed start of clot formation. In addition, no drug interaction between 
TIN816 and anticoagulant agents with respect to coagulation cascade (clot formation) is 
anticipated since in vitro incubation of human whole blood with TIN816 in combination with 
heparin showed absence of additive effect on clot formation. However, concomitant use of 
TIN816 with anticoagulant agents may increase the bleeding risk. Caution is required when 
TIN816 is concomitantly administered with anticoagulant agents, and adequate monitoring of 
respective coagulation parameters is required. 
2.3.6 
Blood sample volume 
The approximate volumes are mentioned in the informed consent form (ICF). Additional 
samples may be required for safety monitoring. 
Timings of blood sample collection are outlined in Section 1.3. 
3 
Objectives, endpoints, and estimands 
The following objectives will be evaluated in the study period: 
Table 3-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 

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Objective(s) 
Endpoint(s) 
• 
To assess pharmacokinetics (PK) of 
TIN816 with a single dose of IV infusion 
• 
TIN816 concentrations in serum 
PK parameters: Cmax, Tmax, T1/2, Cl, Vz, AUClast 
and AUCinf of TIN816 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess safety and tolerability of 
TIN816 vs placebo 
• 
Safety evaluations (including adverse 
events/serious adverse events, safety laboratory 
parameters, vital signs and immunogenicity) 
3.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during study conduct which could impact the interpretation of the study results 
(eg. premature discontinuation of treatment). 
The primary clinical question of interest is: What are the pharmacokinetic characteristics 
(systemic exposure) of TIN816 (IV infusion) in hospitalized adult participants with diagnosis 
of SA-AKI, who received the complete treatment infusion? 
The primary estimand is described by the following attributes: 
1. Population: hospitalized adult patients with diagnosis of SA-AKI with complete IV infusion 
and at least one available valid PK concentration measurement who survived at Day 7. 
2. Primary endpoint: PK parameters, including Cmax, Tmax, T1/2, Cl, Vz, AUClast and AUCinf. 
3. Treatment of interest: A single dose of investigational study treatment TIN816 will be 
administered via an IV infusion. 

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with CHMP (2017) and  CDER (2005) guidelines. The administration of 0.1, 0.3, 1.0 and 2.0 
mg/kg of TIN816 or placebo as a single IV infusion was well tolerated and did not reveal any 
safety signals related to the investigational medicinal product (IMP). The effect of TIN816 on 
purinergic signaling was assessed in two ex-vivo PD assays in whole blood by studying 
inhibition of LPS/ATP induced IL-1β release and inhibition of ADP induced platelet 
aggregation. Ex-vivo, an IC90 of 0.25μg/mL was derived for inhibition of ADP-induced platelet 
aggregation and an IC90 of 7.8μg/mL for inhibition of LPS/ATP-induced IL-1β release. In FIH, 
exposure was determined systemically and in skin interstitial fluid. Results indicate that TIN816 
may attenuate purinergic signaling systemically for roughly three weeks at a dose of 2 mg/kg. 
This conclusion depends; however, on the PD assay considered (LPS/ATP induced IL-1β 
release or ADP-induced platelet aggregation, assessed in-vitro or ex-vivo), on the relevance of 
the determined inhibiting TIN816 concentrations (e.g. IC50s, IC90s) for the clinical situation 
and on the required exposure in the relevant tissues. 
In this study, participants will be administered the study drug at a dose of 2 mg/kg or placebo 
via a 2-hour intravenous infusion in a participant and investigator-blinded fashion. Dose 
administration by 2 hour infusion approximately, allows time to react if unexpected safety 
related reactions occur during dosing. The dose of 2 mg/kg is selected in this study to serve the 
purpose of evaluation of the PK profile in septic patients. In the FIH study a dose of 2 mg/kg 
was well tolerated and safe. At 2 mg/kg, the expected exposure systemically and in relevant 
tissue interstitia is believed to inhibit purinergic signaling and provide a beneficial 
pharmacological effect. Total exposure (AUCinf) of a single dose of 2 mg/kg in human is 
approximately 10.4-fold lower compared to the NOAEL overall exposure from 4 IV doses of 
10 mg/kg TIN816 administered q4d in the 2 weeks minipig study (compared to AUCtau,ss from 
the 4th dose in minipig at steady state the exposure margin is 2.6-fold) and Cmax shows a 7-fold 
margin to the NOAEL exposure. Participants will be followed-up for a total duration of 90 days 
and PK/biomarker data will be used to support the dosing strategy for subsequent studies in this 
indication. 
4.4 
Rationale for choice of control drugs (comparator/placebo) 
The choice of placebo as treatment control will allow an objective assessment of safety, 
tolerability, efficacy and target engagement of TIN816. Placebo is further justified in this SA-
AKI participant study given that there is no approved treatment for this disease. 
Notwithstanding the absence of approved treatment, all participants including those treated with 
study drug or placebo should be managed and treated as locally appropriate for SA-AKI. 
4.5 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and study integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 

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4.6 
Purpose and timing of interim analyses/design adaptations 
An IA will be performed at the time when 8 participants have completed Day 14 visit. The 
intent of this IA is to provide PK concentration data on sepsis AKI participants. Participants 
will continue to be recruited while this analysis is being completed up to a cap of 12 participants. 
If a similar PK profile of TIN816 compared to that in the HVs is confirmed, the study will 
continue without modification. Otherwise, the study design may be amended with options of 
additional arms for testing a higher dose, multiple bolus doses, extended infusion dosing 
regimens or combination of bolus dose and extended infusion. The total sample size may 
increase to provide adequate PK data after dose level and/or dose regimens are changed. In the 
circumstance that the data from the first IA is not conclusive, an additional IA will be added 
when all 20 patients have completed Day 14 visit. 
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 hospitalized male and female patients with a 
diagnosis of sepsis and AKI. Approximately 20 participants will be enrolled in the study and 
randomized to receive either TIN816 or placebo. 
The investigator must ensure that all participants being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator in order 
to ensure that the study population will be representative of all eligible participants. Deviation 
from any entry criterion excludes a participant from enrollment into the study. Replacement 
participants may be enrolled to replace participants who discontinue the study for reasons other 
than safety, based on the sponsor’s decision. 
In the case where a safety laboratory assessment at screening is outside of the range specified 
below, the assessment may be repeated once prior to randomization. If the repeat value remains 
outside of the specified ranges, the participant is excluded from the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria at 
screening assessment, unless otherwise specified at randomization  (Day 1) : 
1. Signed informed consent must be obtained prior to participation in the study. 
2. ≥ 18 and ≤ 85 years of age. 
3. Admitted to ICU or intermediate/HDU. 
4. Diagnosis of sepsis according to criteria defined by The Third International Consensus 
Definitions for Sepsis and Septic Shock (Sepsis-3) based on: 

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• Suspected or confirmed infection 
• SOFA score of 2 or more (excluding renal component) 
5. Diagnosis of AKI Stage 1 or greater per the following criterion at randomization : 
• An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5 µmol/L) 
within 48 hours or presumed to have occurred in the previous 48 hours as compared to the 
reference creatinine baseline 
• For hospital-acquired AKI, a stable serum creatinine obtained in the hospital prior to AKI 
should be used as reference baseline, otherwise, baseline serum creatinine in the following 
order of preference: 
1. Median value within 3 months of the hospital admission. If not available: 
2. Median value between 3 and 6 months prior to hospital admission. If not available: 
3. At hospital admission. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria at screening assessment, unless otherwise 
specified at randomization (Day 1) , are not eligible for inclusion in this study. 
1. Not expected to survive for 24 hours. 
2. Not expected to survive for 30 days due to medical conditions other than SA-AKI. 
3. History of CKD with a documented estimated GFR <45 ml/min prior to development of AKI. 
4. Receiving RRT or a decision has been made to initiate RRT within 24 hours of admission. 
5. Weight is less than 40 kg or more than 125 kg . 
6. Has life support limitations (eg, do not resuscitate, do not dialyze, do not intubate). 
7. AKI diagnosis according to the AKI inclusion criteria for a period longer than 48 hours prior 
to study drug administration. 
8. Presence of AKI for a period longer than 48 hours prior to study drug administration as 
suggested by clinical manifestations, e.g., prolonged oliguria or severe renal dysfunction (eg, 
serum creatinine > 4 mg/dL) on admission without a history of CKD. 
9. Evidence of recovery from AKI based on the investigator’s clinical judgement prior to 
randomization. 
10. AKI is most likely attributable to causes other than sepsis such as nephrotoxic drugs (Non-
steroidal anti-inflammatory drugs (NSAIDs), contrast, aminoglycosides), other medical 
conditions (e.g. heart failure, liver failure, acute abdominal aortic aneurysm, dissection, renal 
artery stenosis) or urinary obstruction. 
11. Documented (biopsy proven) or suspected history of acute or sub-acute kidney diseases 
such as rapidly progressive glomerular nephritis (RPGN) and acute interstitial nephritis (AIN). 
12. Patients who are post-nephrectomy. 
13. Patients who are on dual antiplatelet therapy. 

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14. Patients who are thrombocytopenic at screening (Platelet count <100,000 microliter) or 
other high risk for bleeding in the opinion of the investigator. 
15. Immunosuppressed patients: 
• History of immunodeficiency diseases or known HIV test positive. 
• Is receiving immunosuppressant treatment or is on chronic high doses (high-dose therapy 
exceeding 2 weeks of treatment) of steroids equivalent to prednisone/prednisolone 0.5 
mg/kg/day, including solid organ transplant patients. Patients with septic shock treated 
with hydrocortisone (e.g., 3 × 100 mg) can be included. 
16. Active hepatitis (defined as (a) abnormal liver enzymes (Alanine aminotransferase (ALT), 
Gamma-glutamyl transferase (GGT), 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 or patients with advanced chronic liver disease, confirmed by a Child-Pugh score of 
10–15 (Class C). 
17. Acute pancreatitis with no established source of infection. 
18. Active hematological malignancy (previous hematological malignancies that are not 
actively treated are allowable). 
19. Burns requiring ICU treatment. 
20. Sepsis attributed to confirmed COVID-19. 
21. Use of other investigational drugs within 5 half-lives of enrollment within 30 days (e.g., 
small molecules) / or until the expected pharmacodynamic effect has returned to baseline (e.g., 
biologics), whichever is longer; or longer if required by local regulations. 
22. History of hypersensitivity to the study treatment or its excipients or to drugs of similar 
chemical classes. 
23. Any medical conditions that could significantly increase risk of participants’ safety by 
participating in this study according to investigator’s judgement. 
24. Women with a positive pregnancy test, pregnancy or breast feeding. 
25. 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 for 38 days of study treatment after stopping medication. 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, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking investigational drug. 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 

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• 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. 
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. 
If local regulations are more stringent from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
5.3 
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 randomly assigned to study treatment. 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 SAE. 
No rescreening is permitted in this study. 
5.3.1 
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 study. 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 will be manufactured by Novartis and supplied to the 
unblinded site pharmacist or unblinded qualified site designee. The unblinded 
pharmacist/unblinded qualified site designee will prepare the appropriate dosage (detailed 
instructions will be provided in the Pharmacy Manual). A blinded nurse/blinded qualified 
specialist will administer TIN816 (as described in the Pharmacy Manual). The placebo will be 
sourced locally by the study site as 0.9% saline solution. Saline sourced locally will also be 

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used a dilutant during the preparation of TIN816. Preparation and administration of the study 
treatment will be in a blinded fashion. 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering and administration of the study treatment are outlined in 
the Pharmacy Manual. 
6.1 
Study treatment(s) 
The investigational drug, TIN816 (Table 6-1) will be supplied as open labeled medication in 
vials to an unblinded site pharmacist or an unblinded qualified site designee. Each vial contains 
70mg TIN816. 
TIN816 is provided as a lyophilisate which needs to be reconstituted with sterile water for 
injection (SWFI) and, diluted using sterile 0.9% saline solution before use. 
An unblinded pharmacist or an unblinded qualified site designee will prepare the investigational 
and control drug to dispense to the blinded staff for study drug administration. Please refer to 
Pharmacy Manual for detailed instructions. 
Study treatment will be administered as a 2 hour IV infusion (approximately) via a perfusor 
syringe at the clinical site by the study personnel in accordance with the specified study 
procedures and the Pharmacy Manual. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
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 70mg 
(lyophilisate in 
vial) 
Powder for 
Solution for 
infusion 
Intravenous use 
Open label 
supply; vials 
Sponsor (global) 
Placebo 
(Saline) 
0.9% sodium 
chloride solution 
Intravenous use 
Open label 
infusion bags 
Site (local) 
6.1.1 
Additional study treatments 
No other study treatment beyond investigational drug are included in this study. 
6.1.2 
Treatment arms/group 
Approximately 20 participants will be assigned at Day 1 to one of the following two treatment 
arms/groups in a ratio of 3:1; TIN816:placebo 
• TIN816: 2 mg/kg; intravenous infusion; one-time administration 
• Placebo: intravenous infusion; one-time administration 

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6.1.3 
Treatment duration 
TIN816 is a one-time, single dose treatment for SA-AKI at the randomization (Day 1) visit 
(refer to Section 6.1). 
Study treatment drug will be administered as an 2 hour IV infusion (approximately) via a 
perfusor syringe at the clinical site by the study personnel in accordance with the specified study 
procedures. 
6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section in Table 6-1. For details on drug preparation, please refer to the 
Pharmacy Manual. 
A unique medication number is printed on the study medication label. 
An unblinded pharmacist/qualified site designee will identify the study medication kits to 
prepare the TIN816 treatment for this one-time administration by contacting the interactive 
response technology (IRT) and obtaining the medication number(s). The study medication has 
a 2-part label (base plus tear-off label), the unblinded site personnel (pharmacist or 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 the unblinded pharmacist or a qualified site designee at 
the study site, handled and stored safely and properly and kept in a secured location to which 
only the unblinded pharmacist or qualified site designated site personnel have access. Upon 
receipt, all study treatment must be stored according to the instructions specified on the labels 
for TIN816 and as per packaging instructions for locally sourced saline (placebo). Clinical 
supplies are to be prepared and administered for IV administration only in accordance with the 
protocol and the Pharmacy Manual. 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 unblinded designated site staff 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 study. The unblinded pharmacist or unblinded designated site staff 
must provide accountability also for locally sourced materials used for administration (i.e., 
saline solution). 
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. 

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6.2.2 
Handling of other treatment 
Not applicable. 
6.2.3 
Instruction for prescribing and taking study treatment 
There should be a period of at least 1 hour after the infusion whereby the participant requires 
close observation. Patient care should be managed as per local medical practice. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
At randomization visit (Day 1), all eligible participants will be randomized via IRT to one of 
the treatment arms. The investigator or his/her delegate will contact the IRT after confirming 
that the participant fulfills all the inclusion/exclusion criteria. 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 unique medication numbers of study treatment TIN816 to be administered 
to the participant or placebo treatment administered as 0.9% saline solution, sourced locally. 
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, and persons performing the assessments will remain blind to the 
identity of the treatment from the time of randomization until database lock. All unblinded 
personnel will keep randomization lists and data or information that could unblind other study 
team members confidential and secure except as described below. 
Novartis Clinical Trial Team (CTT), including sample analyst(s) (PK, PD 
) will 
be unblinded to the identity of treatment and will have full access to trial data. 
Site staff 
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study. 
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. 
Sponsor staff 
In addition to Novartis CTT, the following unblinded sponsor roles are required for this study. 

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• Unblinded field monitor(s) 
• Unblinded clinical staff managing drug re-supply to site 
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual participants. The unblinded monitors will also be able to 
review the treatment allocation provided by IRT to the unblinded pharmacist. 
If sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product, these individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs via the unblinded site pharmacists. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team. 
The study statistician will be able to access the full randomization list from the start of the study 
and is allowed to share unblinded information with the rest of the clinical trial team as 
appropriate for internal decision purposes. For example, unblinded summaries and unblinded 
individual data can be shared with the team whenever necessary. 
Study programmers and other personnel involved in study data analysis 
are allowed to access treatment assignment information from the start of the study for the 
purpose of data analysis. 
The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g. 
decision boards) and to an external Steering Committee, as required for internal decision 
making on the study or the project at the time of interim analyses while the study is ongoing. 
Following final database lock all roles may be considered unblinded. 
Table 6-2 
Blinding and unblinding plan 
Role 
Time or Event 
Randomization list 
generated 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Participants 
B 
B 
B 
Site Staff 
B 
B 
UI 
Unblinded site staff, e.g. pharmacy staff 
B 
UI 
B 
Sponsor CTT 
B 
UI 
UI 
All other Sponsor staff not identified 
above (i.e. project team, management 
& decision boards, support functions) 
B 
UI 
UI 
Independent committees used for 
assessing interim results, if required 
(e.g. DMC) 
B 
UI 
UI 
B Complete blinded 
UI Unblinded to individual participant treatment codes 

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6.3.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, 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 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 system  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 
An one time intravenous infusion will be administered in the ICU/HDU. This information must 
be captured in the source document, the appropriate eCRF and in the Drug Accountability Log. 
The site personnel should reflect total volume administered as well as the date and time of 
administration in the eCRF page. Any reason for dose interruption of the IV infusion will also 
be captured in the source document and the eCRF. 
PK parameters (measures of treatment exposure) will be determined in all participants treated 
with TIN816, as detailed in PK section (Section 8.7). 
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 study drug. 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 eCRF. 
6.5 
Dose modification 
Investigational or other study treatment dose adjustments are not permitted as this is an one-
time IV dose administration. 
6.6 
Continued access to study treatment after the end of the study 
Not applicable for this PK study of a single dose IV infusion investigational drug. 

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6.6.1 
Post trial access 
Not applicable for this PK study of a single dose IV infusion investigational drug. 
6.7 
Treatment of overdose 
Study treatment overdose is the administration of a quantity of the investigational medicinal 
product which is above the maximum recommended dose according to study protocol. 
In the event of an overdose, the treating physician, in collaboration with the investigator should: 
• Contact the medical monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
drug can no longer be detected systemically (at least 38 days). 
• Obtain a plasma sample for PK analysis (within 15 minutes after infusion interruption or 
infusion end, the latter marking the first PK time point post-dose). 
• Document the quantity of the excess dose. 
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 administration errors and uses outside of what is foreseen in the protocol will 
be recorded on the appropriate eCRF irrespective of whether or not associated with an AE/SAE. 
Study treatment errors will be collected and reported in the safety database irrespective of it 
being associated with an AE/SAE within 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 medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate eCRFs. 
Each concomitant drug must be individually assessed against all exclusion criteria/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. 

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Prior medications related to the treatment of sepsis and AKI taken within 2 weeks prior to 
screening will be recorded on the eCRF. 
Administered resuscitation fluids should only be recorded as total daily volume in the 
concomitant eCRFs. Blood products should be recorded separately. 
6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
Administration of nephrotoxic drugs such as contrast agents, NSAIDs, angiotensin-converting 
enzyme (ACE) inhibitors,  amphotericin B, high doses of loop diuretics, anti-microbial drugs 
like acyclovir and aminoglycoside drugs should be avoided or used with caution, as 
recommended in the KDIGO Clinical Practice Guideline for AKI (KDIGO (2012)). 
In addition, based on the mechanism of action of TIN816 (removal of ADP and inhibition of 
P2Y12 activation), there is a theoretical bleeding risk. Although no relevant bleeding 
complications were observed in the preclinical toxicology and FIH study at exposure resulting 
in a full inhibition of ADP/thrombin-induced platelet aggregation, an additive inhibitory effects 
of platelet aggregation caused by TIN816 was found in the presence of antiplatelet drugs 
(ticagrelor or acetylsalicylic acid) at a clinical therapeutic dose. Thus, careful monitoring of 
coagulation/clinical signs of bleeding should occur if antiplatelet agents or other anticoagulant 
drugs are used concomitantly during the study. Management of bleeding in patients treated with 
TIN816 may include temporary discontinuation of antiplatelet or anticoagulant drugs, 
resuscitation with intravenous fluid, packed red cell transfusion and platelet transfusions, as per 
local practice. 
6.8.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed after the start of study 
treatment 
Table 6-3 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Dual antiplatelet therapy 
30 days after randomization 
Discontinue dual antiplatelet 
therapy 
7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
Since this is a one time single dose intravenous infusion, a permanent interruption of the 
infusion will be considered as discontinuation from study treatment. 
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. 

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Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
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 agree to return for the end of treatment and 
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 done according to the study visit 
schedule. 
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
7.2 
Participant discontinuation from the study 
Discontinuation from study is defined as when a participant permanently stops any 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 

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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. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments will 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/opposition to use data/biological samples/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 
included in the corresponding informed consent form. 
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 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 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination include (but are 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 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 in 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 Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) of the early 
termination of the study. 

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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. 
Adherence to the study design requirements, including those specified in Section 1.3 Schedule 
of Activities, is essential and required for study conduct. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Screening 
Re-screening is not allowed if a participant fails screening and does not meet eligibility criteria. 
8.1.1 
Eligibility Screening 
Patients admitted to ICU or intermediate/HDU care with AKI and a suspected or proven sepsis 
can be considered to be enrolled in the study. 
The following key assessments and procedures will be performed at the screening visit: 
• Signature of the ICF by the participant, or his/her legal representative, or other according 
to local regulatory requirements. 
• Sepsis and AKI diagnosis 
• SOFA score 
• Hematology (local lab) 
• Clinical Chemistry (local lab) 
• Hepatitis screen (local lab) 
 
 
• Collection of demographics, vital signs, medical history/current medical conditions 
(including alcohol and smoking history), and concomitant medications 
• Reference serum creatinine 
• Pregnancy test (serum) performed by local laboratory. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate 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 
SAE Section 8.6.2 for reporting details). 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. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate case report form. 

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8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
The following key assessments will be performed at the baseline (Day 1) visit, unless otherwise 
specified: 
• Vital signs (temperature, heart rate, respiratory rate, and blood pressure) 
• AKI diagnosis 
• APACHE II score 
• SOFA score 
 
 
• Clinical chemistry (local lab) 
• Hematology (local lab) 
• Urinalysis (local lab) 
• PK/PD/ADA blood collection (central lab) 
• Urine collection (central lab) 
• Serum creatinine, creatinine clearance (central lab) 
Demographics, relevant medical histories and current medical conditions collected at screening 
visit are considered as baseline. 
8.2.1 
Demographics and Medical History 
Demographics to be collected include age, sex, race/predominant ethnicity (if permitted) and 
medical history (until date of signature of informed consent) should be recorded at screening. 
Medical history at screening should be recorded in the appropriate section of the eCRF with 
special emphasis on pre-existing renal disease and the use of immunosuppressant medication, 
steroids, and nephrotoxic drugs. 
For determination of study drug dosage and calculation of fluid corrected creatinine, body 
weight (in kg/lb) should be estimated or measured. 
Height and weight will be collected at screening for calculation of body mass index (BMI) 
(BMI= body weight (kg)/[height (m)]2). Depending on availability, the order of preference for 
weight value to be used for dose calculation is: 
1. Hospital admission measured weight 
2. Patient reported weight 
3. Ideal body weight (Devine formula)(Devine, 1974) 
• Men = 50kg +2.3kg x (height - 60inches) 
• Women = 45.5kg +2.3kg x (height - 60 inches) 
4. Estimated body weight 

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mL/hour and there are no other indications for RRT, then endogenous creatinine clearance 
should be calculated using a 6-hour urine collection period. If endogenous creatinine clearance 
≥ 20 mL/min, RRT should be discontinued. If endogenous creatinine clearance ≤ 12 mL/min, 
RRT should be continued. However, although the criteria for starting and stopping mentioned 
above are strongly preferred within the protocol setting, based on clinical judgment 
investigators may deviate from these criteria. 
8.3.5 
Scoring Systems 
8.3.5.1 
Sequential Organ Failure Assessment Score (SOFA) 
The SOFA score was developed to assess the acute morbidity of critical illness at a population 
level and has been widely validated as a tool for this purpose across a range of healthcare 
settings 
and 
environments 
(Vincent et al., 1996, Vincent et al 1998). 
Following 
the 
development of new definitions, it is now used as a key criterion in the diagnosis of sepsis 
syndrome on an individual patient level. The score is routinely calculated on admission to ICU 
and at each 24-hour period that follows. It is composed of six criteria which reflect the function 
of a specific organ system (respiratory, cardiovascular, renal, neurological, hepatic and 
hematological) and allocates a score of 0-4. 
Scores ranges from 0-24, with higher scores indicating greater dysfunction. 
The SOFA score has been applied in a range of clinical and research applications. 
In the context of randomized controlled trials, a meta-analysis identified 25 studies where the 
change in SOFA score from baseline or maximum to a defined time point was used and revealed 
a strong association between change in SOFA and mortality – with 32% of the observed 
mortality effects explained by the delta SOFA score (de Grooth et al., 2017). This association 
of SOFA score at admission and during ICU stay with longer term outcomes has led to the 
acceptance by the EMA that use of delta SOFA is a valid surrogate endpoint in exploratory 
clinical trials of patients with sepsis (CHMP 2006). 
The SOFA score will be assessed based on local laboratory results due to time requirements. 
Table 8-2 
Components of the SOFA score 
 
Score 
0 
1 
2 
3 
4 
Respiratory 
system 
 
PaO2/FiO2 
(mmHg) 
≥400 
<400 
<300 
<200 with 
respiratory 
support 
<100 with 
respiratory 
support 
Hepatic 
system 
 
Bilirubin 
(mg/dL) 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
>12.0 
Cardiovascul
ar system 
 

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MAP ≥70 
mmHg 
MAP <70 
mmHg 
Dopamine <5 
mcg/kg/min or 
dobutamine 
(any dose)a 
Dopamine 
5.1-15 
mcg/kg/min or 
epinephrine 
≤0.1 
mcg/kg/min or 
norepinephrin
e ≤0.1 
mcg/kg/mina 
Dopamine >1
5 mcg/kg/min 
or 
epinephrine >
0.1 
mcg/kg/min or 
norepinephrin
e >0.1 
mcg/kg/mina 
Coagulation 
 
Platelets × 103 
μl 
≥150 
<150 
<100 
<50 
<20 
Central 
nervous 
system 
 
Glasgow 
coma scale 
15 
13-14 
10-12 
6-9 
<6 
Renal system 
 
 
 
 
 
Creatinine 
(mg/dL) 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
>5.0 
Urine output 
(mL/d) 
- 
- 
- 
<500 
<200 
Notes: aAll catecholamine doses represent μg/kg/min. Organ dysfunction is identified as an increase in 
the SOFA score of ≥2 points. In patients with not known preexisting organ dysfunction, the baseline 
SOFA score is assumed to be zero. The SOFA (Sepsis-related Organ Failure Assessment) score to 
describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the 
European Society of Intensive Care Medicine. 22(7), 1996, 707-710.Vincent JL. Moreno R, Takala J, 
et al. 
Abbreviations: PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen; MAP, mean arterial 
pressure. 
Source: Lopez et al., 2017 
8.3.5.2 
Acute Physiology and Chronic Health Evaluation Score (APACHE-II) 
The APACHE-II (acute physiology and chronic health evaluation II) score is a severity-of-
disease classification system for the assessment of critically unwell patients. It is applied within 
24 hours of admission of a patient to an ICU or intermediate/HDU. An integer score from 0-71 
is computed based on several measurements: higher scores correspond to more severe disease 
and a higher risk of death in ICU patients. 
The APACHE-II score will be assessed at baseline and recorded in the eCRF. 
Table 8-3 
Components of the APACHE-II score 
Physiologic 
variableb 
Point score 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
1 
Temperatur
e 
≥41° 
39-
40.9
° 
- 
38.5
-
38.9
° 
36-
38.4
° 
34-
35.9
° 
32-
33.9
° 
30-
31.9
° 
≤29.9° 

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2 
Mean 
arterial 
pressure 
(mmHg) 
≥16
0 
130-
159 
110-
129 
- 
70-
109 
- 
50-
69 
- 
≤49 
3 
Heart rate 
≥18
0 
140-
179 
110-
139 
- 
70-
109 
- 
55-
69 
40-
54 
≤39 
4 
Respiratory 
rate(non-
ventilated 
or 
ventilated) 
≥50 
35-
49 
- 
25-
34 
12-
24 
10-
11 
6-9 
- 
≤5 
5 
Oxygenatio
n: 
a)FiO2≥0.5: 
use A-aDO2 
b)FiO2<0.5: 
use PaO2 
(mm Hg) 
≥50
0 
350-
499 
200-
349 
- 
<20
0 
- 
- 
- 
- 
- 
- 
- 
- 
>70 
61-
70 
- 
55-
60 
<55 
6 
Arterial pH 
≥7.7 
7.6-
7.69 
- 
7.5-
7.59 
7.33
-
7.49 
- 
7.25
-
7.32 
7.15
-
7.24 
<7.15 
7 
Serum Na 
(mMol/L) 
≥18
0 
160-
179 
155-
159 
150-
154 
130-
149 
- 
120-
129 
111-
119 
≤110 
8 
Serum K 
(mMol/L) 
≥7 
6-
6.9 
- 
5.5-
5.9 
3.5-
5.4 
3-
3.4 
2.5-
2.9 
- 
<2.5 
9 
Serum 
creatinine 
(mg/dL):dou
ble point 
score for 
acute renal 
failure 
≥++
++3.
5 
2-
3.4 
1.5-
1.9 
- 
0.6-
1.4 
- 
<0.6 
- 
-- 
10 
Hematocrit 
(%) 
≥60 
- 
50-
59.9 
46-
49.9 
30-
45.9 
- 
20-
29.9 
- 
<20 
11 
WBC (in 
1000s) 
≥40 
- 
20-
39.9 
15-
19.9 
3-
14.9 
- 
1-
2.9 
- 
<1 
12 
Glasgow 
coma score 
Score= 15 minus actual Glasgow coma score 
Acute physiology score is the sum of the 12 individual variable points 
Add 0 points for the age <44.2 points. 45-54 years: three points. 55-64 years: five points. 65-74 
years: six points ≥ 75 years 
APACHE II score = acute physiology score + age points + chronic health points. Minimum score = 
0; maximum score = 71. Increasing score is associated with increasing risk of hospital death 
Add chronic health status points: two points if elective postoperative patient with 
immunocompromise or history of severe organ insufficiency: five points for nonoperative patient or 
emergency postoperative patient with immunocompromise or severe organ insufficiencyc 
13d 
Seru
m 
HC
≥52 
41-
51.9 
- 
32-40.9 
22-
31.9 
- 
18-
21.9 
15-
17.9 
<15 

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O3 (
Ven
ous-
mM
ol/L) 
use 
only 
if no 
ABG
s52 
Adapted from (Knaus et al., 1985) APACHE II: A severity of disease classification system. Critical care 
medicine 13: 818-829, 1985. Interpretation of APPACHE II scores (predicted mortality rate). 
0-4=~4% death rate 10-14 =~15% death rate 20-24=~40% death rate 30-34=~75% death rate 
5-9=~8% death rate 15-19=~25% death rate 25-29=~55% death rate Over 34=~85% death rate 
aAPACHE II score = acute physiology score + age points + chronic health points. Minimum score = 0; 
maximum score = 71. Increasing score is associated with increasing risk of hospital death 
bChoose worst value in the past 24h. 
cChronic health status: Organ sufficiency (e.g. hepatic, cardiovascular, renal, pulmonary) or immuno-
compromised state must have preceded current admission. 
dOptional value: use only if no ABGs. 
Source: (Sam et al., 2009) 
8.3.6 
Appropriateness of efficacy assessments 
There are no efficacy assessments for the primary and secondary endpoints. 
8.3.7 
Serum Creatinine 
Serum creatinine samples will be collected as part of the creatinine clearance assessments and 
shipped to the central laboratory. For the 6 ±1 hour urine collections whilst an inpatient on the 
ICU or intermediate/HDU, one sample will be taken at approximately the mid-point of the urine 
collection. If the participant is discharged from the ICU or intermediate care unit to general 
ward, the Foley catheter might be removed. In this case, a participant might urinate 
spontaneously and all efforts should be undertaken to start collecting urine produced from this 
time point onward for the next 6 hours. A blood sample for serum creatinine will be drawn at 
approximately the mid-point of the urine collection. The urine volume produced over 
approximately 6 hours will be entered in the eCRF. After participants are discharged from 
hospital, only one blood sample for serum creatinine will be drawn at the end of the 24 hour 
urine collection period. 
8.4 
Safety and tolerability assessments 
Safety assessments are specified below with Section 1.3 Schedule of Activities detailing when 
each assessment is to be performed. 
The following assessments will be considered safety measurements: 
• Vital signs, including blood pressure, respiratory rate and body temperature at baseline 
Day 1 and at all post-baseline visits. 
• Physical examination at screening,  baseline Day 1,  Day 14 and Day 90 visits. 
• Local ECG at baseline Day 1 visit. 

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• Local arterial/venous blood gas sampling for PaO2/carbon dioxide partial pressure 
(PaCO2)/pH/HCO3 
• Local laboratory at screening, baseline Day1 visit and at post-baseline visits. 
• Hematology at screening and baseline Day 1, Day 5, Day 14, Day 30 and Day 90 
visits. 
• Clinical chemistry, including liver function parameters at screening and baseline Day 
1, Day 5, Day 14, Day 30 and Day 90 visits. 
• Urinalysis at screening, baseline Day 1, Day 3, Day 5, Day 14, Day 30 and Day 90. 
• Coagulation parameters at screening, baseline Day 1, Day 5, Day 14, Day 30 and Day 
90. 
• Central laboratory for anti-drug antibodies at baseline (Day 1/ pre-dose) and at visits on 
Days 14, 30 and 90. 
• Concomitant medication at screening and all visits from Day 1 to Day 90. 
• AEs/SAEs during the duration of the study. 
• Mortality (monitored continuously throughout the study) 
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 be performed as per local standard/guidelines at 
screening, baseline Day 1, Day 14 and Day 90 visits (Table 1-2). If indicated based on medical 
history and/or symptoms, further focused organ specific exams should be performed. The 
physical examination should be performed by a physician or another study team member with 
appropriate training to perform the examination. 
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 eCRF 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. 
8.4.1.1 
Height and weight 
Height is obtained in centimeters (cm) and body weight is obtained in kilograms (kg) and 
rounded to the nearest 0.1 kg. 
Depending on availability, the order of preference for weight value to be used for dose 
calculation is: 
1. Hospital admission measured weight 

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2. Patient reported weight 
3. Ideal body weight (Devine formula)(Devine, 1974) 
• Men = 50kg +2.3kg x (height - 60inches) 
• Women = 45.5kg +2.3kg x (height - 60 inches) 
4. Estimated body weight 
 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. 
Body weight measurements will be taken at screening, baseline Day 1, Day 14, Day 30, Day 60 
and Day 90. 
8.4.2 
Vital signs 
Vital signs will include the collection of body temperature (recorded in °C), blood pressure 
(BP), and pulse measurements at all visits (Table 1-2). 
In those participants who already have an arterial line placed as part of standard of care, readings 
from invasive blood pressure monitoring will be recorded preferentially. Otherwise, non-
invasive blood pressure measurements should be used. 
Additionally, vital signs will also be monitored during study drug infusion, and data will be 
collected at the following timepoints: a) immediately before the administration of the study 
drug, and b) immediately after the completion of the administration of the study drug, which 
includes post-dose saline flushing. Routine monitoring can continue based on local guidelines. 
8.4.3 
Electrocardiograms 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions, e.g. at the 
screening visit.  The investigator must calculate QTcF if it is not auto-calculated by the ECG 
machine. 
During study drug infusion, participants should have continuous ECG monitoring as per local 
guidelines. A 12 lead ECG should be acquired 15 minutes after the end of study drug infusion 
and evaluated for new abnormalities. Interpretation of the tracing must be made by a qualified 
physician. 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 ECG abnormalities present at the screening or baseline visit 
should be reported on the appropriate eCRF. Clinically significant abnormalities must be 
recorded on the eCRF as either medical history/current medical conditions or adverse events as 
appropriate. New or worsened clinically significant findings occurring after informed consent 
must be recorded as adverse events. 
The original ECGs 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, 

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When available, urine samples will be obtained from urinary catheters. In those patients without 
a catheter, a mid-stream urine sample (approx. 30 mL) will be obtained in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. 
Table 8-4 
Local Laboratory evaluations 
Test Category 
Test Name 
Hematology 
Hematocrit, hemoglobin, platelets (platelets 
count, platelets clumps count, mean platelets 
volume), erythrocytes, leukocytes, differential 
(basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, bands, other (absolute 
value and percentage) 
Chemistry 
Albumin, alkaline phosphatase (ALP), alanine 
transaminase (ALT), aspartate 
transaminase (AST), bicarbonate, gamma-
glutamyl-transferase (GGT), lactate 
dehydrogenase (LDH), C-reactive protein 
(CRP),  calcium, magnesium, phosphate, 
chloride, sodium, potassium, creatinine, 
creatinine kinase (CK), direct bilirubin, indirect 
bilirubin, total bilirubin, total cholesterol, low 
density lipoprotein (LDL), high density 
lipoprotein (HDL), total protein, triglycerides, 
blood urea nitrogen (BUN) or urea, uric acid, 
lipase, amylase, glucose, ferritin, cystatin C. 
Urinalysis 
Microscopic panel (erythrocytes, leukocytes, 
casts, crystals, bacteria, epithelial cells) 
Macroscopic panel (dipstick) (color, bilirubin, 
blood, glucose, ketones, leukocytes esterase, 
nitrite, pH, protein, specific gravity, urobilinogen) 
Coagulation 
Prothrombin time (PT), international normalized 
ratio (INR), partial thromboplastin time (PTT), 
activated partial thromboplastin time (APTT) 
Thyroid 
T3 [free], T4 [free], Thyroid-stimulating hormone 
(TSH) 
Hepatitis markers 
Hepatitis B virus surface antigen (HBsAg), anti-
HBs, anti-HBc, anti-HCV, HCV polymerase 
chain reaction if anti-HCV is positive (screening). 
Pregnancy Test 
Serum pregnancy test / urine pregnancy test 
(refer to Section 8.4.5) 
8.4.5 
Pregnancy testing 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
At screening, a locally-analyzed serum pregnancy test with beta-human chorionic gonadotropin 
(β-hCG) must be performed for all females of childbearing potential. Any participant with a 
positive pregnancy test at screening will be excluded from enrolling in the study. The test result 
must be  negative in order to proceed with the administration of the study treatment. 

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In general, the levels of a TIN816 in semen is expected to be low, the subsequent levels in 
female partner would be negligible. Based on this principle, the probability that TIN816 would 
cause teratogenicity is very low. Therefore, no restrictions will be placed on male participants 
with regard to sexual activity or condom use. 
If participants cannot visit the site to have serum pregnancy tests 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, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site.  A communication process should be established with the participant so that the site is 
informed and can verify the pregnancy test results (e.g., following country specific measures). 
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 his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile. 
In the absence of the above medical documentation, follicle stimulating hormone (FSH) testing 
is required of any female participant regardless of reported reproductive/menopausal status at 
screening/baseline. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 
8.5.1 
Clinical Outcome Assessments (COAs) 
Not applicable. 

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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 (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
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. 
8.6.1 
Adverse events 
An adverse event 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 participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on study-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. The common terminology criteria for adverse events (CTCAE) grade (version 5 or higher). 
If CTCAE grading does not exist for an adverse event, use 1=mild; 2=moderate, 3=severe; and 
4=life threatening. CTCAE 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. 

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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 
• 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. 
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. 
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. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.3. 
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 

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caused death if it were more severe (please refer to the International Council for Harmonization 
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. 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition. 
• 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 2004). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
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). Novartis 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 

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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  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: 
Sepsis, Septic shock, Acute kidney injury, Multiple organ dysfunction syndrome, Acute 
respiratory distress syndrome, Disseminated intravascular coagulation, Pneumonia, 
Hypotension, Fever, Tachypnea, Leucocytosis, Leucopenia, Respiratory alkalosis, Metabolic 
acidosis. 
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. INs 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. 
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with European (EU) Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries. 

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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. 
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 study participant becomes pregnant, 
the pregnancy consent form should be presented to the study 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 90 day 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 
The following are adverse events of special interest: 
Bleeding 
TIN816 ability to decrease ADP levels can reduce ADP and thrombin-induced platelet 
aggregation and is linked to a potential risk of increased bleeding. In the FIH study cohorts 1-

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4, inhibition of ADP-induced platelet aggregation was seen in ex vivo whole blood 
aggregometry assay and was not associated with bleeding AE. In one participant in cohort 3 at 
1.0 mg/kg that suffered from trauma and had subsequent surgeries, no abnormal bleeding nor 
hemorrhage were seen during and after surgical interventions despite inhibition of ex vivo ADP-
induced platelet aggregation. In cohort 4 at 2.0 mg/kg, compared to placebo and baseline, no 
increase in bleeding/clotting time was noted in 5 out of 6 participants receiving TIN816, 
although a slight increase in closure time was noted up to 2 weeks after TIN816 administration 
in the ex vivo platelet function assay using a P2Y cartridge. One participant had a slight increase 
in bleeding/clotting time from baseline to Day 8 (within normal range) and returned to normal 
values by Day 15. 
Standard coagulation tests (including PT, PTT and INR) should be monitored. In the 
CTIN816B12201 study, TIN816 will not be used in participants who are receiving dual 
antiplatelet agents; therefore, these participants will be excluded from study participation. In 
addition, adequate monitoring of respective coagulation parameters will be done in study 
participants. 
Perivascular/vascular mineralization 
Perivascular/vascular mineralization of minimal to mild severity was observed in minipig. In 
the FIH study cohorts 1-4, there was no change in serum calcium nor serum phosphorus noted. 
No changes were observed in kidney function markers (e.g., eGFR) and no abnormalities were 
seen in urine dipstick parameters (protein, blood glucose, ketones, bilirubin, urobilinogen, pH, 
leukocyte esterase, specific gravity). There was no change in cardiovascular parameters (blood 
pressure, ECG) or joint AE pointing to mineralization. 
In the CTIN816B12201 study, the risk is minimized by administration of single dose only and 
ensuring an appropriate safety margin and dose which was tested in healthy volunteers. In 
addition, serum calcium, phosphorus and free pyrophosphate levels should be monitored in 
study participants. 
Infusion reactions and hypersensitivity 
Injection of a foreign protein into humans may trigger immune response with or without 
inflammatory signs and symptoms. Such reactions, if they occur, may be immediate or delayed 
up to several weeks. Since TIN816 is a modified version of a naturally occurring human protein, 
immunogenicity may occur. 
The CTIN816B12201 study will apply single dosing. A prolonged IV infusion time of 2 hours 
will reduce Cmax exposure, and a single dose administration of TIN816 will further reduce the 
exposure duration. Despite the very low risk of a theoretical infusion reaction due to Monocyte 
chemoattractant protein-1 (MCP-1) related histamine release, signs and symptoms of any 
allergic reaction should be closely monitored, and IV infusion could be stopped at any time. 
Anti-drug antibody mediated reactions (immunogenicity) 
As with other therapeutic recombinant proteins, there is a possibility of TIN inducing an 
immune response in human participants. Presence of host cell proteins in preclinical and clinical 
TIN816 
batches, 
is 
also 
known 
to 
enhance 
the 
risk 
of 
immunogenicity 
(Vanderlaan et al., 2018). The primary consequence of immunogenicity may be altered PK and 

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PD properties of the drug, leading to a potential loss in efficacy. There is also a theoretical 
possibility of immune-mediated reactions. 
Development of anti-TIN816 antibodies and their neutralization potential of TIN816 and/or 
endogenous CD39 will be assessed in dedicated plate and cell-based in-vitro assays and are 
interpreted in the context of PK, PD and safety. Potential reactions related to such antibodies, 
such as antibody-mediated arthropathy, should be monitored closely. 
8.7 
Pharmacokinetics 
PK serum samples will be collected at the time points defined in the Assessment Schedule 
(Table 1-2). Two samples will be collected on Day 1: one sample pre-dose and one sample post-
dose within 15 minutes at the end of the two hour study drug infusion. In addition, PK samples 
should be collected at additional days as indicated in Table 1-2, optimally always at that time 
point of the day when study drug administration started on Day 1 (e.g. Day 2 sample should be 
taken 24 h after starting TIN816/placebo infusion). 
Instructions regarding sample collection, numbering, processing and shipment are outlined in 
the Laboratory Manual. The exact time of treatment administration, sample number and time 
of sample collection are recorded for each sample collected in the eCRF. Sampling problems 
are to be documented in the eCRF and may include but are not limited to hemolyzed or lipemic 
samples, insufficient sample volumes, and/or a lack of sample collections. 
Pharmacokinetic (PK) samples will be evaluated in all participants treated with TIN816. 
TIN816 concentrations will be determined in serum by a validated ligand binding assay with a 
lower limit of quantification (LLOQ) of approximately 10 ng/mL. The detailed method 
description of analysis will be given in the method validation report. Concentrations below the 
LLOQ will be reported as “zero” and missing data will be labeled as such in the Bioanalytical 
Data Report. Values below the LLOQ will be treated as zero for calculation of PK parameters 
as well as for summary statistics. 
For standard pharmacokinetic abbreviations and definitions refer to Appendix 2 (Section 10.2) 
of this protocol. The following pharmacokinetic parameters will be determined from the serum 
concentration time data using the actual recorded sampling times and non-compartmental 
method(s) with Phoenix WinNonlin (Version 6.4 or higher): Cmax, Tmax, AUClast, AUCinf, T1/2, 
Vz, Cl, and other relevant PK parameters (data permitting). 
The linear trapezoidal rule will be used for AUC calculation, starting with the initiation of IV 
infusion. Regression analysis of the terminal elimination phase for the determination of the T1/2 
will include at least 3 data points after Cmax. If the adjusted R2 value of the regression analysis 
of the terminal phase is less than 0.75, no values will be reported for the corresponding T1/2. If 
the T1/2 is not calculable, AUCinf, Vz and CL will not be reported and AUClast will be used. 
Urine collected for creatinine clearance as defined in the Assessment Schedule (Table 1-2) will 
also be saved for potential urine PK analysis (refer to Creatinine Clearance Section 8.3.1 for 
additional sample collection details). 
TIN816 urine concentrations will be determined by a qualified ligand binding assay. 
Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled as 

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such in the Bioanalytical Data Report. Values below the LLOQ will be treated as zero for 
calculation of PK parameters as well as for summary statistics. 
If data permit, renal clearance (CLr) will be determined using blood and urine TIN816 
concentrations, the actual recorded sampling times and non-compartmental method(s) with 
Phoenix WinNonlin (Version 6.4 or higher). 

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and did not receive any study drug will be excluded from this set. This will be the analysis set 
used for all efficacy analyses. 
The safety set (SAF) includes all participants who received one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the participant took at least one dose of that study treatment regardless 
treatment group randomized to. This will be the analysis set used for safety analysis except for 
PK/PD analysis. 
9.2 
Statistical analyses 
9.2.1 
General considerations 
This study is to investigate PK, safety, tolerability and efficacy. There is no inferential analysis 
to be performed. The analyses will be mainly based on descriptive statistics. 
Categorical data will be presented as frequencies and percentages, including quartiles. For 
continuous data, mean, standard deviation, median, minimum, and maximum will be presented. 
For PK parameters, n, mean, median, minimum, maximum, coefficient of variation (CV (%)) 
to mean, geometric mean, and CV(%) to geometric mean will be presented. 
The baseline visit is defined at Day 1 unless specified. Parameters that are not collected at Day 
1, the screening visit will be used as baseline. 
For hospital-acquired AKI, a stable serum creatinine obtained in the hospital prior to AKI will 
be used  used as reference baseline: otherwise, a baseline serum creatinine is defined in the 
following order of preference: 
1. Median value within 3 months of the hospital admission. If not available: 
2. Median value between 3 and 6 months prior to hospital admission. If not available: 
3. At hospital admission. 
The study will exclude participants whose AKI diagnosis or AKI presence based on 
investigator’s clinical judgement has a period longer than 48 hours prior to study drug 
administration because of the criticality of an early treatment for patients with SA-AKI. 
9.2.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all participants and by treatment group. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, for all participants and by treatment group. 
9.2.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. Descriptive statistics will be 
provided. 

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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the anatomical therapeutic chemical 
(ATC) classification system by treatment group. 
9.3 
Primary endpoint(s)/estimand(s) analysis 
The primary endpoint is all TIN816 concentrations in serum PK parameters, including Cmax, 
Tmax, T1/2, Cl, Vz, AUClast and AUCinf. It will be summarized descriptively for participants with 
at least one dose of study treatment. 
There is no inferential analysis to be performed. 
9.3.1 
Definition of primary endpoint(s) 
The primary endpoint is all PK related parameters (Table 9-1). The analyses will be performed 
on PK population set. 
TIN816 serum concentration data will be listed by treatment, participant and visit/sampling 
time point. Descriptive summary statistics of TIN816 serum concentration data will be provided 
by treatment, and visit/sampling time point, including the frequency of concentrations below 
the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), Standard Deviation (SD), CV 
(arithmetic and geometric), median, minimum and maximum. An exception to this is Tmax 
where median, minimum, and maximum will be presented. PK data will also be represented 
graphically (including spaghetti plots, boxplots and mean plots with SD) by treatment arm, 
participant and visit. 
Drug concentrations below LLOQ will be treated as missing for the calculation of the geometric 
means and geometric CV%, and as zero for all other calculations including calculation of PK 
parameters. Pharmacokinetic parameters will be calculated as described in Section 8.7 and will 
be listed by treatment and participant and summarized by treatment with descriptive statistics 
as listed below. 
The pharmacokinetic parameters listed in the table below will be determined from the serum 
concentration time data using the actual recorded sampling times and non-compartmental 
method(s) with Phoenix WinNonlin (Version 6.4 or higher). Other relevant PK parameters may 
be added (data permitting). 
Table 9-1 
Non-compartmental pharmacokinetic parameters 
PK parameter 
Definition 
AUClast 
The AUC from time zero to the last measurable 
concentration sampling time (tlast) (mass × time 
× volume-1) 
AUCinf 
The AUC from time zero to infinity (mass × time 
× volume-1) 
Cmax 
The maximum (peak) observed serum drug 
concentration after single dose administration 
(mass × volume-1) 

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Tmax 
The time to reach maximum (peak) serum drug 
concentration after single dose administration 
(time) 
T1/2 
The elimination half-life associated with the 
terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier for 
other half-lives 
Cl 
The total body clearance of drug from the serum 
following intravenous administration (volume × 
time-1) 
Vz 
The apparent volume of distribution during 
terminal phase following intravenous 
administration (associated with λz) (volume) 
9.3.2 
Statistical model, hypothesis, and method of analysis 
The analysis will be mainly based on summary statistics, no inferential statistical analysis is 
planned. The graphical summaries on PK concentration will also be provided. 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) 
All PK data will be presented as recorded in the descriptive statistics. For participants who 
discontinue from study or death where PK information is not available, the impact of this on 
the interpretation of the results will be considered. Additional summaries as needed to support 
this interpretation may be presented. It is not intended to impute missing data after 
discontinuation. 
9.3.4 
Handling of missing values not related to intercurrent event 
Missing primary endpoint values due to protocol deviations or other issues related to a pandemic 
are not anticipated as measures have been put in place, where possible, to allow for the protocol 
assessments to be conducted. In case missing values do occur for such reasons, only data 
available will be used. 
9.3.5 
Sensitivity analyses 
No sensitivity analyses are planned. 
9.3.6 
Supplementary analysis 
No subgroup analyses or other supplementary analyses are planned. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
The analysis for secondary endpoints will be based on descriptive statistics by treatment group. 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) 
The secondary endpoint is all safety. There is no efficacy analysis in secondary endpoint. 

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9.4.2 
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). 
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 participant and 
investigator-blind 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. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
The number (and proportion) of participants with adverse events of special interest/related to 
identified and potential risks will be summarized by treatment. 
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. 
The following adverse events will be counted during 90-day study period: 
• These events are those with an onset after the start of the treatment period, or which were 
present prior to the start of the treatment period but increased in severity, changed from 
being not suspected to being suspected of study treatment relationship, or developed into 
SAEs after the start of the treatment period. 
Vital signs 
Summary statistics will be provided for all vital signs data by treatment and visit/time. Where 
ranges are available, abnormalities (and relevant orthostatic changes) will be listed by treatment 
group, participant, and visit/time. If appropriate, summary statistics of the occurrence of 
abnormalities may be provided by treatment. 
Clinical laboratory evaluations 
Summary statistics for all laboratory data will be provided by treatment and visit/time. Shift 
tables using the low/normal/high/ (low and high) classification may be used, as appropriate, to 
compare baseline to the worst on-treatment value. Where normal ranges are available, 
abnormalities in laboratory data will be listed by treatment group, participant, and visit/time. 

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Graphical displays of selected safety parameters (e.g. hematological parameters, thyroid and 
reproductive hormone levels) over time will be provided by treatment group. 
Immunogenicity 
All immunogenicity results will be listed by cohort, treatment group, subject and visit/time. The 
listing will contain ADA status (negative or positive) and for ADA-positive samples a titer and 
ADA neutralization potential of TIN816 and/or endogenous CD39. Subjects with one or more 
treatment emergent ADAs are counted as ADA-positive subjects and they will be summarized 
by treatment arm to derive an ADA incidence. Incidences for neutralizing ADAs will be 
assessed as well, if appropriate. Visualizations overlaying ADA status including 
characterizations, along with PK concentration and potentially efficacy read-outs, will be 
presented. 
9.4.3 
Pharmacokinetics 
Please refer to Section 9.3.1 for details. 
 
 
 
 
 
 
 

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9.6 
(Other) Safety analyses 
Not applicable 
9.7 
Other analyses 
No other analyses are planned. 
9.8 
Interim analysis 
An interim analysis is planned when approximately 8 patients complete Day 14 visit. The study 
will continue to recruit participants while this interim analysis is being completed up to a cap 
of 12 participants. The study will continue without modification if a similar PK profile of 
TIN816 to that in the healthy volunteers (CTIN816A02101) is confirmed. Otherwise, the study 
may be amended with options of additional arms for testing a higher dose, multiple bolus doses, 
extended infusion dosing regimens or combination of bolus dose and extended infusion.  The 
total sample size may increase to provide adequate PK data after dose level and/or dose 
regimens are changed. In the circumstance that the data from the first IA does not provide 
sufficient PK data to support the phase 2b, an additional IA will be added when all 20 patients 
complete Day 14 visit. 

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9.9 
Sample size determination 
The sample size was determined to achieve a target margin of error of the mean for 
PK parameters Cmax and AUCinf. The assumption of geometric coefficient of variation 
(GCV) rate was referenced from FIH study (CTIN816A02101) interim safety report. 
9.9.1 
Primary endpoint(s) 
The proposed sample size of 15 participants in TIN816 study treatment arm is sufficient to 
achieve a target margin of error not larger than 15% of the geometric mean (half-width of a 2-
sided 95% confidence interval for the PK parameters) assuming geometric coefficient of variant 
(GCV) is 0.25 in AUCinf or Cmax. It will also be able to exclude a 1.5-fold change in AUCinf 
or Cmax assuming GCV increased variability of 0.75. 
Different GCV rates and corresponding precision of confidence interval are shown in below 
table. 
Table 9-2 
Sensitivity of confidence interval precision to change in assumption 
for GCV rate 
GCV rate * 
Width of 95% confidence interval 
0.25 
[GCV mean/1.15, GCV mean x 1.15] 
0.50 
[GCV mean/1.31, GCV mean x 1.31] 
0.75 
[GCV mean/1.47, GCV mean x 1.47] 
*GCV mean of AUCinf and Cmax for 2 mg/kg are 8% and 22%, respectively in FIH study 
(CTIN816A02101) interim safety reports 

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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 Code of Federal Regulation (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 authority 
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 

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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 or their legally authorized representative (defined as individual 
or judicial or other body authorized under applicable law to consent on behalf of a prospective 
participant to the participant's participation in the procedure(s) involved in the research) and 
answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives 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 or their legally authorized 
representative. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
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 
might require an update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent Global Informed Consent 
• Legal Authorized Representative consent 
Both consents will also include: 

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• 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 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
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 prevail 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 
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. 
Novartishas 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 Steering Committee 
The Steering Committee (SC) may be comprised of investigators participating in the study. A 
Steering Committee member will not be a member of the data monitoring Committee (DMC) 
and Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
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 

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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. 
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 eCRFs. 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 electronic data 
capture (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 
archiving at the investigational site. 
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 contract research organization (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 and study completion, as well as 
randomization codes and data about the study treatment administered to the participant will be 
tracked using an IRT system. 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. 

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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. Unblinded data will be available during the trial conducting 
period for programmer and statistician. 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 
guidelines. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH Good Clinical Practice (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 /Computing Research Association (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 . 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 and 
EudraCT. website, etc.). 

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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 patient 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 
implemented. 
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 
ACE 
Angiotensin-converting enzyme 
ADA 
Anti-drug antibodies 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
AIN 
Acute interstitial nephritis 
AKI 
Acute kidney injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMP 
Adenosine monophosphate 
APACHE II 
Acute physiology and chronic health evaluation II 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CDER 
Center for drug evaluation and research 
CFR 
Code of federal regulations 
CHMP 
Committee for medicinal products for human use 
CIOMS 
Council for international organizations of medical sciences 
CK 
Creatinine kinase 
CKD 
Chronic kidney disease 
CLP 
Cecal ligation and puncture 
CLr 
Renal clearance 
Cmax 
Maximum serum concentration 
CMO&PS 
Chief medical office and patient safety 
CO2 
Carbon dioxide 
COA 
Clinical outcome assessment 
CONSORT Consolidated standards of reporting trials 
COVID-19 
Coronavirus SARS-CoV-2 
CPAP 
Continuous positive airway pressure 
CPK 
Creatine phosphokinase 
CR 
Creatinine 
CRA 
Computing Research Association 
CrCl 
Creatinine clearance 
CRF 
Case report/record form (paper or electronic) 
CRO 
Contract research organization 

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CRP 
C-reactive protein 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CTT 
Clinical trial team 
CV 
Coefficient of variation 
DILI 
Drug-induced liver injury 
DIN 
Drug inducted nephrotoxicity 
DLT 
Dose limiting toxicity 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report/record form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European medicines agency 
EOS 
End of Study 
eSAE 
Electronic serious adverse event 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and drug administration 
FIH 
First in human 
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GCS 
Global clinical supply 
GCV 
Geometric coefficient of variation 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
h 
Hour 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
HDU 
High dependency care unit 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related quality of life 
HV 
Healthy volunteer 
IA 
Interim analysis 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International council for harmonization of technical requirements for pharmaceuticals 
for human use 

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ICU 
Intensive care unit 
IDFU 
Investigational directions for use 
IEC 
Independent ethics committee 
IG 
Immunogenicity 
 
 
 
 
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 
IV 
Intravenous 
KDIGO 
Kidney disease improving global outcomes 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LFTs 
Liver function tests 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
LPLV 
Last patient last visit 
LPS 
Lipopolysaccharide 
MAKE 
Major adverse kidney event 
MCP-1 
Monocyte chemoattractant protein-1 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
MRI 
Magnetic resonance imaging 
Nab 
Neutralizing antibody 
NOAEL 
No observed adverse effect level 
NSAID 
Non-Steroidal Anti-inflammatory Drug 
PaCO2 
Carbon dioxide partial pressure 
PaO2 
Partial pressure of oxygen 
PCR 
Protein-creatinine ratio 
PD 
Pharmacodynamic(s) 
PEEP 
Positive end-expiratory pressure 
PK 
Pharmacokinetic(s) 
PPi 
Inorganic pyrophosphate 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTcF 
QT interval corrected by Fridericia’s formula 
RAS 
Randomized analysis set 

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RPGN 
Rapidly progressive glomerular nephritis 
RRT 
Renal replacement therapy 
SA-AKI 
Sepsis-associated acute kidney injury 
SAE 
Serious adverse event 
SAF 
Safety set 
SC 
Steering committee 
SD 
Standard deviation 
SMQ 
Standardized MedDRA Query 
SoA 
Schedule of activities 
SOFA 
Sequential organ failure assessment 
SUSAR 
Suspected unexpected serious adverse reaction 
SWFI 
Sterile water for injection 
Tmax 
Time to maximum concentration 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
US 
United States 
UTI 
Urinary tract infection 
VA/NIH 
Veterans affairs/National Institutes of Health 
WB 
Whole blood 
WHO 
World health organization 
10.2.2 
Definitions 
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) 
Assessment 
A procedure used to generate data required by the study 
AUCinf 
The AUC from time zero to infinity (mass × time × volume-1) 
AUClast 
The AUC from time zero to the last measurable concentration sampling time 
(tlast) (mass × time × volume-1) 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Cl 
The total body clearance of drug from the serum following intravenous 
administration (volume × time-1) 
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or 
survives 
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. 
Cmax 
The maximum (peak) observed serum drug concentration after single dose 
administration (mass × volume-1) 
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 

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Control drug 
A study intervention (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 intervention 
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 study 
data using data collection systems, such as Web-based 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. 
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 Novartis 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. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
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 
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. 

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Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, 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) 
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-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the participant 
about the status of a participant's health condition without amendment or 
interpretation of the participant'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 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
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. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site. 
Rescreening 
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 
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 
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 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi 
logarithmic concentration-time curve (time). Use qualifier for other half-lives 

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Tele-visit 
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the Investigator will conduct the trial. 
Tmax 
The time to reach maximum (peak) serum drug concentration after single 
dose administration (time) 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 
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. 
Vz 
The apparent volume of distribution during terminal phase following 
intravenous administration (associated with λz) (volume) 
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. 

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10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
Clinically notable laboratory values and vital signs 
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. 
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 
×106/μL 
>50% 
increase, >30% 
decrease 
×1012/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 
×103/μL 
>50% 
increase, >50% 
decrease 
×109/L 
Platelet Count 
>75% 
increase, >50% 
decrease 
×103/μL 
>75% 
increase, >50% 
decrease 
×109/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 
Creatine 
phosphokinase 
(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% 
mEq/L 
>20% 
increase, >20% 
mmol/L 

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Parameter 
Conventional 
Alert Value 
Conventional 
Units 
SI Alert Value 
SI Units 
decrease, or any 
value >5.3 
decrease, or any 
value >5.3 
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. 
Thank You letter 
Plain language trial summary - after Clinical study report (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. 
 If a liver event is subsequently reported, any local liver chemistry tests previously conducted 
that are associated with this event should have results recorded on the appropriate eCRF. 
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
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. 
Imaging such as abdominal US, CT or Magnetic Resonance Imaging (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 
eCRF. 
10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-2 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
If ALT or AST normal at baseline: 
 
Liver laboratory triggers 
3 × ULN < ALT or AST ≤ 5 × ULN 
TBL > ULN* 

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Liver events 
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 (TBL > 2 × ULN OR 
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 elevated at baseline: 
 
Liver laboratory triggers 
ALT or AST > 2 × baseline or > 200 U/L 
(whichever occurs first) 
TBL > ULN* 
Liver events 
ALT or AST > 3 × baseline or > 300 U/L 
(whichever occurs first) 
(ALT or AST > 2 × baseline or > 200 U/L 
[whichever occurs first]) AND (TBL > 2 × ULN 
OR INR > 1.5) 
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) 
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 > 2 × baseline or > 200 U/L 
[whichever occurs first]) accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia 
Any adverse event potentially indicative of a liver 
toxicity 
* Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) or alternative causes of bilirubin 
elevation. Treat alternative causes according to local institutional guidelines 

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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 > 3 × ULN 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline 
TBL 
None 
• 
Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin, CK, and 
Glutamate 
dehydrogenase 
(GLDH) in 48-72 
hours. 
• 
Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
If normal at baseline: 
ALT > 5 × ULN for 
more than two weeks 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline 
TBL 
None 
• 
Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 
hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
If elevated at 
baseline: 
ALT > 3 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) for more than two 
weeks 
If normal at baseline: 
ALT > 8 × ULN 
Normal 
None 
ALT increase with bilirubin increase: 
If normal at baseline: 
ALT > 3 × ULN 
TBL > 2 × ULN (or 
INR > 1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
If normal at baseline: 
ALT > 3 × ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain 
If elevated at 
baseline: 
ALT > 2 × baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 

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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 
• 
Maintain treatment 
• 
Repeat Liver Function 
Tests (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) 
• 
Interrupt treatment 
• 
Repeat LFTs within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate eCRF 
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 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate eCRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
investigator discretion) 
Any AE potentially indicative of 
a liver toxicity 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate eCRF 
Investigator discretion 
Based on the Investigator’s clinical judgement, investigation(s) of the 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, and/or exclusion of underlying liver disease. 

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10.6 
Appendix 6: Renal safety monitoring 
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period: 
Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
Any one of the following: 
Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR 
New onset dipstick proteinuria ≥ 3+, OR 
New onset dipstick hematuria ≥ 3+ (after excluding menstruation, Urinary tract infection (UTI), 
extreme exercise, or trauma) 
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment. 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed-up by the Investigator or designated trial staff as summarized 
in Table 10-5. 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up 
Table 10-5 
Specific renal alert criteria and actions 
Renal event 
Actions 
Confirmed serum creatinine increase of 25-49% 
from baseline 
• 
Consider causes and possible interventions 
• 
Follow-up within 2-5 days 
Confirmed serum creatinine increase ≥ 50% 
from baseline (corresponds to KDIGO criterion 
for acute kidney injury) 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48h if possible 
• 
Consider patient hospitalization and 
specialized treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory) 
• 
Consider causes and possible interventions 
• 
Assess serum albumin and serum total 
protein 
• 
Repeat assessment to confirm 
New onset of hematuria ≥ 3+ on urine dipstick 
Assess and document 
• 
Repeat assessment to confirm 
• 
Exclude infection, trauma, bleeding from the 
distal urinary tract or bladder, menstruation 
• 
Distinguish hemoglobinuria from hematuria 
• 
Urine sediment microscopy 
• 
Assess serum creatinine 
• 
Consider bleeding disorder 
10.6.1.1 Follow-up of renal events 
Assess and document: 

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Urine dipstick and sediment microscopy evidence of drug-induced nephrotoxicity (DIN): 
crystals, red blood cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white 
blood cells, tubular epithelial cells. 
Blood pressure and body weight. 
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium) and uric acid. 
Urine output. 
Review and record possible contributing factors to the renal event (co-medications, other co-
morbid conditions) and any additional local diagnostic procedures performed in the CRF. 
Monitor patient regularly (frequency at investigator's discretion) until: 
Event resolution: serum creatinine within 10% of baseline or PCR < 1g/g creatinine, or albumin-
creatinine ratio < 300 mg/g creatinine 
Or 
Event stabilization: serum creatinine level with ±10% variability over last 6 months or protein-
creatinine ratio stabilization at a new level with ±50% variability over last 6 months. 
Analysis of urine markers in samples collected over the course of the DIN event. 

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11 
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