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

Acute Kidney Injury Due to Sepsis Clinical Trial

Official title:

A Participant and Investigator-blinded, Randomized, Placebo-controlled Phase 2a Study to Investigate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of TIN816 in Patients With Sepsis-associated Acute Kidney Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05507437
• Other study ID #: CTIN816B12201
• Secondary ID: 2022-000887-23
• Status: Completed
• Phase: Phase 2
• Start date: November 22, 2022
• Est. completion date: April 25, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile and to evaluate the safety and tolerability of TIN816 in hospitalized adult participants in an intensive care setting with a diagnosis of sepsis-associated acute kidney injury (SA-AKI).

Description:

This is 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 will enroll hospitalized adult participants with a diagnosis of sepsis and acute kidney injury (AKI). Approximately 20 participants will be randomized in the study. The study consists of a screening period (24-48 hours), a treatment period (day 1), and post-treatment period (days 2 to 90).

Screening will take place during hospitalization in a intensive care unit (ICU) (or intermediate/high dependency unit (HDU care) where potential participants will undergo screening to assess the presence of sepsis and AKI. Pre-identified participants will provide informed consent and undergo screening assessments to determine eligibility. Potential study candidates will be 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 will be 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 is followed by a 90 day post-treatment period for pharmocokinetic, pharmacodynamic, safety and tolerability assessments.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: April 25, 2024
• Est. primary completion date: April 25, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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/HDU.

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 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

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.

25. Women of child-bearing potential

Related Conditions & MeSH terms

• Acute Kidney Injury
• Acute Kidney Injury Due to Sepsis
• Sepsis
• Toxemia
• Wounds and Injuries

Intervention

Biological:
• TIN816 70 mg lyophilisate powder
Recombinant human CD39 enzyme

Other:
• Placebo
0.9% sterile sodium chloride solution

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Genk
Belgium	Novartis Investigative Site	Ottignies
France	Novartis Investigative Site	Strasbourg Cedex
France	Novartis Investigative Site	Toulouse 4
Germany	Novartis Investigative Site	Kiel
Hungary	Novartis Investigative Site	Debrecen
Spain	Novartis Investigative Site	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Hungary,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CMax:The maximum (peak) observed serum drug concentration	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Primary	AUClast:The AUC from time zero to the last measurable concentration sampling time (tlast) (mass × time × volume-1)	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Primary	AUCinf: The AUC from time zero to infinity	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Primary	Tmax: - Time to reach observed maximum drug concentration following TIN816 administration	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Primary	T1/2: Terminal half-life	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Primary	CL: - Total clearance of drug from serum after intravascular administration	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Primary	Vz: Volume of distribution from a systemic dose	To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion	Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Secondary	Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs)	Number of participants with AEs/SAEs as measures of safety and tolerability.	Baseline up to 90 days