Clinical trial NCT05996835: Phase 2b Study to Investigate the Safety and Efficacy of TIN816 in Sepsis-associated Acute Kidney Injury (SA-AKI)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Kidney Injury Due to Sepsis
Keywords: Sepsis
acute kidney injury
anti-inflammatory
immunosuppression
intensive care unit
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-08-18
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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 with permanent incapacitation
17. Patients who are thrombocytopenic at screening (platelet count \<50,000 per microliter) who have active/uncontrolled bleeding or who present current or past conditions indicating high risk for bleeding in the opinion of the investigator (e.g. coagulopathies, previous history of major non-traumatic bleeding etc.)
18. 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)
19. Patients with known or presumed latent or active TB based on clinical history or imaging e.g. patients on TB preventive therapy or close/household contacts of pulmonary TB patients
20. 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)
21. Acute pancreatitis with no established source of infection
22. Active hematological malignancy (previous hematological malignancies that are not actively treated are allowable)
23. Burns requiring ICU treatment
24. Sepsis attributed to confirmed COVID-19
25. 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
26. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes
27. Any medical conditions that could significantly increase risk of participants' safety by participating in this study according to investigator's judgement
28. Women with a positive pregnancy test, pregnancy or breast feeding
29. Women of childbearing potential, unless they are using highly effective methods of contraception for the entire duration of the trial.

Primary outcomes:
measure: Average of area under the time-corrected creatinine clearance curve (AUC1-8)
timeFrame: Day 1 to Day 8
Secondary outcomes:
measure: Percentage of participants with major adverse kidney events (MAKE)
timeFrame: Day 1 to Day 90
measure: Area under the time-corrected endogenous serum creatinine curve for Day 1 to Day 14 and Day 1 to Day 30.
timeFrame: Day 1 to Day 14 and Day 1 to Day 30
measure: Area under the time-corrected endogenous serum cystatin C curve for Day 1 to Day 14 and Day 1 to Day 30
timeFrame: Day 1 to Day 14 and Day 1 to Day 30
measure: Area under the time-corrected creatinine clearance curve (AUC5-14)
timeFrame: Day 5 to Day 14
measure: Percentage of participants who had renal replacement therapy (RRT) from Day 1 to Day 90
timeFrame: Day 1 to Day 90
measure: Percentage of participants with RRT dependency at Day 90
timeFrame: Day 90
measure: Number of days participants alive and free of RRT from Day 1 to Day 90
timeFrame: Day 1 to Day 90
measure: Change in Kidney disease improving global outcomes (KDIGO) score from Baseline to Day 14
timeFrame: 14 Days
measure: Percentage of participants with ≥25% reduction in eGFR at Day 90
timeFrame: 90 Days
measure: Mean change of sequential organ failure score (SOFA) from baseline to Day 30
timeFrame: 30 Days
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UC San Francisco Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Healthcare
state: California
city: Johns Creek
country: United States
facility: Emory Johns Creek Hospital
state: Georgia
city: Evanston
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Iowa City
country: United States
facility: Univ Of Iowa Hospitals And Clinics
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital and Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Univ School of Medicine
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Corvallis
country: United States
facility: Good Samaritan Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Uni Of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor Scott and White
state: Texas
city: Murray
country: United States
facility: Utah Intermountain Medical Center
state: Utah
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Spokane
country: United States
facility: Providence Med Resch Center and Chindren Hosp
state: Washington
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Pilar
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
state: Tyrol
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Genk
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Ottignies
country: Belgium
facility: Novartis Investigative Site
city: Brasilia
country: Brazil
facility: Novartis Investigative Site
state: DF
city: Curitiba
country: Brazil
facility: Novartis Investigative Site
state: Parana
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Salvador
country: Brazil
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Kingston
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sainte Foy
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Shijiazhuang
country: China
facility: Novartis Investigative Site
state: Hebei
city: Zhengzhou
country: China
facility: Novartis Investigative Site
state: Henan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guang Zhou
country: China
facility: Novartis Investigative Site
city: Wuhan
country: China
facility: Novartis Investigative Site
city: Limoges
country: France
facility: Novartis Investigative Site
state: Haute Vienne
city: Argenteuil
country: France
facility: Novartis Investigative Site
city: Garches
country: France
facility: Novartis Investigative Site
city: Le Kremlin Bicetre
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Paris cedex 10
country: France
facility: Novartis Investigative Site
city: Pessac
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse 4
country: France
facility: Novartis Investigative Site
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Gyor
country: Hungary
facility: Novartis Investigative Site
city: Szekesfehervar
country: Hungary
facility: Novartis Investigative Site
city: Ahmedabad
country: India
facility: Novartis Investigative Site
state: Gujarat
city: Pune
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Belgavi
country: India
facility: Novartis Investigative Site
city: Delhi
country: India
facility: Novartis Investigative Site
city: Hyderabad
country: India
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Kamogawa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Asahikawa
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Yokohama
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Izumisano-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Ureshino
country: Japan
facility: Novartis Investigative Site
state: Saga
city: Izumo
country: Japan
facility: Novartis Investigative Site
state: Shimane
city: Hachioji-city
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Itabashi-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Kumamoto
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Sabadell
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Jerez
country: Spain
facility: Novartis Investigative Site
state: Cadiz
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Terrassa
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Guildford
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Bristol
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: