LSALT Peptide for Prevention or Attenuation of Acute Kidney Injury (AKI) in Patients Undergoing On-Pump Cardiac Surgery

Phase 2 Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of LSALT Peptide for the Prevention or Attenuation of Acute Kidney Injury (AKI) in Patients Undergoing On-Pump Cardiac Surgery

To evaluate the percentage of subjects with AKI within 7 days following on-pump cardiac surgery defined by the KDIGO (Kidney Disease: Improving Global Outcomes) criteria:

1. Increase in baseline (pre-surgery) serum creatinine (SCr) by ≥26.5 μmol/L (≥0.3 mg/dL) within 7 days; OR
2. Increase in baseline SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the first 7 days following surgery; OR
3. Urine output < 0.5 mL/kg/h for >6 hours.

This study is a randomized, double-blind, multicenter interventional study to assess safety and efficacy of LSALT peptide versus placebo (matching drug-free saline) in patients undergoing on-pump cardiac surgery. Patients will be followed for safety and efficacy up to Day 28 (EOS), with Day 1 being the day of randomization of study drug administered at least 1 hour prior to induction of anesthesia.

A total of 240 patients will be included in the study, 120 patients each will be randomized to LSALT peptide or placebo. This study will be double-blinded with only the pharmacist at the site unblinded for the purpose of preparing drug/placebo for injection.

All subjects will undergo tests during the Screening period (window days -14 to Day 1). After satisfying all inclusion and exclusion criteria, the patient will be randomized equally to the following study arms:

• LSALT peptide 10 mg IV administered over 1 hour twice daily, every 12 ± 1hour, for 5 days
• Placebo IV administered over 1 hour twice daily, every 12 ± 1 hour, for 5 days

Study treatment will be initiated pre-operatively on Day 1 and continued for 5 days. Physical examinations, vital signs and urine output will be recorded daily throughout the treatment period and on days 6 and 7. Adverse events will be recorded daily throughout the treatment period, on Days 6, 7, and 28 EOS (Day 28). Kidney function (serum creatinine, serum cystatin C, and BUN), clinical laboratory tests, and other biomarkers will be assessed at baseline (prior to initiation of study drug) and monitored daily throughout the treatment period, on Days 6, 7, and EOS (Day 28). All patients will be maintained on the standard of care (SOC) as per institutional guidelines. Thus, SOC will be followed in each patient with the addition of LSALT peptide or placebo.

Subjects will be followed until EOS (Day 28 ± 3 days) to assess renal function as discussed above.

An independent Data and Safety Monitoring Board (DSMB) will evaluate patients on a continuing basis for primarily safety assessments. Per the DSMB Charter, the DSMB will meet at least monthly if not more frequently based upon enrollment throughout the study period.

Inclusion Criteria:

1. Male and female ≥ 18 years of age.

2. Scheduled for a non-emergent coronary and/or valve surgery procedure requiring on-pump cardiopulmonary bypass including but not limited to:

   • Coronary artery bypass graft (CABG) alone
   • CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair
   • Aortic valve replacement or repair alone, with or without aortic root repair
   • Mitral, tricuspid, or pulmonic valve replacement or repair alone
   • Simultaneous replacement of several cardiac valves.

3. Have the following AKI risk factors:

   • CKD Stage 3 (CKD-EPI eGFR ≥ 30 and < 60 mL/min/1.73 m2) and ONE or more of the following additional risk factors OR

   • CKD Stage 2 (CKD-EPI eGFR ≥ 60 and < 90 mL/min/1.73 m2) and ONE or more of the following additional risk factors:

     • Age ≥ 75 years;
     • Combined valve & coronary artery surgery;
     • Left ventricular ejection fraction (LVEF) ≤ 35% by invasive or noninvasive techniques;
     • Urinary (TIMP-2 x IGFBP7) > 0.3
     • Diabetes mellitus
     • Hypertension
     • Hyperlipidemia

4. Sexually active women of child-bearing potential (WCBP) must be using a medically acceptable method of birth control throughout the study and for at least 1 day following the end of study and have a negative urine pregnancy test at the Screening visit. A WCBP is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months, surgical sterilization, or the implant. In patients who are not sexually active, abstinence is an acceptable form of birth control and urine will be tested per protocol. Women who are of nonchild-bearing potential, i.e., post-menopause, must have this condition captured in their medical history. Pregnant women and nursing mothers are excluded from this study.

5. Patient or Legally Authorized Representative (LAR) is available and willing to give written informed consent, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures.

Exclusion Criteria:

1. The presence of AKI (KDIGO criteria) at the time of randomization
2. Off-pump cardiac surgery
3. Surgery to be performed under conditions of circulatory arrest or hypothermia with rectal temperature < 28°C (82.4° F)
4. Severe chronic kidney disease: CKD-eGFR < 30 mL/min/1.73 m2) OR requiring dialysis
5. Imminent or recent surgery for aortic dissection
6. Surgery to correct a major congenital heart defect (e.g., Tetralogy of Fallot, transposition of the great vessels, single ventricle, or Ebstein's anomaly. Bicuspid aortic valve is not considered a congenital heart defect)
7. Known history of active cancer which may interfere with interpretation of the results of this study
8. Known or suspected sepsis at time of screening
9. Pregnancy or lactation
10. Known hypersensitivity to the study drug or any of its excipients
11. Treatment with an investigational drug or participation in an interventional trial within 30 days prior to the first dose of study drug and throughout the study
12. Any disease processes or confounding variables that would inappropriately alter the outcome of the study in the opinion of the investigator
13. Inability to comply with the requirements of the study protocol.