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    Summary
    EudraCT Number:2020-005731-67
    Sponsor's Protocol Code Number:NLxxxxxxxxxx
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-03-10
    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 number2020-005731-67
    A.3Full title of the trial
    Complement Inhibition: Attacking the Overshooting Inflammation @fter Subarachnoid Hemorrhage - A phase II trial on the safety and efficacy of C1
    esterase inhibitor for the acute management of subarachnoid hemorrhage
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    C1-inhibitor for the acute management of subarachnoid hemorrhage
    A.3.2Name or abbreviated title of the trial where available
    CIAO@SAH
    A.4.1Sponsor's protocol code numberNLxxxxxxxxxx
    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 SponsorHaaglanden Medisch Centrum
    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 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 organisationHaaglanden Medisch Centrum
    B.5.2Functional name of contact pointWouter Moojen
    B.5.3 Address:
    B.5.3.1Street AddressLijnbaan 32
    B.5.3.2Town/ cityDen Haag
    B.5.3.3Post code2512VA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31889792165
    B.5.6E-mailw.moojen@haaglandenmc.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 nameC1 ESTERASE INHIBITOR (HUMAN)
    D.3.9.4EV Substance CodeSUB39564
    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
    Subarachnoid hemorrhage
    E.1.1.1Medical condition in easily understood language
    Hemorrhagic stroke
    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 10042320
    E.1.2Term Subarachnoid hemorrhage
    E.1.2System Organ Class 100000004852
    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 C1-INH in patients with subarachnoid hemorrhage (SAH)

    Primary hypothesis: The hypothesis is that random assignment to C1-INH in SAH will lead to a reduction in delayed cerebral ischemia (DCI) compared to random assignment to placebo. Furthermore, to access safety, no difference should be detected in complication rate during hospitalization between the two groups
    E.2.2Secondary objectives of the trial
    Secondary Objective: To determine differences between C1-INH and placebo treatment in the following outcomes for patients with SAH:
    - Clinical outcomes: cerebral infarction on brain CT/MRI, mortality, hospital and ICU length of stay, ventilator days, hospital disposition, functional outcome (mRS and GOSE), cognitive function (MoCA) and quality of life (EQ-5D-5L and SF-36)
    - Neurological damage: BANYAN (GFAP/UCHL-1) blood biomarker
    - Complement activation: human serum (WIESLAB assay), total terminal complement activity levels (CH50) and protein levels of complement component (C3b/C, C4b/C and C5b-9) in plasma and CSF
    - Coagulation cascade activation (PT, aPPT, PLT, D-dimer, fibrinogen)
    - Inflammatory markers in serum and CSF (TNF-alpha, intraleukin)
    - Level of C1-inhibitor activity in plasma and CSF
    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:
    - Confirmed diagnosis of aneurysmal subarachnoid hemorrhage on CT-scan or lumbar puncture (in the presence of a negative CT-scan);
    - Age ≥ 18 years on admission;
    - WFNS grade 1-5
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    - Subarachnoid hemorrhage deemed most likely to ‘peri mesencephalic’ origin after consideration of history, clinical examination and radiological findings (including angiographic imaging);
    - Subarachnoid hemorrhage deemed most likely of post-traumatic origin after consideration of history, clinical examination and radiological findings (including angiographic imaging);
    - Participation in another clinical therapeutic study;
    - Patients with a known hereditary complement deficiency (including hereditary angioedema);
    - Patients with a history of sensibility to blood products or C1-inhibitor;
    - Patients with a history of thrombosis;
    - Pregnant woman
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    To assess efficacy of C1-INH in SAH patients, the difference of delayed cerebral ischemia (DCI) will be analysed between the treatment groups. The criteria consisted of either a new focal neurological impairment (such as hemiparesis, aphasia, apraxia, hemianopia, or neglect), or a decrease of at least 2 points on the Glasgow Coma Scale (either on the total score or on one of its individual components). This should last for at least 1 hour, is not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies (e.g. hydrocephalus or rebleeding).

    Safety:
    As this is a phase II trial, we use a primary safety endpoint in addition to our primary efficacy endpoint. This safety endpoint will be patient complication rate during hospitalization. This rate includes 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
    DCI: day 1-14 after ictus
    SAEs: daily during hospitalization
    E.5.2Secondary end point(s)
    During hospitalization:
    - Cerebral infarction on brain CT at 14 days
    - Mortality
    - Daily neurological condition measured by GCS during the first 14 days
    - Complement activity in serum and CSF
    - Inflammatory markers in serum and CSF
    - Coagulation cascade activation
    - ICU length of stay, ventilator days
    At discharge:
    - Hospital length of stay
    - Hospital disposition
    During follow-up at 6 months:
    - Modified Rankin Scale (mRS Score)
    - Glasgow Outcome Score extended (GOSE)
    - Montreal Cognitive Assessment (MoCA)
    - Quality of life (EQ-5D-5L)
    - Quality of life (SF-36)
    E.5.2.1Timepoint(s) of evaluation of this end point
    During hospitalization up to 6 months 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 included in the study
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 subarachnoid hemorrhage are often incapacitated due to loss of conscience and mental confusion and therefore informed
    consent must be obtained by proxy
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state128
    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 Decision2021-03-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-02
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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