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    Summary
    EudraCT Number:2016-004974-16
    Sponsor's Protocol Code Number:IL1ra03
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-06-20
    Trial results View 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 ConcernedUK - MHRA
    A.2EudraCT number2016-004974-16
    A.3Full title of the trial
    DOUBLE-BLIND PLACEBO-CONTROLLED RANDOMISED CLINICAL DOSE-RANGING STUDY TREATING MODERATE-SEVERE TRAUMATIC BRAIN INJURY PATIENTS WITH RECOMBINANT HUMAN INTERLEUKIN 1 RECEPTOR ANTAGONIST.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial treating brain injured patients with the anti-inflammatory drug Kineret:
    IL1ra-TBI
    A.3.2Name or abbreviated title of the trial where available
    IL1ra-TBI
    A.4.1Sponsor's protocol code numberIL1ra03
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02997371
    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 SponsorCambridge University Hospitals NHS Foundation Trust and the University of Cambridge
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSobi (Swedish Orphan Biovitrum AB)
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportSwedish Society of Medicie
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportNational Institute of Health Research
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportSwedish Brain Foundation
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCambridge University Hospitals NHS Foundation Trust
    B.5.2Functional name of contact pointCarrie Bayliss
    B.5.3 Address:
    B.5.3.1Street AddressCambridge University Hospitals NHS Foundation Trust
    B.5.3.2Town/ cityAddenbrooke's Hospital
    B.5.3.3Post codeCB20QQ
    B.5.4Telephone number01223348158
    B.5.5Fax number01223256763
    B.5.6E-mailcctu@addenbrookes.nhs.uk
    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 Yes
    D.2.1.1.1Trade name Kineret
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum AB (publ)
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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.3.1Product nameKineret
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    Intravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAnakinra
    D.3.9.1CAS number 143090-92-0
    D.3.9.3Other descriptive nameRecombinant human Interleukin-1 receptor antagonist protein
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboSolution for injection/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
    We wish to study the drug Kineret in patients suffering from moderate-to-severe traumatic brain injury
    E.1.1.1Medical condition in easily understood language
    Traumatic brain injury is defined as blunt trauma to the brain causing injuries and hemorrhages, which in turn lead to a harmful environment for surviving brain cells.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10060690
    E.1.2Term Traumatic brain injury
    E.1.2System Organ Class 100000004863
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10051288
    E.1.2Term Central nervous system inflammation
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Our primary research aim is to detect a dose-response decrease of pro-inflammatory cytokines (components of the immune system called tumor necrosis factor alpha and interferon gamma) in the brain parenchyma during the first 48 hours after first dose of the IMP following traumatic brain injury. The cytokine-extraction will be done using the microdialysis which will extract these cytokines from the extracellular fluid of the brain.

    Our main hypothesis is that following administration of Kineret, there will be a dose-response modification of the inflammatory response, possible to measure using microdialysis probes in brain parenchyma. With escalating dose, and versus placebo, the pro-inflammatory cytokines tumor necrosis factor alpha and interferon gamma, will decrease in the brain parenchyma. The null hypothesis is that there is no difference in cytokine concentration between an escalating dose of Kineret and placebo.

    Placebo group (A) will be compared with the intermediate dose of the
    E.2.2Secondary objectives of the trial
    To determine a dose-response effect of Kineret following traumatic brain injury on:
    - Patient outcome after 6 and 12 months.
    - Brain immune system activation ("Microglial" activation) and assessment of special kind of brain injury ("diffuse
    axonal injury").
    - Release of brain enriched proteins to the blood and spinal fluid.
    - Pressure and amount of oxygen in the injured brain.
    - Drug delivery to the brain.
    - Drug safety for the patient (amount of side-effects).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Have given written informed consent to participate provided by the patient's legal representative or by agreement with an independent health provider (as the patient will initially lack capacity).
    • Aged 18-64 years.
    • Head injury patients (Glasgow Coma Scale 3-13), requiring ventilation, sedation and a cranial access device for their clinical management for at least 72 hours.
    • Head injury should be compatible with survival.
    • Possible to deliver the first dose of IMP within 12 hours after trauma.
    E.4Principal exclusion criteria
    • Head injury unlikely to survive 5 days (CT evidence of above as judged by clinical team, bilateral fixed and dilated
    pupils).
    • Not able to provide the initial dose of IMP within 12 hour after trauma.
    • Follow up not possible
    • Not suitable for insertion of Cranial Access Device (bleeding diathesis)
    • Participation in other CTIMP

    - As per the SmPC

    • Immunosuppression (evidence of neutropenia (ANC <1.5 x 109/l), immunosuppression secondary to immunomodulatory medications, chemotherapy or radiation therapy in the 3 months preceding study entry)
    • Severe Renal Insufficiency or End Stage Renal Disease (defined as a creatinine clearance <30 ml/min)
    • Pregnancy/Nursing mothers
    • Known hypersensitivity to E. coli derived products
    • Administration of live vaccine
    • Known presence or suspicion of active bacterial, fungal or viral infections, including tuberculosis, or HIV infection or hepatitis B or C infection.
    • Uncontrolled clinically significant hematologic, pulmonary, endocrine, metabolic, gastrointestinal, or hepatic disease as judged by the investigator.
    • Concurrent treatment with TNF-alpha antagonists (Etanercept®).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is a dose-dependent difference in cerebral cytokine concentrations following 48 hours of IMP administration, primarily for tumor necrosis factor alpha and interferon gamma.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The cytokine concentration will be sampled and analyzed the first 48-72 hours following injury.
    E.5.2Secondary end point(s)
    To determine a dose-response effect of recombinant human Interlekukin-1 receptor antagonist (Kineret) following traumatic brain injury on several outcome metrics, including:
    - Clinical outcome by assessing neurological function and recovery using standardized scales (e.g. extended Glasgow Outcome Score, and neuropsychiatric assessment) at 6 months and 1 year. This will provide an estimate of the variability in outcome metrics which will allow a definitive power calculation to be estimated for a phase III study.
    - Imaging outcome by magnetic resonance imaging, including a technique called diffusion tensor imaging (DTI) at repeated time points to determine degree of brain injury on the connectivity between the brain’s axons (connections) globally as well as in the locality of the microdialysis catheter (a semipermeable membrane inserted into affected brain tissue) to monitor brain metabolism and inflammation.
    - Biochemical outcome by concentrations of protein biomarkers of tissue fate, including S100B, Neurofilament Light (NF-L), microtubule associated protein tau (tau) and amyloid-beta which all have been shown to increase in patients with different brain diseases including traumatic brain injury, Alzheimer’s and multiple sclerosis.
    - Monitoring outcome by assessing intracranial pressure, cerebral metabolism, brain tissue oxygen as well as alterations in cerebral blood flow.
    - Pharmacokinetic outcome by measuring how much drug that reaches the affected brain using the microdialysis
    technique.
    - Inflammatory outcome by analysing microglial activation, the inflammatory cells of the brain, using positron emission tomography, a radiological technique, during hospital stay. We also wish to see how the body’s immune system reacts by measuring the adaptive immune system’s reactivity toward brain specific proteins as
    a surrogate marker of injury severity
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Clinical outcome will be assessed at 6 months and 1 year.
    - Radiological outcome using DTI will be analyzed during hospital stay
    - Monitoring outcome, consisting of intracranial pressure, cerebral metabolism and brain tissue oxygen pressure will be assessed the first week, or longer depending on the clinical course of the patient, following trauma.
    - Pharmacokinetic outcome will be assessed the first 5 days following injury during drug administration.
    - Inflammatory outcome using positron emission tomography will be done during hospital stay
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 Yes
    E.8.2.3.1Comparator description
    Different dose of the Kineret in the two treatment groups.
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days4
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients will be unconscious due to brain injury when included in the study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    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)
    The IMP will only be administered in the first 48 hours after trauma. Participants will return to normal standard of care following this treatment and their stay in the neuro-critical care unit.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-09-08
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