E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute kidney injury Due to sepsis |
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E.1.1.1 | Medical condition in easily understood language |
Acute kidney injury Due to sepsis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 26.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10069339 |
E.1.2 | Term | Acute kidney injury |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To characterize the pharmacokinetic profile of TIN816 |
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E.2.2 | Secondary objectives of the trial |
To assess safety and tolerability of TIN816 vs placebo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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/high dependency care unit. 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: - 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: 1. Median value within 3 months of the hospital admission. If not available: 2. Median value between 3 and 6 months prior to hospital admission. If not available: 3. At hospital admission.
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E.4 | Principal 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 at Screening. 25. Women of child-bearing potential |
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E.5 End points |
E.5.1 | Primary end point(s) |
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Cmax : The maximum (peak) observed serum drug concentration
AUClast : The AUC from time zero to the last measurable concentration sampling time (tlast) (mass × time × volume-1)
AUCinf : The AUC from time zero to infinity
Tmax : The time to reach observed maximum drug concentration following TIN816 administration
T1/2 : Terminal half life
Cl : Total clearance of drug from serum after intravascular administration
Vz : Volume of distribution from a systemic dose |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cmax : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
AUClast : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
AUCinf : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Tmax : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
T1/2 : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Cl : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Vz : Baseline day 1, Day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 |
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E.5.2 | Secondary end point(s) |
Number of participants with treatment emergent adverse events (AEs) and Serious Adverse Events (SAEs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 15 |