NOVARTIS (CTIN816B12202)

2.     Intubated patients, not on ECLS, with high normalized respiratory system elastance (≥2.5 cm H2O/(ml/kg predicted body weight)) at the time of eligibility assessment

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 admission to hospital

4.     eGFR <45mL/min at admission without any other reference serum eGFR within last 12-months

5.     Receiving RRT or a decision has been made to initiate RRT within 24 hours after randomization

6.     Weight is less than 40 kg or more than 125 kg.

7.     Limitations to the use of mechanical ventilation, RRT or vasopressors/inotropes (N.B. limitations on Cardiopulmonary resuscitation (CPR)e.g., do-not-resuscitate orders are not an exclusion criterion unless associated with likely poor outcome in next 24 hours)

8.     Sepsis diagnosis according to sepsis inclusion criteria for a period longer than 72 hours prior to ICU admission

9.     AKI diagnosis according to AKI inclusion criteria over 48 hours after admission to ICU

10.  Inability to administer study drug within 24 hours of diagnosis of AKI according to AKI inclusion criteria

11.  Presence of AKI, in the Investigator's opinion, as suggested by clinical manifestation, e.g., prolonged oliguria or severe renal dysfunction on admission without a history of CKD, for a period longer than 24 hours prior to study drug administration

12.  Evidence of recovery from AKI based on the investigator’s clinical judgement prior to randomization

13.  AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs (Non-steroidal anti-inflammatory drugs (NSAIDs), contrast, aminoglycosides, etc.) or renal perfusion-related (acute abdominal aortic aneurysm, dissection, renal artery stenosis), urinary obstruction

14.  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)

15.  Patients who are post-nephrectomy

16.  Patients who are thrombocytopenic at screening (platelet count <50,000 per microliter) or other high risk for bleeding in the opinion of the investigator

17.  Immunosuppressed patients

·      History of immunodeficiency diseases

·      Receiving immunosuppressant treatment or 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 corticosteroids (as per the Surviving Sepsis Guidelines) can be included. See Appendix Section 10.6 Immunosuppresant drugs, (Table 10‑5 Immunosuppressant drug exclusions)

18.  Known active hepatitis B or C infection, or 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)

19.  Acute pancreatitis with no established source of infection

20.  Active hematological malignancy (previous hematological malignancies that are not actively treated are allowable)

21.  Burns requiring ICU treatment

22.  Sepsis attributed to confirmed COVID-19

23.  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

24.  History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes

25.  Any medical conditions that could significantly increase risk of participants’ safety by participating in this study according to investigator’s judgement

26.  Women with a positive pregnancy test, pregnancy or breast feeding

27.  Women of childbearing potential, defined as all women physiologically capable of becoming. pregnant, unless they are using highly effective methods of contraception for the entire duration of the trial. 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

·      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.