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 |
Leak of cerebrospinal fluid during surgery |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024091 |
E.1.2 | Term | Leakage of cerebrospinal fluid |
E.1.2 | System Organ Class | 100000055316 |
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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 |
To evaluate the efficacy of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as an adjunct to sutured dural closure. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as an adjunct to sutured dural closure. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients ≥18 years of age undergoing craniotomy/craniectomy for pathological processes in the PF or ST region
2. Patients must be willing and able to participate in the study and provide written IC before any protocol specific assessment is performed
3. Patients must be willing to receive peri-operative antibiotic prophylaxis
4. Female patients of childbearing potential must present with a negative serum pregnancy test, and must agree to employ adequate birth control measures [restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products] for the duration of their participation in the study
5. Patients are willing and able to comply with the requirements of the protocol
INTRA-OPERATIVE
1. Patients with surgical wound classification Class I
2. The cuff of native dura along the craniotomy edge on each side is adequate, based on surgeon's judgment, to facilitate suturing and to allow for sufficient surface area for adherence of the IP
3. Patient’s CSF leak was present intra-operatively following completion of primary dural closure (with or without non-autologous duraplasty or autologous tissue); either spontaneously or upon Valsalva manoeuver (25 cm H2O for up to 5 - 10 seconds) |
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E.4 | Principal exclusion criteria |
1. Patients with a dural lesion from a recent surgery that still has the potential for CSF leakage
2. Patients who had undergone chemotherapy treatment, excluding hormonal therapy, within 3 weeks prior to the planned procedure, or with chemotherapy scheduled within 7 days following surgery
3. Patients with radiation therapy to the surgical site or standard fractionated radiation therapy scheduled within 7 days following surgery
4. Patients with a previous craniotomy/craniectomy within 6 months prior to the study surgery
5. Use of corticosteroids on a chronic basis (defined as daily use of corticosteroids for ≥8 weeks) for purposes other than decreasing the symptoms of systemic chemotherapy (unless if those steroids were discontinued 4 weeks prior to the planned surgery)
6. Patients with a known hypersensitivity to the components of the IP or control (human fibrinogen, synthetic aprotinin, human albumin, human FXIII, tri sodium citrate, histidine, niacinamide, polysorbate 80, human thrombin, polyethylene glycol [PEG], trilysine amine)
7. Patients with a known hypersensitivity to US Federal Drug & Cosmetic Blue #1 dye
8. Evidence of an infection indicated by any one of the following: clinical examination supporting the diagnosis of infection, fever (temperature >100.7°F or 38.2°C), positive urine culture, positive blood culture, positive chest X ray consistent with pulmonary infection, or infection along the planned surgical path. A white blood cell (WBC) count of <20000 cells/µL is permitted if the patient is being treated with steroids in the absence of all other infection parameters
9. Female patients of childbearing potential with a positive pregnancy test or intent to become pregnant during the clinical study period
10. Female patients who are nursing
11. Patients with exposure to another investigational drug or device clinical trial within 30 days prior to enrolment or anticipated in the 60-day Follow-up period
12. Patients with severely altered renal function as confirmed by local laboratory reference ranges for serum creatinine and/or hepatic function (alanine aminotransferase [ALT], aspartate aminotransferase >3 × upper limit of normal [ULN])
13. Patients who currently have or have had a compromised immune system (such as Acquired Immune Deficiency Syndrome [AIDS]) or autoimmune disease, or were on chronic immunosuppressant agents
14. Patients with uncontrolled diabetes as evidenced by the institution’s standard of care (glycated haemoglobin [HbA1c] >7%, blood glucose, etc.)
15. Patients with traumatic injuries to the head
16. Patients with dural injury during craniotomy/craniectomy that cannot be eliminated by widening the craniotomy/craniectomy to recreate the native dural cuff
17. Patients requiring surgical approaches that would not allow sutured dural closure such as trans-sphenoidal or translabyrinthine/-petrosal/-mastoid. Superficial penetration of mastoid air cells is allowed
18. Patients with hydrocephalus, except occlusive hydrocephalus caused by PF pathology or incompletely open cerebrospinal fluid pathways, to be treated during surgical procedure
19. Existing CSF (ventricular, etc.) drains, Cushing/Dandy cannulation, or Burr holes which damage the dura
20. Patients with confined bony structures where nerves are present and neural compression may result due to swelling
INTRA-OPERATIVE
1. Patient has a gap between durotomy edges of >2 mm after primary dural closure in the judgment of the investigator
2. Patients requiring the use of implants made of synthetic materials coming into direct contact with dura
3. Patient has 2 or more separate dural defects
4. Patients with intersecting durotomy scars in the surgical path from a previous operation that cannot be completely removed by the planned dural resection
5. Placement of Gliadel Wafers
6. Major intra-operative complications that require resuscitation or deviation from the planned surgical procedure
7. Patients in whom application of the Valsalva manoeuver is not found appropriate due to increased safety risk
8. Patients requiring the use of other FSs or PEG-based sealants
9. Patients with any other intra-operative findings identified by the surgeon that may preclude the conduct of the study procedure
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients who have neither of the following:
- Intra-operative CSF leakage from dural repair after up to two FS VH S/D 500 s apr/control applications during Valsalva manoeuvre (25 cm H2O for up to 5 - 10 seconds)
- Post-operative CSF leakage within 30 (+3) days post-operatively
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
intraoperative : 3 Minutes
post-operative : Day 30 (+-3) |
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E.5.2 | Secondary end point(s) |
Efficacy:
- Incidence of intra-operative CSF leakage following final Valsalva manoeuvre
- Incidence of CSF leaks within 30 (+3) days post-operatively
- Time in surgery (minutes)
- Time from dural closure (application of investigational product) until end of surgery
- Length of stay in hospital (days)
Safety:
- Incidence of CSF leaks within 60 (+3) days post-operatively
- Incidence of adverse events (AEs) up to 60 (+3) days post-operatively
- Incidence of surgical site infections (SSIs) according to the United States (US) National Healthcare Safety Network (NHSN) within 30 (+3) days post-operatively
- Number of unplanned interventions within 30 (+3) days post-operatively
- Abnormal laboratory values and vital signs (e.g., elevated white blood cell [WBC] count, fever [temperature >100.7°F or 38.2°C], tachycardia [pulse >100], hypotension [mean arterial pressure <60]) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
day 0 (day of surgery), day 5 (+-2) , day 30 (+-3), day 60 (+-3) |
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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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Integra DuraSeal Dural Sealant System for Cranial Surgery, CE marked Medical Device |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Czech Republic |
Germany |
Poland |
Spain |
United States |
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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 visit last subject (LVLS) |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |