Cerebrospinal Fluid Leaks
Conditions
Keywords
CSF leaks, Skull base surgery, pseudomeningocele, TachoSil®, Prevention, post-operative
Brief summary
The primary objective is to demonstrate superiority of TachoSil® compared to current practice as an adjunct in sealing the dura mater. The efficacy of the dura mater sealing must be evaluated post-operatively. The secondary objective is to evaluate the safety of TachoSil® as an adjunct in sealing the dura mater. The trial population will consist of 726 randomised (1:1) patients elected for skull base surgery. The trial duration consists of screening, surgery, efficacy follow-up after 7±1 weeks and safety follow-up 28±2 weeks after surgery.
Interventions
PROCEDURETachoSil®
Primary suture must be performed. Duraplasty may be performed at the discretion of the investigator. TachoSil® must be applied under aseptic conditions during the closure of the dura.
PROCEDURECurrent Practice
Primary suture must be performed. Duraplasty may be performed at the discretion of the investigator. In addition to primary suture, whatever means of dura closure deemed necessary by the investigator may be used with the exception of TachoSil®.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria (Positive response): • Is the surgical approach/procedure consistent with skull base surgery? I.e. one of the following: * Lateral approach to the foramen magnum: Far lateral, extreme lateral, anterolateral, posterolateral * Approach to the jugular foramen: Infratemporal, juxta condylar, transjugular * Approach to the cerebello pontine (CP) angle and petrous apex retrosigmoid * Approach to the middle fossa: Subtemporal (+/- petrous apex drilling), pterional approach (any fronto temporal approach +/- orbitozygomatic deposition) * Approach to the anterior fossa: Subfrontal (uni or bilateral) * Approach to the midline posterior fossa Main
Exclusion criteria
(Negative response): * Has the patient been subject to neurosurgery involving opening of the dura mater within the last 3 months? * Is the patient anticipated to undergo any additional neurosurgery involving opening of the dura mater which may affect the efficacy evaluation (e.g. re-operation or anticipation to undergo several neurosurgeries) before the Efficacy Follow-up Week 7±1 week? * Is the patient anticipated to undergo any additional neurosurgery involving opening of the dura mater which may affect the safety evaluation (e.g. re-operation or anticipation to undergo several neurosurgeries) before the Safety Follow-up Week 28±2 weeks? * The surgical approach/procedure is consistent with any transcranial or transfacial or combination of transcranial - transfacial approaches with wide defect in the skull base? I.e. any of the following: * Trans basal approach * Total petrosectomy * Trans facial approach * Trans sphenoidal approach * Endoscopic procedures * Trans oral approach (and any extension: Le Fort, mandibulotomy) * The surgical approach is consistent with one of the following approaches? * Translabyrinthine approach * Retrolabyrinthine approach * Transcochlear (limited transpetrosal) approach * Did the arachnoid membrane and the CSF containing system remain intact during surgery? * Does the patient have more than one dura opening (not including dura openings from extraventricular or lumbar drains)? * Has TachoSil, fibrin or polymer sealants been used during the current surgery prior to randomization?
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinically Evident Verified Post-Operative Cerebrospinal Fluid Leak or Clinically Evident Pseudomeningocele or Treatment Failure | Up to 8 Weeks (7 Weeks ± 1 Week) | An assessment was performed daily from randomization to Day of Discharge and at the Efficacy Follow-up visit at week 7 ± 1 week. Clinically evident cerebrospinal fluid leak was confirmed by: 1. Glucose concentration test and/or 2. β-2-transferrin test. A clinically evident pseudomeningocele was considered to be present post-operatively if the following criteria were fulfilled: 1. A subcutaneous, visible/palpable fluctuant fluid accumulation was noted at the site of the surgical incision or adjacent to it; 2. It is suspected the fluid accumulation is cerebrospinal fluid. A treatment failure was defined as application of a new and/or different treatment after application of the study treatment or a third application of (or part of) the selected study treatment on the outside of the dura. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Post-Surgical Non-Clinically Evident Post-Operative Pseudomeningocele | Assessment at least once prior to discharge from neurosurgical ward, with the expected discharge from neurosurgical ward after an average of 10 days (Up to 28 Weeks) | Non-clinically evident pseudomeningocele was defined as a cerebrospinal fluid accumulation found on a postoperative computerized tomography (CT) or magnetic resonance imaging (MRI) scan which fulfilled the following criteria according to the radiologist assessment before Day of Discharge: CT Scan-Fluid accumulation seen as Hypodense signal, MRI Scan-Fluid accumulation seen as Hypointense signal in T1-weighted image and/ OR Fluid accumulation seen as Hyperintense signal in T2-weighted image. |
Countries
Austria, Belgium, France, Germany, Greece, Italy, Netherlands, Poland, Russia, Spain, Sweden
Participant flow
Recruitment details
Participants took part in the study at thirty-five Centres in a total of 10 countries: Belgium, France, Germany, Greece, Italy The Netherlands, Poland, Russia, Spain and Sweden from 28 April 2011 to 27 June 2013.
Pre-assignment details
Participants requiring dura sealing techniques for the prevention of post-operative cerebrospinal fluid (CSF) leaks were enrolled; 726 participants were randomized equally in 1 of 2 treatment groups, TachoSil® or Current practice group.
Participants by arm
| Arm | Count |
|---|---|
| TachoSil® Primary suture was performed. Duraplasty could be performed at the discretion of the investigator. TachoSil® was applied under aseptic conditions during the closure of the dura. | 361 |
| Current Practice Group Primary suture was performed. Duraplasty could be performed at the discretion of the investigator. In addition to primary suture, whatever means of dura closure treatment, alone or in combination, as deemed necessary by the investigator was used with the exception of TachoSil®. | 365 |
| Total | 726 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Fatal Adverse Event | 19 | 23 |
| Overall Study | Lost to Follow-up | 8 | 7 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Request By the Patient to Discontinue | 5 | 7 |
Baseline characteristics
| Characteristic | Current Practice Group | TachoSil® | Total |
|---|---|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 14.22 | 53.1 years STANDARD_DEVIATION 13.8 | 53.1 years STANDARD_DEVIATION 14 |
| Age, Customized 18-65 years | 293 participants | 288 participants | 581 participants |
| Age, Customized >65 years | 72 participants | 73 participants | 145 participants |
| Body Mass Index (BMI) | 26.42 kg/m^2 STANDARD_DEVIATION 5.1 | 26.20 kg/m^2 STANDARD_DEVIATION 4.44 | 26.31 kg/m^2 STANDARD_DEVIATION 4.79 |
| Fertility Status Fertile | 74 participants | 74 participants | 148 participants |
| Fertility Status Not Applicable | 154 participants | 128 participants | 282 participants |
| Fertility Status Post-Menopausal | 111 participants | 140 participants | 251 participants |
| Fertility Status Surgically Sterile | 26 participants | 19 participants | 45 participants |
| Height | 168.5 cm STANDARD_DEVIATION 9.18 | 167.4 cm STANDARD_DEVIATION 9.44 | 168.0 cm STANDARD_DEVIATION 9.32 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 62 participants | 55 participants | 117 participants |
| Race/Ethnicity, Customized Non-Hispanic and Non-Latino | 289 participants | 295 participants | 584 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Unknown | 14 participants | 11 participants | 25 participants |
| Race/Ethnicity, Customized White/Caucasian | 361 participants | 355 participants | 716 participants |
| Region of Enrollment Belgium | 87 participants | 87 participants | 174 participants |
| Region of Enrollment France | 26 participants | 24 participants | 50 participants |
| Region of Enrollment Germany | 29 participants | 33 participants | 62 participants |
| Region of Enrollment Greece | 38 participants | 34 participants | 72 participants |
| Region of Enrollment Italy | 14 participants | 14 participants | 28 participants |
| Region of Enrollment Netherlands | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Poland | 61 participants | 59 participants | 120 participants |
| Region of Enrollment Russian Federation | 8 participants | 9 participants | 17 participants |
| Region of Enrollment Spain | 54 participants | 54 participants | 108 participants |
| Region of Enrollment Sweden | 46 participants | 44 participants | 90 participants |
| Sex: Female, Male Female | 211 Participants | 233 Participants | 444 Participants |
| Sex: Female, Male Male | 154 Participants | 128 Participants | 282 Participants |
| Weight | 75.2 kg STANDARD_DEVIATION 16.79 | 73.6 kg STANDARD_DEVIATION 14.4 | 74.4 kg STANDARD_DEVIATION 15.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 92 / 362 | 102 / 364 |
| serious Total, serious adverse events | 94 / 362 | 97 / 364 |
Outcome results
Primary
Percentage of Participants With Clinically Evident Verified Post-Operative Cerebrospinal Fluid Leak or Clinically Evident Pseudomeningocele or Treatment Failure
An assessment was performed daily from randomization to Day of Discharge and at the Efficacy Follow-up visit at week 7 ± 1 week. Clinically evident cerebrospinal fluid leak was confirmed by: 1. Glucose concentration test and/or 2. β-2-transferrin test. A clinically evident pseudomeningocele was considered to be present post-operatively if the following criteria were fulfilled: 1. A subcutaneous, visible/palpable fluctuant fluid accumulation was noted at the site of the surgical incision or adjacent to it; 2. It is suspected the fluid accumulation is cerebrospinal fluid. A treatment failure was defined as application of a new and/or different treatment after application of the study treatment or a third application of (or part of) the selected study treatment on the outside of the dura.
Time frame: Up to 8 Weeks (7 Weeks ± 1 Week)
Population: Full Analysis Population included all enrolled randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TachoSil® | Percentage of Participants With Clinically Evident Verified Post-Operative Cerebrospinal Fluid Leak or Clinically Evident Pseudomeningocele or Treatment Failure | 6.9 percentage of participants |
| Current Practice Group | Percentage of Participants With Clinically Evident Verified Post-Operative Cerebrospinal Fluid Leak or Clinically Evident Pseudomeningocele or Treatment Failure | 8.2 percentage of participants |
p-value: 0.485Regression, Logistic
Secondary
Percentage of Participants With Post-Surgical Non-Clinically Evident Post-Operative Pseudomeningocele
Non-clinically evident pseudomeningocele was defined as a cerebrospinal fluid accumulation found on a postoperative computerized tomography (CT) or magnetic resonance imaging (MRI) scan which fulfilled the following criteria according to the radiologist assessment before Day of Discharge: CT Scan-Fluid accumulation seen as Hypodense signal, MRI Scan-Fluid accumulation seen as Hypointense signal in T1-weighted image and/ OR Fluid accumulation seen as Hyperintense signal in T2-weighted image.
Time frame: Assessment at least once prior to discharge from neurosurgical ward, with the expected discharge from neurosurgical ward after an average of 10 days (Up to 28 Weeks)
Population: Full Analysis Population included all enrolled randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TachoSil® | Percentage of Participants With Post-Surgical Non-Clinically Evident Post-Operative Pseudomeningocele | 3.0 percentage of participants |
| Current Practice Group | Percentage of Participants With Post-Surgical Non-Clinically Evident Post-Operative Pseudomeningocele | 3.0 percentage of participants |