Phase 2b Study to Investigate the Safety and Efficacy of TIN816 in Sepsis-associated Acute Kidney Injury (SA-AKI)

A Multicenter, Randomized, Double-blind, Placebo-controlled, Four-arm, Parallel-group, Dose-finding Phase 2b Study to Investigate the Safety and Efficacy of TIN816 Via a Single Intravenous Infusion in the Treatment of Participants With Sepsis-associated Acute Kidney Injury (SA-AKI)

The purpose of this Ph2b study is to characterize the dose-response relationship and to evaluate the safety and efficacy of three different single doses of TIN816 in hospitalized adult participants in an intensive care setting with a diagnosis of sepsis-associated acute kidney injury (SA-AKI).

Study Overview

• Status: Recruiting
• Conditions: Acute Kidney Injury Due to Sepsis
• Intervention / Treatment: Biological: TIN816 70 mg lyophilisate powder; Other: Placebo

Detailed Description

This is a multicenter, randomized, double-blind, placebo-controlled, four-arm, parallel-group, dose-finding phase 2b study. The study will enroll hospitalized adult participants with a diagnosis of sepsis and acute kidney injury (AKI). The study consists of a screening period (24-48 hours), a treatment period (Day 1), and post-treatment period (Day 2 to 90). Screening will take place during hospitalization in ICU (or intermediate care unit/HDU) where potential participants will undergo screening to assess the presence of sepsis and AKI. At Treatment Day 1, participants who meet eligibility criteria at screening and baseline will be randomized in a 3:1:1:3 ratio to receive a one-time treatment of 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 safety and efficacy assessments. An interim analysis (IA) is planned when approximately 120 participants complete Day 30 visit. A final analysis will be performed after all participants have completed Day 90.

• Study Type: Interventional
• Enrollment (Estimated): 320
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Recruiting
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Recruiting
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H4J 1C5
      • Recruiting
      • Novartis Investigative Site
    • Sainte Foy, Quebec, Canada, G1V 4G5
      • Recruiting
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Recruiting
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Recruiting
    • Novartis Investigative Site
• Turkey
  • Istanbul, Turkey, 34093
    • Recruiting
    • Novartis Investigative Site
• United Kingdom
  • Bristol, United Kingdom, BS2 8HW
    • Recruiting
    • Novartis Investigative Site
  • London, United Kingdom, SE1 7EH
    • Recruiting
    • Novartis Investigative Site
• United States
  • Michigan
    • Detroit, Michigan, United States, 48202 2689
      • Recruiting
      • Henry Ford Hospital
      • Contact: Karen Campana; Phone Number: 313-876-1850; Email: Kcampan1@hfhs.org
      • Principal Investigator: Ryann Sohaney
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1071
      • Recruiting
      • Wake Forest Univ School of Medicine U Health Sciences
      • Contact: Lynnette Harris; Phone Number: 513-658-5866; Email: lcharris@wakehealth.edu
      • Principal Investigator: Ashish Khanna
  • Oregon
    • Corvallis, Oregon, United States, 97330
      • Recruiting
      • Good Samaritan Hospital
      • Contact: Anthony Franklin; Phone Number: 541-768-5202; Email: anfranklin@samhealth.org
      • Principal Investigator: Brian Delmonaco
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Recruiting
      • Temple University
      • Contact: Phone Number: 215-707-2230
      • Principal Investigator: Avrum Gillespie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. ≥ 18 to ≤ 85 years of age
3. Admitted to ICU or intermediate care unit/ high dependency care unit (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 AND
   • Acute increase of SOFA score of 2 or more (excluding renal component). The baseline SOFA score should be assumed to be zero unless the participant is known to have pre-existing (acute or chronic) organ dysfunction before the onset of infection
5. Diagnosis of AKI Stage 1 or greater per the following criterion at randomization:

An absolute increase in serum or plasma creatinine 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 serum creatinine.

• For participants with hospital-acquired AKI, a stable serum creatinine obtained in the hospital prior to AKI diagnosis should be used as the reference serum creatinine.

• For participants presenting from community, the reference serum creatinine should be estimated using the following order of preference:

  1. The most recent value within 3 months of the hospital admission. If not available:
  2. The most recent value between 3 and 12 months prior to hospital admission. If not available:
  3. 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 admission to hospital
4. eGFR <45mL/min at admission without any other reference serum eGFR within last 12-months
5. Receiving RRT or a decision has been made to initiate RRT within 24 hours after randomization
6. Weight is less than 40 kg or more than 125 kg.
7. Limitations to the use of mechanical ventilation, RRT or vasopressors/inotropes (N.B. limitations on Cardiopulmonary resuscitation (CPR)e.g., do-not-resuscitate orders are not an exclusion criterion unless associated with likely poor outcome in next 24 hours)
8. Sepsis diagnosis according to sepsis inclusion criteria for a period longer than 72 hours prior to ICU admission
9. AKI diagnosis according to AKI inclusion criteria over 48 hours after admission to ICU
10. Inability to administer study drug within 24 hours of diagnosis of AKI according to AKI inclusion criteria
11. Presence of AKI, in the Investigator's opinion, as suggested by clinical manifestation, e.g., prolonged oliguria or severe renal dysfunction on admission without a history of CKD, for a period longer than 24 hours prior to study drug administration
12. Evidence of recovery from AKI based on the investigator's clinical judgement prior to randomization
13. AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs (Non-steroidal anti-inflammatory drugs (NSAIDs), contrast, aminoglycosides, etc.) or renal perfusion-related (acute abdominal aortic aneurysm, dissection, renal artery stenosis), urinary obstruction
14. 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)
15. Patients who are post-nephrectomy
16. Patients who are thrombocytopenic at screening (platelet count <50,000 per microliter) or other high risk for bleeding in the opinion of the investigator

17. Immunosuppressed patients

    • History of immunodeficiency diseases
    • Receiving immunosuppressant treatment or 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 corticosteroids (as per the Surviving Sepsis Guidelines) can be included. See Appendix Section 10.6 Immunosuppresant drugs, (Table 10 5 Immunosuppressant drug exclusions)
18. Known active hepatitis B or C infection, or 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)
19. Acute pancreatitis with no established source of infection
20. Active hematological malignancy (previous hematological malignancies that are not actively treated are allowable)
21. Burns requiring ICU treatment
22. Sepsis attributed to confirmed COVID-19
23. 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
24. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes
25. Any medical conditions that could significantly increase risk of participants' safety by participating in this study according to investigator's judgement
26. Women with a positive pregnancy test, pregnancy or breast feeding
27. Women of childbearing potential, unless they are using highly effective methods of contraception for the entire duration of the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TIN816 Dose A; Administered as a one time intravenous dose	Biological: TIN816 70 mg lyophilisate powder; Immunotherapy Recombinant human CD39 enzyme
Experimental: TIN816 Dose B; Administered as a one time intravenous dose	Biological: TIN816 70 mg lyophilisate powder; Immunotherapy Recombinant human CD39 enzyme
Experimental: TIN816 Dose C; Administered as a one time intravenous dose	Biological: TIN816 70 mg lyophilisate powder; Immunotherapy Recombinant human CD39 enzyme
Placebo Comparator: Placebo; 0.9% sterile saline administered as a one time intravenous dose	Other: Placebo; 0.9% sterile saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average of area under the time-corrected creatinine clearance curve (AUC1-8)	The weighted average of area under the time-corrected endogenous creatinine clearance curve. Urine volume, urinary creatinine, and the serum creatinine measurements will be used for calculation. Day 1-8 measurements will be included.	Day 1 to Day 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants with major adverse kidney events (MAKE)	A binary composite endpoint of major adverse kidney events (MAKE) including death, use of Renal Replacement Therapy (RRT) and ≥25% reduction in estimated Glomular Filtration Rate (eGFR) at Day 90.	Day 1 to Day 90
Area under the time-corrected endogenous serum creatinine curve for Day 1 to Day 14 and Day 1 to Day 30.	The weighted average of area under the time-corrected endogenous serum creatinine curve from Day 1 to Day 14 and Day 1 to Day 30.	Day 1 to Day 14 and Day 1 to Day 30
Area under the time-corrected endogenous serum cystatin C curve for Day 1 to Day 14 and Day 1 to Day 30	The weighted average of area under the time-corrected endogenous serum cystatin-C curve from Day 1 to Day 14 and Day 1 to Day 30.	Day 1 to Day 14 and Day 1 to Day 30
Area under the time-corrected creatinine clearance curve (AUC5-14)	The weighted average of area under the time-corrected endogenous creatinine clearance curve. Urine volume, urinary creatinine, and the serum creatinine measurements will be used for calculation. Day 5-14 measurements will be included.	Day 5 to Day 14
Percentage of participants who had renal replacement therapy (RRT) from Day 1 to Day 90	Use of RRT at any time during the treatment period will be reported.	Day 1 to Day 90
Percentage of participants with RRT dependency at Day 90	Use of RRT dependency at Day 90 will be reported	Day 90
Number of days participants alive and free of RRT from Day 1 to Day 90	Participants who are alive and free of RRT, defined as any participant receiving any form of RRT, will be reported.	Day 1 to Day 90
Change in Kidney disease improving global outcomes (KDIGO) score from Baseline to Day 14	The KDIGO classification system stages AKI into three levels based on serum creatinine elevation in parallel with degree and duration of oliguria. Participants are classified based on the worst finding (either serum creatinine or oliguria). The stages range from 1-3, with higher scores indicating the most severe stage of AKI.	14 Days
Percentage of participants with ≥25% reduction in eGFR at Day 90	Percentage of participants with ≥ 25% reduction from baseline to Day 90.	90 Days
Mean change of sequential organ failure score (SOFA) from baseline to Day 30	The SOFA score was developed to assess the acute morbidity of critical illness at a population level. The score is routinely calculated on admission to ICU and at each 24-hour period that follows. It is composed of six criteria which reflect the function of a specific organ system (respiratory, cardiovascular, renal, neurological, hepatic and hematological) and allocates a score of 0-4. Scores ranges from 0-24, with higher scores indicating greater dysfunction.	30 Days

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2024
• Primary Completion (Estimated): January 9, 2026
• Study Completion (Estimated): March 30, 2026

Study Registration Dates

• First Submitted: August 10, 2023
• First Submitted That Met QC Criteria: August 10, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: intensive care unit; immunosuppression; acute kidney injury; anti-inflammatory; Sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Sepsis; Toxemia; Wounds and Injuries; Acute Kidney Injury
• Other Study ID Numbers: CTIN816B12202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No