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    Summary
    EudraCT Number:2022-000794-47
    Sponsor's Protocol Code Number:CTIN816A12201
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-10-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2022-000794-47
    A.3Full title of the trial
    A randomized, multi-centric, placebo-controlled, participant and investigator-blinded study to evaluate the safety, tolerability and efficacy of TIN816 in adult patients at risk for acute kidney injury following cardiac surgery
    Randomizované, multicentrické, placebem kontrolované klinické hodnocení, zaslepené vůči pacientovi i zkoušejícímu, vyhodnocující bezpečnost, snášenlivost a účinnost přípravku TIN816 u dospělých pacientů s rizikem akutního poškození ledvin po operaci srdce
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-center study to evaluate the safety, tolerability and efficacy of TIN816 in patients at risk for acute kidney injury following a cardiac surgery.
    A.4.1Sponsor's protocol code numberCTIN816A12201
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis s.r.o.
    B.5.2Functional name of contact pointlnformacni sluzba - klin. hodnoceni
    B.5.3 Address:
    B.5.3.1Street AddressNa Pankraci 1724/129
    B.5.3.2Town/ cityPraha 4
    B.5.3.3Post code140 00
    B.5.3.4CountryCzechia
    B.5.4Telephone number+420 2 25775 111
    B.5.5Fax number+420 2 25775 205
    B.5.6E-maildotazy.klinickehodnoceni@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TIN816
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeTIN816
    D.3.9.4EV Substance CodeSUB218012
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute kidney injury
    E.1.1.1Medical condition in easily understood language
    Acute kidney injury
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 26.0
    E.1.2Level PT
    E.1.2Classification code 10069339
    E.1.2Term Acute kidney injury
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the effect of TIN816 on serum creatinine level in high-risk patients undergoing major cardio-vascular surgery, versus placebo
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of TIN816
    To assess the effect of TIN816 on the incidence and severity of AKI in patients at high-risk patients undergoing major cardio-vascular surgery, versus placebo
    To assess the pharmacokinetics (PK) of TIN816
    To assess immunogenicity (IG) of TIN816
    To assess the effect of TIN816 on the incidence of AKD in high-risk patients undergoing major cardio-vascular surgery, versus placebo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Signed informed consent must be obtained prior to participation in the study

    Participants must be able to communicate well with the investigator and to understand and comply with the requirements of the study.

    Male and female patients ≥45 years at screening

    Participants must weigh at least 50 kg and maximum 150 kg to participate in the study and must have a body mass index (BMI) below 40. BMI = Body weight (kg) / [Height (m)]2

    At screening, vital signs should be assessed in the sitting position. Sitting vital signs should be within the the following ranges:

    a. body temperature between 35.0-37.5 °C

    b. blood pressure (systolic 100-160 mmHg, diastolic < 100 mmHg)

    c. pulse rate (50-100/min) stable with or without medication(s) as per Investigator assessment.

    6. Stable renal function with no known increase in SCr of ≥25% at screening visit compared to a previous value not older than 6 weeks. If a SCr obtained within the last 6 weeks is not available, a SCr value obtained within the last 3months can be used as the previous value (as documented by a local laboratory using standard assay methodology).

    7. Non-emergent open chest cavity major cardiopulmonary bypass (CPB) surgery with expected CPB time ≥1 hour
    E.4Principal exclusion criteria
    eGFR at screening <15 mL/min/1.73 m2 (calculated using CKD-EPI 2021 equation)

    Receiving renal replacement therapy (RRT) currently or at any time within 3 months prior to screening, or scheduled to start RRT shortly after cardiac surgery.

    Patients with bleeding risk at screening,or identified as such pre
    surgery if screening was performed earlier than Day -1). The Investigator should  make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence of any of the following:

    History of bleeding with suspected or confirmed bleeding disorder or any other high risk for bleeding in the opinion of the investigator

    Thrombocytopenia: platelet count <100x109/L

    History of Platelet dysfunction:e.g. ADP induced platelet aggregation lower than 60 %

    History of coagulation factor deficiency: including, but not limited to fibrinogen < 2.5-2.8 g/L or Von Willebrand factor (vWF) ≤ 50 IU/dL.

    Any emergency surgeries performed less than 30 days before screening, including aortic dissection, and/or major congenital heart defects.

    Schedules to undergo cardiac surgery off CPB or with hypothermic circulatory arrest

    Cardiogenic shock or hemodynamic instability within four weeks prior to surgery, requiring inotropes or vasopressors or mechanical devices such as intra-aortic balloon counter-pulsation (IABP). Current or within four
    weeks prior to surgery, clinically significant arrhythmias associated with syncope, dyspnea or hemodynamic instability.

    Have received cardiopulmonary resuscitation (CPR) within 30 days prior to cardiac surgery

    Use of other investigational drugs at the time of enrollment or within 5 half lives of enrollment or until the expected PD effect has returned to baseline, whichever is longer ; or longer if required by local regulations.

    Patients who are post-nephrectomy

    Have ongoing sepsis or history of sepsis within the past 8 weeks or untreated diagnosed infection prior to screening visit. Sepsis is defined as presence of a confirmed pathogen, along with fever or hypothermia, and hypoperfusion or hypotension.

    Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.).

    Pregnant or nursing (lactating women)

    Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and until the end of study. Highly effective contraception methods include:
    • Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    • Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
    • Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.
    • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
    In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
    If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
    Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child-bearing potential.

    Use of plasma exchange, plasmapheresis, and other extracorporeal filtration techniques within last month prior to screening or if planned to be used during or after the surgery.
    E.5 End points
    E.5.1Primary end point(s)
    Ratio of the highest serum creatinine value within 5 days post dose versus baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1 until Day 6
    E.5.2Secondary end point(s)
    Assessment of Safety based on vital signs, physical examination, ECGs, laboratory assessments and collection of AEs assessed from baseline until the end of the study visit
    AKI stages 1, 2 and 3 as defined by modified AKI Network (AKIN) criteria
    Serum PK parameters Cmax, Tmax, T1/2, CL, Vz, AUClast and AUCinf of TIN816
    Anti-drug antibodies against TIN816
    Occurrence of major adverse kidney events at day 90 (MAKE90)
    Occurence of MAKE30
    Occurrence of individual components of the MAKE criteria at Days 30 or 90.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety based on vital signs, physical examination, ECGs, laboratory assessments and collection of AEs : screening, day 2,3,4,30 and 90, EoS

    AKI stages 1, 2 and 3 as defined by modified AKI Network (AKIN) criteria Day 1 until Day 6

    Serum PK parameters Cmax, Tmax, T1/2, CL, Vz, AUClast and AUCinf of TIN816 : from baseline until Day 90

    Anti-drug antibodies against TIN816 : from Baseline until Day 90

    Occurrence of major adverse kidney events : Day 30 and day 90

    Occurrence of individual components of the MAKE criteria : day 30 or day 90
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Singapore
    Taiwan
    Brazil
    India
    Belgium
    Czechia
    Estonia
    France
    Germany
    Hungary
    Lithuania
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days12
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-01-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-23
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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