E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe traumatic Brain Injury (TBI) with GCS < 13 |
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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] - Injuries, poisonings, and occupational diseases [C21] |
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 | 10060690 |
E.1.2 | Term | Traumatic brain injury |
E.1.2 | System Organ Class | 100000004863 |
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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 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. |
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E.2.2 | Secondary 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 |
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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: - 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;
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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: - 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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) |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During hospitalization, at discharge and during six months of 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 undergoing the trial |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |