Fibrin Sealant for the Sealing of Dura Sutures

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate the efficacy and safety of FS VH S/D 500 s-apr, a double virus-inactivated biological two-component fibrin sealant, for use in posterior fossa surgery as an adjunct to dura and dura substitute sutures in preventing postoperative cerebrospinal fluid (CSF) leakage.

Official Title
-----------------
An Exploratory Phase 2 Study Evaluating the Efficacy and Safety of Fibrin Sealant, Vapor Heated, Solvent/Detergent Treated (FS VH S/D) 500 S-APR for the Sealing of Dura Defect Sutures in Posterior Fossa Surgery

Conditions
-----------------
Pathological Processes in the Posterior Fossa, Dura Defects

Intervention / Treatment
-----------------
* Biological: Fibrin Sealant, Vapor Heated, Solvent/Detergent-treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr)
* Procedure: Standard of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Preoperative Inclusion Criteria: Subjects undergoing elective craniotomy / craniectomy for pathological processes in the posterior fossa (such as benign and malignant tumors, vascular malformations, and Chiari 1 malformations) that result in dura defects requiring dura substitution for closure and who are able and willing to comply with the procedures required by the protocol Signed and dated written informed consent from the subject or from his/her legal representative prior to any study-related procedures Age >= 3 years, either gender Intraoperative Inclusion Criteria: Surgical Wound Classification Class I and Risk Index Category (RIC) <= 2. Penetration of mastoid air cells during partial mastoidectomy is permitted and will be recorded. A patch of autologous fascia or pericranium or suturable collagen-based dura substitute was cut to size and then sutured into the dura defect. The hem of native dura exposed along and under the craniotomy edge is wide enough to facilitate suturing and to allow for sufficient surface area for adherence of the investigational product. Exclusion Criteria: Preoperative Exclusion Criteria: Female subjects who are breastfeeding, pregnant, or intend to become pregnant during the clinical study period Subjects with a dura lesion from a recent surgery that still has the potential for cerebrospinal fluid (CSF) leakage unless it can be expected that the lesion will be excised completely, including all old suture holes Chemotherapy scheduled within 7 days following surgery Radiation therapy to the head scheduled within 7 days following surgery Subjects with severely altered renal (serum creatinine > 2 mg/dL) and/or hepatic function [ALT, AST > 5 x upper limit of norm (ULN)] Evidence of an infection indicated by any one of the following: fever > 101°F, white blood cell (WBC) count < 3500/μL or > 13000/μL, positive blood culture, positive chest X-ray. A positive urine culture (> 10^5 colony-forming units (CFU)/mL) leads to exclusion unless acute cystitis is the sole cause. Evidence of infection along the planned surgical path. A WBC count of < 20000/μL is permitted if the patient is being treated with steroids in the absence of all the other infection parameters. Conditions compromising the immune system; existence of autoimmune disease Known hypersensitivity to aprotinin or other components of the investigational product Non-compliant or insufficient treatment of diabetes mellitus [glycosylated hemoglobin (HbA1c) > 7.5%] Hydrocephalus, except occlusive hydrocephalus caused by posterior fossa pathology to be treated Existing CSF (ventricular, etc.) drains. Burr holes are permitted as long as the dura remains intact. Cushing cannulation excludes the subject. Female subjects of childbearing potential with a positive urine or serum pregnancy test within 24 hours prior to surgery Participation in another clinical trial with exposure to another investigational drug or device within 30 days prior to enrollment Scheduled or foreseeable surgery within the follow-up period Intraoperative Exclusion Criteria: Dura injury during craniotomy / craniectomy that cannot be eliminated by recreating a sufficiently wide native dura hem Failure to administer preoperative antibiotic prophylaxis Use of implants made of synthetic materials coming into direct contact with dura (e.g., polytetrafluoroethylene (PTFE) patches, shunts, ventricular and subdural drains) Placement of Gliadel wafers Chiari 1 subjects without injury to the arachnoid Persistent signs of increased brain turgor Use of product(s) other than FS VH S/D 500 s-apr for the sealing of dura sutures, including packing with Gelfoam Brain surface visible between suture loops as a manifestation of increased suture tension CSF leakage from completed dura sutures presenting as dripping drops, growing beads or running trickles. Slight oozing is consistent with successful dura repair and will not lead to exclusion. Intersecting durotomy scars in the surgical path from a previous operation that cannot be completely removed by the planned dura resection Dura lesion from a recent surgery that cannot be completely excised, including all old suture holes Two or more separate dura defects Major intraoperative complications that require resuscitation or deviation from the planned surgical procedure

Ages Eligible for Study
-----------------
Minimum Age: 3 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FS VH S/D 500 s-apr<br>Application of FS VH S/D 500 s-apr on top of suture | Biological: Fibrin Sealant, Vapor Heated, Solvent/Detergent-treated with 500 IU/mL thrombin and synthetic aprotinin (FS VH S/D 500 s-apr)<br>* Application of a thin layer of FS VH S/D 500 s-apr to the entire length of the suture loop and the adjacent area to at least 5 mm away from the suture line, including all suture holes. After application, the product is to be allowed to polymerize for 3 minutes.<br>* Other names: FS VH S/D 500 s-apr (a double virus-inactivated biological two-component fibrin sealant);|
| Active Comparator: Standard of Care (Control group)<br>The treatment of the control group consisted of Standard of Care (SoC) which was defined as the closure of a dura defect by suturing in a patch of autologous fascia, pericranium or suturable collagen based dura substitute. | Procedure: Standard of care<br>* Standard care: defined as the closure of a dura defect by suturing in a patch of autologous fascia, pericranium or suturable collagen-based dura substitute.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Cerebrospinal Fluid (CSF) Leakage Observed After Surgery | Study-relevant CSF leakage is defined as one or more of following: Discrete subcutaneous or subgaleal CSF collection (pseudomeningocele) in surgical area confirmed by positive test for β2-transferrin, or by computed tomography (CT) or magnetic resonance imaging (MRI) Epidural CSF collection in surgical area depicted by CT or MRI Leakage of CSF through surgical wound observed during physical examination, confirmed by a positive test for β2-transferrin Progressive pneumatocephalus (air in subarachnoidal space) depicted by repeat CT in absence of CSF drainage. | 33 +/- 3 days after surgery | 
| Number of Participants With Cerebrospinal Fluid (CSF) Leakage Observed After Surgery | Study-relevant CSF leakage is defined as one or more of following: Discrete subcutaneous or subgaleal CSF collection (pseudomeningocele) in surgical area confirmed by positive test for β2-transferrin, or by computed tomography (CT) or magnetic resonance imaging (MRI) Epidural CSF collection in surgical area depicted by CT or MRI Leakage of CSF through surgical wound observed during physical examination, confirmed by a positive test for β2-transferrin Progressive pneumatocephalus (air in subarachnoidal space) depicted by repeat CT in absence of CSF drainage. | 33 +/- 3 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Procedures Resulting From the Treatment of CSF Leaks | The incidence of surgical revisions, number and duration of compression bandage applications and of liquor drainage procedures | until resolution or 30 days after final follow-up visit (Day 33+/-3), whichever is first | 
| Number of Participants With Procedures Resulting From the Treatment of CSF Leaks | The number of participants with surgical revisions, number and duration of compression bandage applications and of liquor drainage procedures. | until resolution or 30 days after final follow-up visit (Day 33+/-3), whichever is first | 
| Incidence of Surgical Site Infections (SSI) According to National Nosocomial Infection Surveillance (NNIS) Criteria |  | within 1 month following surgery | 
| Number of Participants With Surgical Site Infections (SSI) According to National Nosocomial Infection Surveillance (NNIS) Criteria |  | within 1 month following surgery |