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    Summary
    EudraCT Number:2020-000140-58
    Sponsor's Protocol Code Number:NL7255100000
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-02-25
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-000140-58
    A.3Full title of the trial
    Complement Inhibition: Attacking the Overshooting Inflammation @fter Traumatic Brain Injury - A phase II trial on the safety and efficacy of C1 esterase inhibitor Cinryze for the acute management of severe traumatic brain injury
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Cinryze for the acute management of severe traumatic brain injury
    A.3.2Name or abbreviated title of the trial where available
    CIAO@TBI
    A.4.1Sponsor's protocol code numberNL7255100000
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    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 supportHersenstichting/Dutch Brain Foundation
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportTakeda pharmaceutical company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointWilco Peul
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 ZA
    B.5.3.4CountryNetherlands
    B.5.6E-mailW.C.Peul@lumc.nl
    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 Cinryze, C1 inhibitor (human)
    D.2.1.1.2Name of the Marketing Authorisation holderShire
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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.3.4Pharmaceutical form Powder and solvent for solution for injection
    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.3.8INN - Proposed INNC1 inhibitor, human
    D.3.9.3Other descriptive nameCOMPLEMENT C1 ESTERASE INHIBITOR
    D.3.9.4EV Substance CodeSUB22696
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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) Yes
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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 placeboInfusion
    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
    Severe traumatic Brain Injury (TBI) with GCS < 13
    E.1.1.1Medical condition in easily understood language
    Severe head trauma
    E.1.1.2Therapeutic area Diseases [C] - Injuries, poisonings, and occupational diseases [C21]
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective: To determine the safety and efficacy of 6000 IU Cinryze in patients with moderate and severe TBI (GCS <13 with a clinical indication for ICP measurements).

    Primary hypothesis: The hypothesis is that random assignment to Cinryze in patients with moderate and severe TBI will experience a reduction in ICP directed therapy intensity levels (TIL) compared to random assignment to placebo (difference of 2.2). Secondary, if efficacy is proven on the TIL scale, a difference of the GOSE at six months will be evaluated. Furthermore, no difference should be detected in complication rate after one month between the two groups.
    E.2.2Secondary objectives of the trial
    Secondary Objective: To determine differences between Cinryze and placebo treatment in the following outcomes for patients with moderate and severe TBI:
    - Clinical outcomes: ICP burden, CT midline shift, GOSE, mortality, hospital and ICU length of stay, ventilator days, hospital disposition, quality of life (as expressed by QoLiBri), health-related quality of life (as expressed by SF-36 and EQ-5D-5L)
    - Neurological damage: BANYAN (GFAP/UCHL-1) blood biomarker
    - Complement activation: human serum (WIESLAB assay) and total terminal complement activity levels (CH50) and protein levels of complement component.
    - Level of Cinryze (C1 inhibitor activity) in plasma and RNA expression
    - Level of Cinryze (C1 inhibitor activity) in plasma
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    - Age at admission ≥ 18 years and < 65 years;
    - Clinical diagnosis of traumatic brain injury with GCS < 13 (with intra cranial deviations);
    - Catheter placement for monitoring and management of increased ICP for at least 24 hours;
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    - A clear, non-traumatic cause of low GCS (e.g. toxic, cardial) on admission;
    - Not expected to survive more than 24 hours after admission;
    - Brain death on arrival in the participating centres;
    - Severe pre-trauma disability, defined as being dependent on other people;
    - Known prior history of sensibility to blood products or Cinryze;
    - Patients with a history of hereditary angioedema;
    - Patients with a history of thrombosis
    - Pregnant women.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    This trial will focus primarily on the intensity of ICP-targeted therapy based on the Therapy Intensity Level (TIL) Scale. The Therapy Intensity Level Scale is designed to integrate all known and relevant ICP directed treatments into a single summary score. The current TIL scale was developed as part of the Interagency Common Data Elements scheme. Since introduction, the novel TIL scale have been widely used in neurotrauma research, with excellent inter- and intra-rater reliability with minimal measurement errors. The TIL includes eight ICP-treatment modalities, termed items. The TILmean based on the daily TIL score over four days will be calculated. The daily TIL score will be calculated based on the highest score in each item per day, to provide a metric of the maximal therapeutic intensity for ICP management for that day.

    The ‘secondary’ primary efficacy endpoint will be the Extended Glasgow Outcome Scale (GOS-E) at six months after trauma. This endpoint can only be tested if the primary difference on the TIL scale is evaluated. If the difference on the TIL scale is not significant after finishing the trial, the co-primary efficacy endpoint will formally be declared ‘non-significant’. Nevertheless, this endpoint is not used primarily used to declare the study success. The so-called serial gatekeeping approach will be used. These multiple primary endpoints are used to also try to determine the role of Cinryze in longer term clinical outcome (six months). The use of the GOS-E as a core global outcome measure is recommended by the interagency TBI Outcomes Workgroup and the International Mission for Prognosis and Analysis of Clinical Trials in TBI group (IMPACT Common Data Elements). The GOS-E, derived from its precursor the GOS, is globally the most commonly used TBI outcome measure. While the GOS grades disability on a 5-point scale and is determined largely by physical deficits, the GOS-E provides a higher sensitivity by defining disability on an 8-point scale and incorporating emotional and cognitive disturbances affecting disability. The GOS-E is designed as a structured interview and can also be applied through telephone and e-mail. This allows for a long-term follow-up without a high burden for patients. Although several other primary outcome measures for TBI exist, the GOS(-E) remains the most widely implemented and best validated tool to assess outcome in TBI and permits comparison to much of the world literature on TBI outcome. Two research nurses or researchers will independently grade outcomes based on the GOS-E in each patient according to the standardized approach. Disagreements will be resolved by consensus between them or by consultation of a third investigator who is unaware of the trial-group assignment.

    Safety:
    The safety endpoint will be patient complication rate at 1-month follow-up. This rate include adverse events (including serious adverse events) possibly related to study medication. This includes, but is not limited to, venous thromboembolic events, hypersensitivity reaction, hyperglycemia, sepsis, mortality. Events will be presented per adverse event type, grade, and seriousness. Patients will be assessed daily by a blinded physician/nurse for these complications. Vital signs will be monitored closely and potential adverse reactions to the experimental treatment will be picked up immediately at the ICU.
    E.5.1.1Timepoint(s) of evaluation of this end point
    TIL: daily on ICU
    GOSE: six months after discharge
    Complication rate: daily (evaluation at 1 month follow-up)
    E.5.2Secondary end point(s)
    Secondary outcomes will be measured during hospitalization up to one-year follow-up.
    During hospitalization:
    - ICP burden
    - CT scan midline shift
    - Mortality
    - Neurological damage markers in the blood using BANYAN biomarker assay
    - Complement activity using different assays
    At discharge:
    - GOS-E
    - Hospital length of stay
    - Hospital disposition
    During follow-up
    - GOS-E
    - QoLiBri
    - SF 36
    - EQ-5D-5L
    E.5.2.1Timepoint(s) of evaluation of this end point
    During hospitalization, at discharge and during six months of follow-up
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Yes
    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 concerned4
    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
    Last follow-up (after six months) of the last subject undergoing the trial
    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 days0
    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: 106
    F.1.3Elderly (>=65 years) No
    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 with severe traumatic brain injury are often incapacitated due to loss of conscience and mental confusion and therefore informed consent must be obtained by proxy or deferred consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state106
    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)
    Normal treatment of the condition (standard care)
    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 Decision2020-02-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-23
    P. End of Trial
    P.End of Trial StatusOngoing
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