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    Summary
    EudraCT Number:2018-000241-39
    Sponsor's Protocol Code Number:ID-054-304
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-07-17
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2018-000241-39
    A.3Full title of the trial
    A prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to assess the efficacy and safety of clazosentan in preventing clinical deterioration due to delayed cerebral ischemia (DCI), in adult subjects with aneurysmal subarachnoid hemorrhage (aSAH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical research study with clazosentan to evaluate its effects on preventing complications due to the narrowing of the blood vessels (vasospasm) in the brain, caused by bleeding onto the surface of the brain
    A.4.1Sponsor's protocol code numberID-054-304
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03585270
    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 SponsorIdorsia Pharmaceuticals Ltd
    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 supportIdorsia Pharmaceuticals Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIdorsia Pharmaceuticals Ltd
    B.5.2Functional name of contact pointClinical Trial Disclosure Desk
    B.5.3 Address:
    B.5.3.1Street AddressHegenheimermattweg 91
    B.5.3.2Town/ cityAllschwil
    B.5.3.3Post code4123
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number41588441977
    B.5.5Fax number41588440108
    B.5.6E-mailclinical-trials-disclosure@idorsia.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/182
    D.3 Description of the IMP
    D.3.1Product nameClazosentan
    D.3.2Product code ACT-108475
    D.3.4Pharmaceutical form Concentrate for solution for 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.3.8INN - Proposed INNCLAZOSENTAN
    D.3.9.1CAS number 180384-56-9
    D.3.9.2Current sponsor codeACT-108475
    D.3.9.3Other descriptive nameCLAZOSENTAN
    D.3.9.4EV Substance CodeSUB25412
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 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 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
    Aneurysmal Subarachnoid Hemorrhage
    E.1.1.1Medical condition in easily understood language
    When a brain aneurysm (bulge) ruptures, it causes bleeding into the compartment surrounding the brain, the subarachnoid space and is therefore also known as aneurysmal subarachnoid hemorrhage (aSAH)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10039330
    E.1.2Term Ruptured cerebral aneurysm
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10042316
    E.1.2Term Subarachnoid haemorrhage
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To determine the efficacy of clazosentan in preventing clinical deterioration due to DCI, in subjects with aSAH.
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of clazosentan on the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation.
    • To evaluate the effect of clazosentan on long-term clinical outcome, cognition, and health-related Quality of Life (QoL) at Week 12 and QoL at Week 24 post aSAH.
    • To evaluate the safety and tolerability of clazosentan in the selected population up to 24 hours post-study drug discontinuation.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent to participate in the study must be obtained from the subject or proxy/legal representative at any time from hospital admission to prior to initiation of any study-mandated procedure

    2. Males and females aged 18 to 70 years (inclusive, at hospital admission).

    3. Subjects with a ruptured saccular aneurysm, angiographically confirmed by DSA or CTA, which has been successfully secured within 72 hours of rupture, by surgical clipping or endovascular coiling

    4. WFNS (World Federation of Neurosurgical Societies) grades 1–4 (based on Glasgow Coma Scale [GCS]) assessed after recovery from the aneurysm-securing procedure and after external ventricular drainage for hydrocephalus, if required

    5. High-risk prevention: Subjects with a "thick and diffuse clot" (thick and diffuse is defined as a thick confluent clot, more than 4 mm in thickness, involving 3 or more basal cisterns) on the hospital admission CT scan, absence of cerebral vasospasm at the time of randomization, and possibility to start study drug in the ICU (or equivalent environment where all protocol assessments can be performed and the Patient Management Guidelines followed), within 96 hours after the time of the aneurysm rupture.

    6.A) Presence of a cerebral CT scan, performed at least 8 hours post-aneurysm-securing procedure and within 24 hours prior to randomization
    6. B) Absence of a significant (e.g., symptomatic) new or worsened cerebral infarct or re-bleeding of the repaired aneurysm on the post-procedure CT scan.

    7. A woman of childbearing potential is eligible only if the pregnancy test performed during the screening period is negative.
    Agreement must be obtained to take the necessary precautions to avoid pregnancy from hospital discharge until 30 days post-study drug discontinuation.
    If breastfeeding, agreement must be obtained to refrain for the duration of the treatment with study drug and until 30 days post-study drug discontinuation.

    8.Males are eligible for study participation only if they agree to take the necessary precautions to avoid pregnancy in a female partner from hospital discharge until 30 days post-study drug discontinuation.
    E.4Principal exclusion criteria
    aSAH, aneurysm-securing procedure, vasospasm:

    1. Subjects with SAH due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms, SAH associated with arterio-venous malformation, vertebral dissections).
    2. Significant bleeding post aneurysm-securing procedure (e.g., due to intra-ventricular drain, intra-cerebral hemorrhage, epidural hematoma, vessel dissection or rupture, re-bleeding of the repaired aneurysm), based on investigator judgment.
    3. Intra-or peri-aneurysm securing procedure complication requiring non-routine medical or interventional treatment such as administration of an antithrombotic or anti-platelet agent (e.g., abciximab), which is not completely resolved prior to randomization.
    4. Intraventricular hemorrhage on the hospital admission CT scan, filling more than 50% of both lateral ventricles and with involvement of the 3rd and 4th ventricles.
    5. Intracerebral hemorrhage on the hospital admission CT scan, with an approximate volume of > 50 mL.
    6. Presence of cerebral vasospasm at hospital admission (initial admission or transfer from another hospital) believed to be associated with a prior bleed (i.e., occurring before the bleed for which the subject is currently hospitalized). Vasospasm occurring during the aneurysm-securing procedure is not an exclusion criterion.

    Neurological and functional status:

    7. Subjects with a new major neurological deficit occurring post aneurysm-securing procedure which is attributable to the procedure and does not improve to pre-procedure status before randomization.
    8. Subjects with a GCS score of ≤ 9 at the time of randomization and without intracranial pressure (ICP) monitoring.
    9. modified Rankin Score of 3 or higher, prior to the aSAH (i.e., due to a chronic condition).

    Other clinical considerations:

    10. Subjects with total bilirubin > 2 times the upper limit of normal, and/or a known diagnosis or clinical suspicion of liver cirrhosis or moderate to severe hepatic impairment
    11. Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) at time of randomization that is refractory to treatment.
    12. Unresolved pulmonary edema or significant pneumonia still present at the time of randomization, or severe hypoxia at the time of randomization in intubated subjects, defined as PaO2/FiO2 ≤ 200.
    13. High sustained ICP (> 25 mmHg lasting > 20 minutes) at time of randomization, despite optimal treatment, in subjects with ICP monitoring.
    14. Severe cardiac failure requiring inotropic support at the time of randomization.
    E.5 End points
    E.5.1Primary end point(s)
    - Occurrence of clinical deterioration due to DCI from study drug initiation up to 14 days post-study drug initiation
    E.5.1.1Timepoint(s) of evaluation of this end point
    From study drug initiation up to 14 days post-study drug initiation
    E.5.2Secondary end point(s)
    1- Main secondary endpoint:
    The occurrence of clinically relevant cerebral infarction at Day 16 poststudy drug initiation defined as:
    o all cause cerebral infarction ≥ 5 cm3 or
    o cerebral infarction < 5 cm3 in subjects with clinical deterioration due to DCI.

    2- Other secondary endpoint:
    o Long-term clinical outcome assessed by the modified Rankin Scale (mRS) at Week 12 post-aSAH, dichotomized into poor outcome (score ≥ 3) and good outcome (score < 3).
    o Long-term clinical outcome assessed by the Glasgow Outcome Scale
    Extended (GOSE) at Week 12 post-aSAH, dichotomized into poor outcome (score ≤ 4) and good outcome (score > 4).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- At Day 16 post study drug initiation
    2- At Week 12 post-aSAH
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    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 Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life
    Biomarkers
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA66
    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
    Canada
    Israel
    United States
    Austria
    Finland
    France
    Poland
    Sweden
    Spain
    Czechia
    Germany
    Italy
    Belgium
    Denmark
    Hungary
    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
    End of the trial is defined as last subject last visit (LSLV)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months41
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months47
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-07-17. Yes
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Written inform consent must be obtained from the subject or proxy/legal representative, according to local regulations
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 264
    F.4.2.2In the whole clinical trial 400
    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 Decision2018-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-11-18
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