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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2018-000241-39
    Trial protocol
    		 FI   DE   SE   FR   CZ   BE   DK   HU   AT   PL   ES   IT  
    Global end of trial date
    18 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2023
    First version publication date
    30 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ID-054-304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03585270
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Idorsia Pharmaceuticals Ltd
    Sponsor organisation address
    Hegenheimermattweg 91, Allschwil, Switzerland, 4123
    Public contact
    Idorsia Clinical Trial Information , Idorsia Pharmaceuticals Ltd, +41 58 844 19 77, idorsiaclinicaltrials@idorsia.com
    Scientific contact
    Idorsia Clinical Trial Information , Idorsia Pharmaceuticals Ltd, +41 58 844 19 77, idorsiaclinicaltrials@idorsia.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of clazosentan in preventing clinical deterioration due to DCI, in subjects with aSAH.
    Protection of trial subjects
    Prior to the start of the study, each study site consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. The protocol and any materials provided to the subject (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate IEC or IRB before the study was started. Sponsor personnel and the investigators were required to conduct the study in full compliance with ICH-GCP Guidelines, the principles of the Declaration of Helsinki, and with the laws and regulations in the country in which the study is conducted. The sponsor had the right to terminate the study at any time globally or locally. The investigators had the right to terminate the participation of their site in the study at any time. The investigator was responsible for protecting the subject's best interests. Study-specific criteria for discontinuation were described in the protocol. The investigators were responsible for maintaining the subjects' identities in strictest confidence. Written informed consent to participate in the study had to be obtained from the participant or proxy/legal representative at any time from hospital admission to prior to initiation of any study-mandated procedure. The informed consent was obtained prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each subject that he or she was completely free to refuse to enter the study, or to withdraw from the study at any time for any reason.
    Background therapy
    		 The usual standard of care for the management of aSAH was allowed until the primary endpoint assessment at 14 days post-study drug initiation, except for those therapies listed in the “forbidden concomitant medication” section and must be documented in the medical charts. Nimodipine (oral or i.v.) could be administered for the usual duration if it was routine standard of care at the site. “Statins” (e.g., simvastatin, pravastatin) could only be administered if the subject was receiving them chronically for the treatment of high cholesterol levels. Vaccines (including those for COVID-19) could be administered at any time during the study. For the purpose of this study, rescue therapy referred to the escalation of medical therapy beyond standard hemodynamic therapy, for the treatment of refractory vasospasm. The following therapies were considered rescue therapies: • balloon angioplasty, • intra-arterial, intrathecal/intra-cisternal/intra-ventricular administration of vasodilators or ozagrel. The decision to administer the above rescue therapies was based on local standard of care and was allowed at any time during the study for refractory vasospasm. Intravenous administration of vasodilators (e.g., nicardipine, milrinone) was allowed as rescue therapy only if preceded by intra-arterial administration of a vasodilator. Study drug had to be temporarily interrupted prior to any rescue therapy and had to be resumed after the completion of the therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    Czech Republic: 47
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Finland: 25
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 42
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    United States: 59
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 29
    Worldwide total number of subjects
    406
    EEA total number of subjects
    314
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    346
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was done from 03 February 2019 to 18 November 2022.

    Pre-assignment
    Screening details
    		 406 participants are considered to be enrolled in the study. 3 of the 409 participants randomized did not receive treatment.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Clazosentan
    Arm description
    		 All participants from the randomized analysis set who started clazosentan 15 mg per hour infusion for up to 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazosentan
    Investigational medicinal product code
    ACT-108475
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a continuous infusion of clazosentan at a rate of 15 mg/hour.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matching clazosentan was administered after randomization for a maximum of 14 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a continuous infusion of placebo matching clazosentan for up to 14 days.

    Number of subjects in period 1
    		Clazosentan Placebo
    Started
    202
    204
    Completed
    167
    190
    Not completed
    35
    14
         Adverse event, serious fatal
    7
    3
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    20
    8
         Other reasons
    5
    2
         Withdrawal by proxy/legal representative
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clazosentan
    Reporting group description
    		 All participants from the randomized analysis set who started clazosentan 15 mg per hour infusion for up to 14 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching clazosentan was administered after randomization for a maximum of 14 days.

    Reporting group values
    		 Clazosentan Placebo Total
    Number of subjects
    		 202 204 406
    Age categorical
    Age at hospital admission
    Units: Subjects
        Adults (18-64 years)
    		 171 175 346
        From 65-84 years
    		 31 29 60
        85 years and over
    		 0 0 0
    Age continuous
    Age at hospital admission
    Units: years
        arithmetic mean (standard deviation)
    		 53.0 ( 10.4 ) 53.7 ( 10.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 138 137 275
        Male
    		 64 67 131
    Race
    (United States NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 3 3
        Asian
    		 4 6 10
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 6 5 11
        White
    		 176 169 345
        Unknown or Not Reported
    		 16 21 37
    Ethnicity
    (NIH / OMB)
    Units: Subjects
        Hispanic or Latino
    		 25 23 48
        Not Hispanic or Latino
    		 155 159 314
        Unknown or Not Reported
    		 22 22 44
    World Federation of Neurological Societies (WFNS) Grade
    The WFNS grade was assessed by the investigator at hospital admission. The WFNS grade ranges from I (best) to V (worst).
    Units: Subjects
        Grade I and II
    		 161 158 319
        Grade III to V
    		 41 46 87
    Aneurysmal subarachnoid hemorrhage diagnosed subgroups
    High-risk prevention participants were diagnosed at an early stage of the disease continuum and were those who were at a high risk of developing cerebral vasospasm. These participants were characterized by the presence of a large quantity of subarachnoid blood on their hospital admission Computed Tomography (CT) scan (with a "thick and diffuse clot" defined as a thick confluent clot, more than 4 mm in thickness and involving more than 3 or more basal cisterns). The confirmed vasospasm participants did not have a "thick and diffuse clot" on their hospital admission CT scan.
    Units: Subjects
        Confirmed vasospasm group
    		 6 5 11
        High risk of vasospasm group
    		 196 199 395
    Body Mass Index
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 26.8 ( 5.7 ) 26.8 ( 5.6 ) -
    Total Glasgow Coma Scale (GCS) Score
    The GCS was performed at hospital admission. The GCS was used to measure the level of consciousness. Scores range from 3 (worst score) to 15 (best score).
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 13.4 ( 3.0 ) 13.1 ( 3.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Clazosentan
    Reporting group description
    		 All participants from the randomized analysis set who started clazosentan 15 mg per hour infusion for up to 14 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching clazosentan was administered after randomization for a maximum of 14 days.

    Subject analysis set title
    Clazosentan (safety set)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects treated with at least one infusion of clazosentan.

    Subject analysis set title
    Placebo (safety set)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects treated with placebo infusion.

    Primary: Occurrence of clinical deterioration due to delayed cerebral ischemia (DCI) from study drug initiation up to 14 days post-study drug initiation

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    End point title
    		 Occurrence of clinical deterioration due to delayed cerebral ischemia (DCI) from study drug initiation up to 14 days post-study drug initiation
    End point description
    Clinical deterioration due to delayed cerebral ischemia is defined as a worsening of at least 2 points compared to the reference score, on the modified Glasgow Coma Scale or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which cannot be entirely attributed to causes other than cerebral vasospasm. It is centrally adjudicated by the Clinical Event Committee (CEC) based on a written charter and review of clinical data, case narratives, angiograms and Computed Tomography scans.
    End point type
    Primary
    End point timeframe
    Up to 14 days post-study drug initiation
    End point values
    		 Clazosentan Placebo
    Number of subjects analysed
    202
    204
    Units: subjects
    32
    35
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs Placebo
    Comparison groups
    Clazosentan v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7338
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    0.072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.426
         upper limit
    		 0.396

    Secondary: Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation

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    End point title
    		 Occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation
    End point description
    A clinical relevant cerebral infarction was defined as: all-cause cerebral infraction greater than or equal to 5 cm^3 or cerebral infarction less than 5 cm^3 in participants with clinical deterioration due to delayed cerebral ischemia. Cerebral infarction refers to new or worsened infarcts and was determined by a central radiology review comparing the total volume of infarcts on the computed tomography (CT) scan performed 16 days after study drug initiation with the total volume on the CT scan performed just prior to randomization.
    End point type
    Secondary
    End point timeframe
    At Day 16 post study drug initiation
    End point values
    		 Clazosentan Placebo
    Number of subjects analysed
    202
    204
    Units: subjects
    15
    23
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs Placebo
    Comparison groups
    Clazosentan v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.177
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    0.341
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.213
         upper limit
    		 0.642

    Secondary: Long-term Clinical Outcome Assessed by the Modified Rankin Scale (mRS) at Week 12 Post-aneurysmal Subarachnoid Hemorrhage (aSAH)

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    End point title
    		 Long-term Clinical Outcome Assessed by the Modified Rankin Scale (mRS) at Week 12 Post-aneurysmal Subarachnoid Hemorrhage (aSAH)
    End point description
    The modified Rankin Scale (mRS) was used to measure the degree of disability in participants who had a ruptured saccular aneurysm and were at a high risk of developing a delayed cerebral infarction (DCI). The mRS is scored by the physician. The mRS scores ranged from 0 (no symptoms) to 6 (dead). The mRS score was dichotomized into poor outcome (score greater and equal to 3) and good outcome (score less than 3).
    End point type
    Secondary
    End point timeframe
    At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)
    End point values
    		 Clazosentan Placebo
    Number of subjects analysed
    202
    204
    Units: Subjects
        Subjects with a mRS score of equal and greater
    50
    41
        Subjects with a mRS score of less than 3
    152
    163
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs placebo
    Comparison groups
    Clazosentan v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1983
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    -0.254
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 0.107

    Secondary: Long-term Clinical Outcome Assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 Post-aSAH

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    End point title
    		 Long-term Clinical Outcome Assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 Post-aSAH
    End point description
    The Glasgow Outcome Scale - Extended (GOSE) is a scale scored by the physician. The GOSE scores range from 1 (dead) to 8 (upper good recovery). The long-term clinical outcome assessed by the GOSE was dichotomized into poor outcome (score ≤ 4) and good outcome (score > 4).
    End point type
    Secondary
    End point timeframe
    At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)
    End point values
    		 Clazosentan Placebo
    Number of subjects analysed
    202
    204
    Units: Subjects
        Subjects with a GOSE score ≤ 4
    50
    41
        Subjects with a GOSE score > 4
    152
    163
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs placebo
    Comparison groups
    Clazosentan v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1983
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    -0.254
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 0.107

    Other pre-specified: Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation (Safety Analysis Set)

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    End point title
    		 Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation (Safety Analysis Set)
    End point description
    Clinical deterioration due to delayed cerebral ischemia was defined as a worsening of at least 2 points compared to the reference score, on the modified Glasgow Coma Scale or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which could not be entirely attributed to causes other than cerebral vasospasm. It was centrally adjudicated by the Clinical Event Committee (CEC) based on a written charter and review of clinical data, case narratives, angiograms and computed tomography (CT) scans.
    End point type
    Other pre-specified
    End point timeframe
    Up to 14 days post-study drug initiation
    End point values
    		 Clazosentan (safety set) Placebo (safety set)
    Number of subjects analysed
    207
    199
    Units: Subjects
    32
    35
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs. placebo
    Comparison groups
    Clazosentan (safety set) v Placebo (safety set)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5591
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    0.119
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.349
         upper limit
    		 0.425

    Other pre-specified: Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Including Rescue Therapy for Non-relevant Vasospasm

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    End point title
    		 Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Including Rescue Therapy for Non-relevant Vasospasm
    End point description
    Clinical deterioration due to delayed cerebral ischemia wa defined as a worsening of at least 2 points compared to the reference score, on the modified Glasgow Coma Scale or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which could not be entirely attributed to causes other than cerebral vasospasm. It was centrally adjudicated by the Clinical Event Committee (CEC) based on a written charter and review of clinical data, case narratives, angiograms and Computed Tomograph (CT) scans.
    End point type
    Other pre-specified
    End point timeframe
    Up to 14 days post-study drug initiation
    End point values
    		 Clazosentan Placebo
    Number of subjects analysed
    202
    204
    Units: Subjects
    34
    47
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs placebo
    Comparison groups
    Clazosentan v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1179
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    0.267
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.085
         upper limit
    		 0.505

    Other pre-specified: Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Based on Neurological Scales and Death

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    End point title
    		 Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Based on Neurological Scales and Death
    End point description
    Clinical deterioration due to delayed cerebral ischemia was defined as a worsening of at least 2 points compared to the reference score, on the modified Glasgow Coma Scale or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which could not be entirely attributed to causes other than cerebral vasospasm. It was centrally adjudicated by the Clinical Event Committee (CEC) based on a written charter and review of clinical data, case narratives, angiograms and Computed Tomograph (CT) scans.
    End point type
    Other pre-specified
    End point timeframe
    Up to 14 days post-study drug initiation
    End point values
    		 Clazosentan Placebo
    Number of subjects analysed
    202
    204
    Units: Subjects
    28
    33
    Statistical analysis title
    		 Relative Risk Reduction: Clazosentan vs placebo
    Comparison groups
    Clazosentan v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5217
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative Risk Reduction
    Point estimate
    0.139
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.365
         upper limit
    		 0.457

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were considered treatment-emergent, if the onset date was from the start of the first infusion on Day 1 to up to 24 hours after study treatment discontinuation. Study treatment was planned for up to 14 days.
    Adverse event reporting additional description
    202 subjects were randomized and treated with clazosentan, an additional 5 subjects that had been randomized to placebo received at least one infusion of clazosentan.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Clazosentan 15 mg/h
    Reporting group description
    		 Subjects that received at least one infusion of clazosentan 15 mg/hour.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Clazosentan 15 mg/h Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 207 (15.94%)
    26 / 199 (13.07%)
         number of deaths (all causes)
    7
    3
         number of deaths resulting from adverse events
    5
    1
    Vascular disorders
    Distributive shock
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Aneurysm repair
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incision site discharge
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    4 / 207 (1.93%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    4 / 207 (1.93%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral microinfarction
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral vasoconstriction
         subjects affected / exposed
    13 / 207 (6.28%)
    12 / 199 (6.03%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delayed ischaemic neurological deficit
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    3 / 207 (1.45%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posthaemorrhagic hydrocephalus
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas aeruginosa meningitis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Clazosentan 15 mg/h Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    156 / 207 (75.36%)
    140 / 199 (70.35%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 207 (7.25%)
    14 / 199 (7.04%)
         occurrences all number
    16
    14
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 207 (6.28%)
    9 / 199 (4.52%)
         occurrences all number
    13
    9
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    24 / 207 (11.59%)
    20 / 199 (10.05%)
         occurrences all number
    24
    20
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 207 (4.83%)
    26 / 199 (13.07%)
         occurrences all number
    10
    28
    Hypotension
         subjects affected / exposed
    18 / 207 (8.70%)
    7 / 199 (3.52%)
         occurrences all number
    18
    9
    Nervous system disorders
    Cerebral vasoconstriction
         subjects affected / exposed
    22 / 207 (10.63%)
    39 / 199 (19.60%)
         occurrences all number
    27
    56
    Headache
         subjects affected / exposed
    31 / 207 (14.98%)
    23 / 199 (11.56%)
         occurrences all number
    42
    24
    Intracranial pressure increased
         subjects affected / exposed
    13 / 207 (6.28%)
    5 / 199 (2.51%)
         occurrences all number
    13
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 207 (5.80%)
    8 / 199 (4.02%)
         occurrences all number
    14
    8
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    42 / 207 (20.29%)
    35 / 199 (17.59%)
         occurrences all number
    44
    38
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    32 / 207 (15.46%)
    28 / 199 (14.07%)
         occurrences all number
    37
    34
    Nausea
         subjects affected / exposed
    17 / 207 (8.21%)
    6 / 199 (3.02%)
         occurrences all number
    17
    6
    Vomiting
         subjects affected / exposed
    17 / 207 (8.21%)
    6 / 199 (3.02%)
         occurrences all number
    19
    6
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    15 / 207 (7.25%)
    3 / 199 (1.51%)
         occurrences all number
    15
    3
    Pulmonary oedema
         subjects affected / exposed
    12 / 207 (5.80%)
    2 / 199 (1.01%)
         occurrences all number
    12
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 207 (6.76%)
    11 / 199 (5.53%)
         occurrences all number
    14
    11
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    7 / 207 (3.38%)
    10 / 199 (5.03%)
         occurrences all number
    8
    10
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 207 (2.90%)
    10 / 199 (5.03%)
         occurrences all number
    6
    10
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    13 / 207 (6.28%)
    6 / 199 (3.02%)
         occurrences all number
    13
    7
    Urinary tract infection
         subjects affected / exposed
    25 / 207 (12.08%)
    24 / 199 (12.06%)
         occurrences all number
    25
    24
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    25 / 207 (12.08%)
    31 / 199 (15.58%)
         occurrences all number
    28
    37
    Hyponatraemia
         subjects affected / exposed
    33 / 207 (15.94%)
    29 / 199 (14.57%)
         occurrences all number
    34
    31

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2019
    Protocol version 3 - Substantial amendment, dated 4 December 2018, to align the protocol with the IB Version 14 which had been amended to address requests received from the US FDA: • Restrictions were made concerning the contraception and breastfeeding requirements by extending them from 24 hours to 30 days post study treatment discontinuation. • Clarification was provided on certain study procedures and entry criteria, new/revised exploratory endpoints were added, and other minor modifications were done. • The statistical methods section was aligned with the most recent version of the statistical analysis plan.
    07 Feb 2020
    Protocol version 4 - Substantial amendment, dated 07 January 2020, to add a Quality of Life assessment at 24 weeks (6 months) post-aSAH. The main changes are summarized below: • The EQ-5D questionnaire was added at Week 24 post-aSAH. • The EOS visit at the individual subject level was rescheduled to Week 24 post aSAH and the previous EOS visit was renamed ‘Week 12 visit’. • SAE reporting was extended from up to 3 months to up to 6 months. • Clarification on supportive data collection for the primary endpoint was provided. • The rules for rescue therapy usage were clarified.
    14 Aug 2020
    Protocol version 5 - Substantial amendment, dated 2 July 2020, to describe the follow-up and collection of data until Day 14 post-study treatment initiation for subjects who were discharged from the study site prior to Day 14. The main changes are summarized below: • A follow-up visit/phone call was introduced for subjects who were discharged from the study site prior to Day 14 post-study treatment initiation. The data to be collected and recorded during this follow-up were described. • It was explained how subjects who were discharged prior to Day 14 could meet the primary efficacy endpoint based on data collected between discharge and Day 14. • A separate dedicated section was added to describe the observation period for the primary endpoint. • Information concerning image archiving at the study sites was added.
    27 May 2021
    Protocol version 6 - Substantial amendment, dated 29 April 2021, to discontinue recruitment into the early treatment group following a recommendation received from the study IDMC on 2 April 2021. The decision to discontinue recruitment into the early treatment group was not based on a planned interim efficacy analysis, nor on urgent safety observations but a low rate of recruitment into this cohort since the outset of the study, making the contribution of these subjects to the overall study futile.
    15 Mar 2022
    Protocol version 7 - Substantial amendment, dated 18 February 2022, to modify the definition of the main secondary efficacy endpoint and the hierarchical statistical testing strategy related to the other secondary endpoints. The main changes are summarized below: • The main secondary endpoint definition was updated: in addition to the already existing all-cause infarcts ≥ 5 cm3 at Day 16 post-study treatment initiation, clinically relevant infarcts < 5 cm3 were added. The latter were defined as those new or worsened infarcts < 5 cm3 that occurred in subjects with CEC-adjudicated clinical deterioration due to DCI. • The initial definition of the main secondary endpoint, i.e., all cause new or worsened infarcts ≥ 5 cm3 at Day 16 post-study treatment initiation was included as an exploratory endpoint. • In addition, the modified Rankin Scale was formally included in the statistical hierarchical testing strategy, prior to the GOSE.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Recruitment into the study was temporarily on hold due to the pandemic. The IRT system was inactive during the temporary recruitment hold.
    05 Jun 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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