Study Description
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). 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.
Interventions
Placebo
TIN816 70 mg lyophilisate powder
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.
Study Location
Novartis Investigative Site
Recruiting
Heidelberg,Victoria,3084,Australia
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Herston,Queensland,4029,Australia
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Innsbruck,Tyrol,6020,Austria
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Ottignies,1340,Belgium
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Gent,9000,Belgium
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Salvador,40301-155,Brazil
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Sao Paulo,SP,01327 001,Brazil
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Curitiba,Parana,80010 030,Brazil
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Brasilia,DF,70390-140,Brazil
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Vancouver,British Columbia,V6z 1y6,Canada
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Kingston,Ontario,K7l 2v7,Canada
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Montreal,Quebec,H2w 1t8,Canada
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Montreal,Quebec,H4j 1c5,Canada
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Sainte Foy,Quebec,G1v 4g5,Canada
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Hangzhou,Zhejiang,310014,China
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Wuhan,430022,China
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Beijing,100730,China
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Zhengzhou,Henan,450003,China
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Guang Zhou,510260,China
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Limoges,Haute Vienne,87000,France
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Paris cedex 10,75010,France
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Nantes Cedex 1,44093,France
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Pessac Cedex,33604,France
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Argenteuil,95107,France
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Strasbourg Cedex,67091,France
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Garches,92380,France
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Le Kremlin Bicetre,94275,France
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Toulouse 4,31054,France
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Muenchen,81377,Germany
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Jena,07740,Germany
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Kiel,24105,Germany
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Stuttgart,70376,Germany
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Perugia,PG,06129,Italy
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Milano,MI,20100,Italy
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Roma,RM,00168,Italy
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Napoli,80131,Italy
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Milano,MI,20162,Italy
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Rozzano,MI,20089,Italy
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Bologna,BO,40138,Italy
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Padova,PD,35128,Italy
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Izumisano-city,Osaka,598-8577,Japan
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Valencia,46026,Spain
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Barcelona,Catalunya,08035,Spain
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Barcelona,08041,Spain
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Santiago De Compostela,Galicia,15706,Spain
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Madrid,28041,Spain
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Cordoba,Andalucia,14004,Spain
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Jerez,Cadiz,11407,Spain
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Sabadell,Barcelona,08208,Spain
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Chiang Mai,50200,Thailand
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Bangkok,10330,Thailand
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Bangkok,10400,Thailand
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Bangkok,10700,Thailand
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Ankara,06230,Turkey
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Istanbul,34093,Turkey
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Bristol,Bs2 8hw,United Kingdom
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Guildford,Surrey,Gu2 7xx,United Kingdom
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London,Se1 7eh,United Kingdom
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Birmingham,B15 2th,United Kingdom
Temple University Temple University
Recruiting
Philadelphia,Pennsylvania,19140,United States
Avrum Gillespie
Northwestern Memorial Hospital Pulmonary and Critical Care
Recruiting
Evanston,Illinois,60611,United States
Francisco Martinez
Richard Wunderink
Mayo Clinic Rochester Main Centre
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Rochester,Minnesota,55905,United States
Kianoush Kashani
Leah Knoke
Utah Intermountain Medical Center
Recruiting
Murray,Utah,84107,United States
Ithan Peltan
Good Samaritan Hospital
Recruiting
Corvallis,Oregon,97330,United States
Brian Delmonaco
Wake Forest Univ School of Medicine U Health Sciences
Recruiting
Winston-Salem,North Carolina,27157-1071,United States
Ashish Khanna
UC San Francisco Medical Center
Recruiting
San Francisco,California,94143-0116,United States
Matthieu Legrand
Montefiore Medical Center
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Bronx,New York,10461,United States
Luke Andrea
Henry Ford Hospital
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Detroit,Michigan,48202 2689,United States
Ryann Sohaney
Baylor Scott and White Research
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Dallas,Texas,75246,United States
Ankit Mehta
Bradley Patterson
Univ Of Iowa Hospitals And Clinics
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Iowa City,Iowa,52242,United States
Benjamin Griffin
Ohio State University Medical Center
Recruiting
Columbus,Ohio,43210,United States
Connor Lang
Matthew Exline
Montefiore Medical Center Montefiore Medical Center
Recruiting
Bronx,New York,10467,United States
Ari Moskowitz
Lahey Hospital and Medical Center
Recruiting
Burlington,Massachusetts,01805,United States
Christopher Hansen
Baystate Medical Center
Recruiting
Springfield,Massachusetts,01199,United States
Mark Tidswell
Worldwide Contacts
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