The purpose of this study was to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile and to evaluate the safety and tolerability of TIN816 in hospitalized adult participants in an intensive care setting with a diagnosis of sepsis-associated acute kidney injury (SA-AKI).

This was a multicenter, participant and investigator-blinded, randomized, placebo-controlled study to characterize PK/PD profile and to evaluate the safety and the tolerability of TIN816. The study enrolled hospitalized adult participants with a diagnosis of sepsis and acute kidney injury (AKI). 20 participants were randomized in the study. The study consisted of a screening period (24-48 hours), a treatment period (day 1), and post-treatment period (days 2 to 90).

Screening took place during hospitalization in a intensive care unit (ICU) (or intermediate/high dependency unit (HDU care) where potential participants were undergo screening to assess the presence of sepsis and AKI. Pre-identified participants provided informed consent and went to screening assessments to determine eligibility. Potential study candidates were hospitalized patients with a diagnosis of sepsis based on Sepsis 3 criteria with suspected or confirmed infection and SOFA score ≥ 2 after excluding the renal component, and a diagnosis of AKI stage 1 or greater. At Treatment Day 1, participants who meet eligibility criteria at screening and baseline were randomized in a 3:1 ratio to treatment with TIN816 or placebo by intravenous infusion in a participant and investigator-blinded fashion.

Treatment day 1 was followed by a 90 day post-treatment period for pharmocokinetic, pharmacodynamic, safety and tolerability assessments.

Inclusion Criteria:

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:

   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:

Median value within 3 months of the hospital admission. If not available:

Median value between 3 and 6 months prior to hospital admission. If not available:

At hospital admission.

Exclusion criteria

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.

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 90 days.