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

Primary Purpose

Acute Kidney Injury Due to Sepsis

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
TIN816 70 mg lyophilisate powder
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Kidney Injury Due to Sepsis focused on measuring Sepsis, acute kidney injury, intensive care, therapy

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

TIN816

Placebo

Arm Description

Administered as an intravenous dose

0.9% sterile sodium chloride solution administered as an intravenous dose

Outcomes

Primary Outcome Measures

CMax:The maximum (peak) observed serum drug concentration
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
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
AUCinf: The AUC from time zero to infinity
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Tmax: - Time to reach observed maximum drug concentration following TIN816 administration
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
T1/2: Terminal half-life
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
CL: - Total clearance of drug from serum after intravascular administration
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Vz: Volume of distribution from a systemic dose
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion

Secondary Outcome Measures

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.

Full Information

First Posted
August 17, 2022
Last Updated
May 19, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT05507437
Brief Title
Pharmacokinetics and Safety of TIN816 in Patients With Sepsis-associated Acute Kidney Injury
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 22, 2022 (Actual)
Primary Completion Date
December 4, 2023 (Anticipated)
Study Completion Date
December 4, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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).
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Kidney Injury Due to Sepsis
Keywords
Sepsis, acute kidney injury, intensive care, therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TIN816
Arm Type
Experimental
Arm Description
Administered as an intravenous dose
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
0.9% sterile sodium chloride solution administered as an intravenous dose
Intervention Type
Biological
Intervention Name(s)
TIN816 70 mg lyophilisate powder
Intervention Description
Recombinant human CD39 enzyme
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
0.9% sterile sodium chloride solution
Primary Outcome Measure Information:
Title
CMax:The maximum (peak) observed serum drug concentration
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Title
AUClast:The AUC from time zero to the last measurable concentration sampling time (tlast) (mass × time × volume-1)
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Title
AUCinf: The AUC from time zero to infinity
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Title
Tmax: - Time to reach observed maximum drug concentration following TIN816 administration
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Title
T1/2: Terminal half-life
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Title
CL: - Total clearance of drug from serum after intravascular administration
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Title
Vz: Volume of distribution from a systemic dose
Description
To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
Time Frame
Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90
Secondary Outcome Measure Information:
Title
Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs)
Description
Number of participants with AEs/SAEs as measures of safety and tolerability.
Time Frame
Baseline up to 90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Facility Information:
Facility Name
Novartis Investigative Site
City
Genk
ZIP/Postal Code
3600
Country
Belgium
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Ottignies
ZIP/Postal Code
1340
Country
Belgium
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Paris
ZIP/Postal Code
75010
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Strasbourg Cedex
ZIP/Postal Code
67091
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Toulouse Cedex 4
ZIP/Postal Code
31054
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Kiel
ZIP/Postal Code
24105
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Budapest
State/Province
Pest Megye
ZIP/Postal Code
1134
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Debrecen
ZIP/Postal Code
4032
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08907
Country
Spain
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

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

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