A Multi-center Study to Evaluate the Safety, Tolerability and Efficacy of TIN816 in Patients at Risk for Acute Kidney Injury Following Cardiac Surgery.

Study Overview
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Brief Summary
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This is a randomized, multi-centric, placebo-controlled, participant and investigator-blinded study to evaluate the safety, tolerability and efficacy of TIN816 in adult patients at risk for acute kidney injury following cardiac surgery.

Detailed Description
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This is a randomized, multi-centric, placebo-controlled, participant and investigator-blinded study to evaluate the safety, tolerability and efficacy of TIN816 in adult patients at risk for acute kidney injury following cardiac surgery. The screening period will last up to 30 days and the whole study will last up to 120 days. Approximately 120 subjects will be randomized to one of the two arms: TIN816 or placebo. Efficacy will be evaluated 5 days after treatment. The randomization ratio is 1:1; TIN816 : placebo.

Official Title
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A Randomized, Multi-centric, Placebo-controlled, Participant and Investigator-blinded Study to Evaluate the Safety, Tolerability and Efficacy of TIN816 in Adult Patients at Risk for Acute Kidney Injury Following Cardiac Surgery.

Conditions
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Acute Kidney Injury Following Cardiac Surgery

Intervention / Treatment
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* Drug: TIN816
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Participants must be able to communicate well with the investigator and to understand and comply with the requirements of the study. Male and female patients ≥45 years at screening. Participants must weigh at least 50 kg and maximum 150 kg to participate in the study and must have a body mass index (BMI) below 40. BMI = Body weight (kg) / [Height (m)]2. At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting or supine position. Vital signs should be within the following ranges: body temperature between 35.0-37.5 °C blood pressure (systolic 100-160 mmHg, diastolic < 100 mmHg) pulse rate (50-100/min) stable with or without medication(s) as per Investigator assessment. No known increase in SCr of ≥25% at screening visit compared to a previous value obtained within the last 3 months (ideally obtained at least 3 weeks before the screening visit) as documented by a local laboratory using standard assay methodology. Non-emergent open chest cavity major cardiopulmonary bypass (CPB) surgery with expected CPB time ≥1 hour Exclusion Criteria: eGFR at screening <15 mL/min/1.73 m2 (calculated using CKD-EPI 2021 equation). Receiving renal replacement therapy currently or at any time within 6 months prior to screening. Patients with bleeding risk at screening. The Investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence of any of the following: History of bleeding with suspected or confirmed bleeding disorder or any other high risk for bleeding in the opinion of the investigator Thrombocytopenia: platelet count< 100x109/L Platelet dysfunction: e.g., ADP induced platelet aggregation lower than 60 % Pre-existing coagulation factor deficiency: including, but not limited to fibrinogen ≤ 2.5 g/L Any emergency surgeries performed less than 30 days before screening, including aortic dissection, and/or major congenital heart defects. Scheduled to undergo cardiac surgery off CPB or with hypothermic circulatory arrest. Cardiogenic shock or hemodynamic instability within four weeks prior to surgery, requiring inotropes or vasopressors or mechanical devices such as intra-aortic balloon counter-pulsation (IABP). Have received cardiopulmonary resuscitation (CPR) within 30 days prior to cardiac surgery. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or longer if required by local regulations. Patients who are post-nephrectomy Have ongoing sepsis or history of sepsis within the past 8 weeks or untreated diagnosed infection prior to screening visit. Sepsis is defined as presence of a confirmed pathogen, along with fever or hypothermia, and hypoperfusion or hypotension. Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.). Pregnant or nursing (lactating) women 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 until the end of study. 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, symptothermal and post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking study treatment. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, multi-centric, placebo-controlled, participant and investigator-blinded study to evaluate the safety, tolerability and efficacy of TIN816 in adult patients at risk for acute kidney injury following cardiac surgery. The screening period will last up to 30 days and the whole study will last up to 120 days. Approximately 120 subjects will be randomized to one of the two arms: TIN816 or placebo. Efficacy will be evaluated 5 days after treatment. The randomization ratio is 1:1; TIN816 : placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIN816<br>TIN816 | Drug: TIN816<br>* TIN816<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of the highest serum creatinine value within 5 days post-dose versus baseline | To assess the effect of TIN816 on serum creatinine level in high-risk patients undergoing major cardio-vascular surgery, versus placebo | from baseline to Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AKI stages 1, 2 and 3 as defined by modified AKI Network criteria | To assess the effect of TIN816 on the incidence and severity of AKI in patients at high risk for AKI and undergoing major cardio-vascular surgery, versus placebo | from baseline to Day 6 | 
| Anti-drug antibodies against TIN816 | To assess immunogenicity (IG) of TIN816 | from baseline to 90 Days | 
| Occurrence of major adverse kidney event at Day 90 (MAKE90) | To assess the effect of TIN816 on the incidence of AKD in high-risk patients undergoing major cardio-vascular surgery, versus placebo | 90 Days | 
| Occurrence of MAKE30 | To assess the effect of TIN816 on the incidence of AKD in high-risk patients undergoing major cardio-vascular surgery, versus placebo | 30 Days | 
| Occurrence of individual components of the MAKE criteria at Days 30 or 90. | To assess the effect of TIN816 on the incidence of AKD in high-risk patients undergoing major cardio-vascular surgery, versus placebo | 30 or 90 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute kidney injury, cardiac surgery