E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042320 |
E.1.2 | Term | Subarachnoid hemorrhage |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
DCI: day 1-14 after ictus SAEs: daily during hospitalization |
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E.5.2 | Secondary 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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During hospitalization up to 6 months follow-up |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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Last follow-up (after six months) of the last subject included in the study |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |