Pharmacokinetics and Safety of TIN816 in Patients With Sepsis-associated Acute Kidney Injury

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

• Signed informed consent must be obtained prior to participation in the study.
• ≥ 18 and ≤ 85 years of age.
• Admitted to ICU or intermediate/HDU.
• 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)

• 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

• Not expected to survive for 24 hours.
• Not expected to survive for 30 days due to medical conditions other than SA-AKI.
• History of CKD with a documented estimated GFR <45 ml/min prior to development of AKI.
• Receiving RRT or a decision has been made to initiate RRT within 24 hours of admission.
• Weight is less than 40 kg or more than 125 kg .
• Has life support limitations (eg, do not resuscitate, do not dialyze, do not intubate).
• AKI diagnosis according to the AKI inclusion criteria for a period longer than 48 hours prior to study drug administration.
• 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.
• 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.
• 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 post-nephrectomy.
• 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.
• 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.

• 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).
• Acute pancreatitis with no established source of infection.
• Active hematological malignancy (previous hematological malignancies that are not actively treated are allowable).
• Burns requiring ICU treatment.
• Sepsis attributed to confirmed COVID-19.
• 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.
• History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
• Any medical conditions that could significantly increase risk of participants' safety by participating in this study according to investigator's judgement.
• Women with a positive pregnancy test, pregnancy or breast feeding.
• Women of child-bearing potential