DOI: 10.5061/dryad.4j0zpc8br
title: Single-arm, open-label, multicenter first in human study to evaluate the safety and performance of Dura Sealant Patch in reducing CSF leakage following elective cranial surgery: The ENCASE trial

description: Objective: The Dural Sealant Patch (DSP) is designed for
 watertight dural closure after cranial surgery. The goal of this
 study is to assess, for the first time, safety and performance of the DSP
 as a means of reducing CSF leakage in patients undergoing elective cranial
 intradural surgery with a dural closure procedure. Design: First
 in human, open-label, single-arm, multicenter study with 360 days (12
 months) follow up.  Setting: Three large tertiary
 reference neurosurgical centers, 2 in the Netherlands and 1 in
 Switzerland.  Participants: Forty patients undergoing elective
 cranial neurosurgical procedures, stratified into 34 supra- and 6
 infratentorial trepanations. Intervention: Each patient received
 one DSP after cranial surgery and closure of the dura mater with sutures.
 Outcome measures: Primary composite endpoint was occurrence of
 one of the following events: postoperative percutaneous CSF leakage,
 intraoperative leakage at 20 cm H2O positive end-expiratory pressure or
 postoperative wound infection. Overall success
 was defined as achieving the primary endpoint in no more than 2
 patients. Secondary endpoints were device related serious adverse events
 (SAEs) or adverse events (AEs), pseudomeningocele and thickness of dura +
 DSP. Additional endpoints were reoperation in 30 days and user
 satisfaction.  Results: No patients met the primary
 endpoint. No device related (S)AEs were observed. There were two
 incidences of self-limiting pseudomeningocele as confirmed on
 MRI. Thickness of dura and DSP were (mean +/- SD) 3.5 mm +/- 2.0
 at day 7 and 2.1 mm +/- 1.2 at day 90. No patients were re-operated within
 30 days. Users reported a satisfactory design and intuitive application.
 Conclusions: DSP, later officially named Liqoseal, is a safe and
 potentially efficacious device for reducing CSF leakage after intracranial
 surgery, with favorable clinical handling characteristics. A randomized
 controlled trial is needed to assess Liqoseal efficacy against the best
 current practice for reducing postoperative CSF leakage. Strengths and
 limitations The trial studies a device to prevent postoperative
 cerebrospinal fluid (CSF) leakage, which is one of the most common
 neurosurgical complications. The study protocol was performed in multiple
 centers, registered, pre-published and strictly followed. The composite
 endpoint of the trial reduced the number of inclusions needed. The study
 did not involve a comparison to current clinical standard and has a
 potential selection bias, so generalization of results with regard to DSP
 efficacy needs to be cautiously undertaken.
description: <strong>In
 this dataset all raw data considering the ENCASE study, methods described
 below, are included in different tables, including patient
 characteristics, procedure characteristics, postoperative variables, AE
 and SAE's</strong> This study was conducted as an open-label, single-arm, multicenter study. The study was performed in accordance with the Medical Device Directive (MDD 93/42/EEC and MEDDEV 2.7/3 rev. 3; 2015), MEDDEV 2.7/4, World Medical Association Declaration of Helsinki and ISO 14155:2011. The ENCASE protocol was approved by the Medical Ethical Commission in Utrecht, the Netherlands (NL64477.041.18), the Dutch Inspection for healthcare and youth (IGJ) and the Swiss Medical ethical board (BASEC 2018-01073).  The study was registered on clinicaltrials.gov under NCT03566602. The study coordinator and investigators followed accredited GCP training and the study was performed according to GCP regulations.  <b>Setting</b> Three large, tertiary reference neurosurgical centers, 2 in the Netherlands and 1 in Switzerland. <strong>Patients</strong> Forty adult patients scheduled for elective cranial surgery with a dural opening of minimal 2 cm were enrolled for this study. At the 3 individual study centers patients were screened for participation. Patients needing an intradural drain, electrodes or other devices passing the dura mater after surgery were excluded. All patients gave written consent. Alternatives were discussed, and patients were specifically informed that this was the first clinical application of this device. We stratified into 34 supra- and 6 infratentorial trepanations.  <b>DSP</b> DSP (Liqoseal, Polyganics, Groningen) is a flexible patch and consists of two layers: the adhesive layer (white) and the sealing layer (blue). The white adhesive layer is foam-shaped and consists of bioresorbable co-polyester. The white foam covalently bonds to the dura due to the incorporated PEG-NHS adhesive component and buffer salt. This layer reacts with amines in the dural tissue in a moist environment, forming covalent bonds between the device and the tissue. <b>Procedure</b> Minimally 2 surgeons per center participated in the trial; all were individually trained on the protocol. Before dura mature closure, the Positive End Expiratory Pressure (PEEP) was increased to 20 cm H2O for 20 seconds to check for hemostasis. The dura mater was then closed by suturing with the intention for watertight closure. However, a maximal dural gap of 3 mm was accepted.  A substitute (autologous tissue only) could be used by the discretion of the surgeon.   The Positive End Expiratory Pressure (PEEP) was increased for the second time to 20 cm H2O for 20 seconds to verify saline or CSF leakage out of the dural closure.   Each patient then received one DSP after closure of the dura mater. The patch had to overlap the dural opening for at least 5 mm, and was slightly compressed with a moist gauze for 2 minutes. Exactly 2 minutes after finishing compression, the Positive End Expiratory Pressure (PEEP) was increased to 20 cm H2O for 20 seconds for the third time. The surgeon assessed CSF leakage during and after this PEEP increase until skin closure. All procedures were filmed and stored on file.  <b>Follow up</b> Follow-up of the subjects was performed clinically at day 7 (or at discharge, whichever came first) and at 30, 90 and 360 days after implantation. Additionally, subjects underwent an MRI on Day 7 or discharge (whichever came first) and on day 90. All imaging was evaluated and scored by an independent neuroradiologist. The study was controlled and monitored by a clinical research organization (CRO), Genae (Antwerpen, Belgium). <b>Endpoints</b> <i>Primary endpoints:</i> Primary composite endpoint was defined as the occurrence of one of the following events: Incidence of wound infection within 30 days as defined in accordance with Centers for Disease Control and Prevention guidelines for superficial incisional, deep incisional and organ space infections (<i>safety endpoint</i>)  Incidence of intra-operative CSF leakage after patch application at 20 cmH<sub>2</sub>O of PEEP (<i>efficacy endpoint</i>) Incidence of percutaneous CSF leak confirmed by β-2 transferrin test up to 30 days after surgery (<i>efficacy endpoint</i>) <i>Secondary endpoints: </i> Incidence of device related SAEs and AEs throughout the study up to 360 days after surgery. (<i>safety endpoint</i>) Incidence of wound infections up to 90 days after surgery. (<i>safety and efficacy endpoint</i>) Incidence of percutaneous CSF leak up to 90 days after surgery. (<i>efficacy endpoint</i>) Incidence of pseudomeningocele with the need of puncture, external lumbar drainage or surgical evacuation as assessed by treating physician up to 90 days after surgery Incidence of pseudomeningocele &gt;20 cc as confirmed on MRI. (<i>efficacy endpoint</i>) Thickness dura mater and Dura Sealant Patch (combined) in mm analyzed with MRI. (<i>safety endpoint</i>) <i>Additional endpoints</i>: Incidence of complication requiring a re-intervention up to 30 days after surgery. (<i>safety endpoint</i>) Ease of use and application of the DSP (closed end questionnaire) (<b>Appendix 2</b>) <b>Statistics</b> The primary (composite) endpoint was scored ‘yes’ if any of the primary outcome events occurred, and ‘no’ otherwise. This binary outcome was assumed to follow a binomial distribution. Overall study success was defined as the proportion meeting the primary endpoint in 7% or less in the study population, based on previously reported complication rates<sup>1,2,4,13</sup>. Therefore, the number of patients experiencing the primary outcome measure would have to be no more than 2 for study success. The sample size calculation was based on using a confidence interval approach for one proportion (exact Clopper-Pearson). Based on an expected proportion of 7% on scoring ‘yes’ on the primary composite endpoint, and a target width of 0.20, a 95% confidence interval of 0.012-0.209 is obtained with a sample size of 35. Allowing for 12.5% drop out, we aimed to recruit 40 patients for this study. <b>Monitoring and Data Safety Management Board (DSMB)</b> Details on data management and safety were published before.<sup>11</sup> <sup> </sup>Monitoring was provided by a professional independent clinical research organization (CRO, Genae, Antwerp, Belgium). The monitor verified all critical data points against the source documents and issued electronic queries for the authorized clinical site personnel to respond.  A critical quality control was performed for the first 2 subjects at each site. A full quality control was performed on the monitored data throughout the clinical investigation and queries were issued where needed. This process was repeated till the end of the clinical investigation so as to allow for a timeline freezing of the database for statistical analysis. An independent Data Safety Monitoring Board (DSMB) The DSMB reviewed all data relating to safety and performance, had a final say on study continuation thereby ensuring the safety, scientific validity and merit of the study. DSMB analysis was performed after 5 patients accomplished 30-day follow-up, after 10 patients accomplished 30-day follow-up, at study enrollment completion, at 90-day follow-up completion and at 360-day follow-up completion. At the end of the study all investigators had access to the final dataset.