CSF Leak
Conditions
Keywords
fibrin sealant, CSF leak
Brief summary
The purpose of this study is to evaluate the safety and efficacy of EVICEL® when used for suture-line sealing in dura-mater closure in elective or urgent paediatric cranial neurosurgery to provide intraoperative watertight closure.
Detailed description
This is a prospective randomized, open-label, multi-center controlled study evaluating the effectiveness of EVICEL® as an adjunct to sutured dural closure compared to control to obtain an intraoperative watertight dural closure. Paediatric subjects, undergoing elective or urgent craniotomy/craniectomy for pathological processes in the posterior fossa (such as benign or malignant tumors, vascular malformations, and Chiari 1 malformations) or in the supratentorial region and who were demonstrated to have persistent cerebrospinal fluid (CSF) leakage following a primary attempt at suture closure of the dural incision. Paediatric subjects for this study are classified as: * Newborn infants (birth to 27 days. Pre-term newborn infants born ≤ 37 weeks gestation will be included within the group) * Infants and toddlers (28 days to \<24 months) * Children (2 to 11 years) * Adolescents (12 to \<18 years) 42 paediatric subjects with intra-operative cerebrospinal fluid (CSF) leak following primary suturing of the dura will be randomized in a 2:1 allocation ratio and will be stratified by surgical procedure, posterior fossa or supratentorial to either EVICEL® Fibrin Sealant (Human) or additional dural sutures. Subjects will be followed post-operatively through discharge and for 30 days (±3 days) post-surgery. The incidence of CSF leaks will be assessed within 5 days (± 2 days) and 30 days (±3 days) post-operatively as detected by any of the following: clinical observation, diagnostic testing or the need for surgical intervention to treat a CSF leak or pseudomeningocele.
Interventions
BIOLOGICALEVICEL® Fibrin Sealant
Subjects randomized to receive EVICEL® Fibrin Sealant (Human), a thin layer will be applied to the entire length of the suture line and the adjacent area to at least 5mm away, including all suture holes.
OTHERSutures Only
Subjects randomized to Control (Additional Sutures) will receive additional dural repair sutures applied immediately to the dural suture line after randomization as deemed necessary by the surgeon.
Sponsors
Ethicon, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
* Patient undergoing elective or urgent craniotomy/craniectomy for pathological processes in the posterior fossa (such as benign or malignant tumors, vascular malformation, and Chiari 1 malformations) or in the supratentorial region and who are demonstrated to have persistent CSF leakage following primary attempt at suture closure of the dural incision; * Administration of perioperative antibiotic prophylaxis; * Patients who are less than 18 years of age; * Patients who are able and willing to comply with the procedures required by the protocol; * The subject's parent/legal guardian must be willing to give permission for the subject to participate in the trial, and provide written informed consent for the subject. In addition, assent must be obtained from paediatric subjects who possess the intellectual and emotional ability to comprehend the concepts involved in the trial. * Surgical wound classification Class I (refer to Appendix II). Penetration of mastoid air cells during partial mastoidectomy is permitted; * The cuff of native dura along the craniotomy edge on each side is wide enough based on surgeon's judgment to facilitate suturing and to allow for sufficient surface area for adherence of the investigational product.
Exclusion criteria
* Subjects with a dura lesion from a recent surgery that still has the potential for CSF leakage; * Conditions or treatments significantly compromising the immune system (such as AIDS); * Known hypersensitivity to the components (human fibrinogen, arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride, human thrombin, human albumin, mannitol and sodium acetate) of the investigational product; * Hydrocephalus, except occlusive hydrocephalus caused by posterior fossa pathology to be treated. * Existing CSF (ventricular, etc.) drains, shunts, Cushing/Dandy cannulation or Burr holes which damage the dura; * Female subjects of childbearing potential with a positive urine or serum pregnancy test within 24 hours prior to surgery; * Female subjects who are breastfeeding or intend to become pregnant during the clinical study period; * Participation in another clinical trial with exposure to another investigational drug or device within 30 days prior to enrollment or expected during the study period; * Scheduled or foreseeable surgery within the follow-up period. * Dura injury during craniotomy/craniectomy that cannot be eliminated by widening the craniotomy/craniectomy to recreate the native dura cuff; * Use of implants made of synthetic materials coming into direct contact with dura (e.g., PTFE patches, shunts, ventricular and subdural drains); * Planned use of dural patches after primary suture closure of the dura; * Placement of Gliadel Wafers; * Persistent signs of increased brain turgor; * Patient has a gap between durotomy edges of greater than 2mm after primary dural closure. * Intersecting durotomy scars in the surgical path from a previous operation that cannot be completely removed by the planned dura resection; * Two or more separate dura defects; * Major intraoperative complications that require resuscitation or deviation from the planned surgical procedure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Success (Intraoperative Watertight Closure) in the Treatment of Intraoperative Cerebrospinal Fluid (CSF) Leakage | Intraoperative (up to 1 day) | Percentage of participants with success (intraoperative watertight closure) in the treatment of intraoperative CSF leakage were reported. Success is defined as no CSF leakage from dural repair intraoperatively, during Valsalva Maneuver 20-25 centimeters (cm) water (H2O) for 5-10 seconds. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing CSF Leakage Within 7 Days Post-operatively | Up to 7 days post-operatively | Number of participants experiencing CSF leakage within 7 days post-operatively were reported. |
| Number of Participants Experiencing CSF Leakage Within 33 Days Post-operatively | Up to 33 days post-operatively | Number of participants experiencing CSF leakage within 33 days post-operatively were reported. |
| Number of Participants With Adverse Events (AEs) | Up to 33 days | An adverse event was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE (also referred to as an adverse experience) could be any unfavorable and unintended sign, symptom, or disease temporarily associated with the use of a drug, without judgment about causality. Since post-operative pain was an expected outcome of this type of surgery, for purposes of this study, only exacerbations of expected post-operative pain based on the investigator's judgment was reported as an AE. |
| Number of Participants With Surgical Site Infections (SSI) According to National Healthcare Safety Network (NHSN) Criteria Within 33 Days Post-operatively | Up to 33 days | Number of participants with SSI according to NHSN criteria within 33 days post-operatively were reported. NHSN CRITERIA states that infections occur within 33 days after the operation and infection involves only skin or subcutaneous tissue of the incision and at least one of the following: a) Purulent drainage, with or without laboratory confirmation, from the superficial incision; b) Organisms isolated from an aseptically obtained culture or fluid or tissue from the superficial incision; c) At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat and superficial incision is deliberately open by surgeon, unless incision is culture-negative; d) Diagnosis of superficial incisional SSI by the surgeon or attending physician. |
Countries
United Kingdom
Participant flow
Pre-assignment details
One participant was randomized to 'Sutures Only' arm but received EVICEL, and hence this participant was analyzed in the 'Sutures Only' arm for efficacy analysis (full analysis set \[FAS\]) and in the EVICEL arm for safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| EVICEL Fibrin Sealant Participants who underwent craniectomy or craniotomy and had an intra-operative cerebrospinal fluid (CSF) leak, received up to 2 applications (maximum 4 layers) of EVICEL; applied to cover the entire length of the suture line and the adjacent area to at least 5 millimeters (mm) away, including all suture holes. | 25 |
| Sutures Only (Control) Participants who underwent craniectomy or craniotomy and had an intra-operative CSF leak, received additional dural repair sutures as deemed necessary by the surgeon. | 15 |
| Total | 40 |
Baseline characteristics
| Characteristic | EVICEL Fibrin Sealant | Sutures Only (Control) | Total |
|---|---|---|---|
| Age, Continuous | 9.7 years STANDARD_DEVIATION 4.4 | 9.2 years STANDARD_DEVIATION 4.3 | 9.5 years STANDARD_DEVIATION 4.3 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Male | 14 Participants | 9 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 14 |
| other Total, other adverse events | 22 / 26 | 13 / 14 |
| serious Total, serious adverse events | 5 / 26 | 8 / 14 |
Outcome results
Primary
Percentage of Participants With Success (Intraoperative Watertight Closure) in the Treatment of Intraoperative Cerebrospinal Fluid (CSF) Leakage
Percentage of participants with success (intraoperative watertight closure) in the treatment of intraoperative CSF leakage were reported. Success is defined as no CSF leakage from dural repair intraoperatively, during Valsalva Maneuver 20-25 centimeters (cm) water (H2O) for 5-10 seconds.
Time frame: Intraoperative (up to 1 day)
Population: The full analysis set (FAS) consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EVICEL Fibrin Sealant | Percentage of Participants With Success (Intraoperative Watertight Closure) in the Treatment of Intraoperative Cerebrospinal Fluid (CSF) Leakage | 92.0 Percentage of participants |
| Sutures Only (Control) | Percentage of Participants With Success (Intraoperative Watertight Closure) in the Treatment of Intraoperative Cerebrospinal Fluid (CSF) Leakage | 33.3 Percentage of participants |
Secondary
Number of Participants Experiencing CSF Leakage Within 33 Days Post-operatively
Number of participants experiencing CSF leakage within 33 days post-operatively were reported.
Time frame: Up to 33 days post-operatively
Population: The safety analysis set consisted of all participants who received treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EVICEL Fibrin Sealant | Number of Participants Experiencing CSF Leakage Within 33 Days Post-operatively | 0 Participants |
| Sutures Only (Control) | Number of Participants Experiencing CSF Leakage Within 33 Days Post-operatively | 1 Participants |
Secondary
Number of Participants Experiencing CSF Leakage Within 7 Days Post-operatively
Number of participants experiencing CSF leakage within 7 days post-operatively were reported.
Time frame: Up to 7 days post-operatively
Population: The safety analysis set consisted of all participants who received treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EVICEL Fibrin Sealant | Number of Participants Experiencing CSF Leakage Within 7 Days Post-operatively | 0 Participants |
| Sutures Only (Control) | Number of Participants Experiencing CSF Leakage Within 7 Days Post-operatively | 1 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
An adverse event was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE (also referred to as an adverse experience) could be any unfavorable and unintended sign, symptom, or disease temporarily associated with the use of a drug, without judgment about causality. Since post-operative pain was an expected outcome of this type of surgery, for purposes of this study, only exacerbations of expected post-operative pain based on the investigator's judgment was reported as an AE.
Time frame: Up to 33 days
Population: The safety analysis set consisted of all participants who received treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EVICEL Fibrin Sealant | Number of Participants With Adverse Events (AEs) | 22 Participants |
| Sutures Only (Control) | Number of Participants With Adverse Events (AEs) | 14 Participants |
Secondary
Number of Participants With Surgical Site Infections (SSI) According to National Healthcare Safety Network (NHSN) Criteria Within 33 Days Post-operatively
Number of participants with SSI according to NHSN criteria within 33 days post-operatively were reported. NHSN CRITERIA states that infections occur within 33 days after the operation and infection involves only skin or subcutaneous tissue of the incision and at least one of the following: a) Purulent drainage, with or without laboratory confirmation, from the superficial incision; b) Organisms isolated from an aseptically obtained culture or fluid or tissue from the superficial incision; c) At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat and superficial incision is deliberately open by surgeon, unless incision is culture-negative; d) Diagnosis of superficial incisional SSI by the surgeon or attending physician.
Time frame: Up to 33 days
Population: The safety analysis set consisted of all participants who received treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EVICEL Fibrin Sealant | Number of Participants With Surgical Site Infections (SSI) According to National Healthcare Safety Network (NHSN) Criteria Within 33 Days Post-operatively | 1 Participants |
| Sutures Only (Control) | Number of Participants With Surgical Site Infections (SSI) According to National Healthcare Safety Network (NHSN) Criteria Within 33 Days Post-operatively | 1 Participants |