The NoSeal Trial - Nasal Outcome Study Evaluating Artificial Leak-Sealing: A Prospective, Randomized, Controlled, Single-Blinded, Single-Center Clinical Trial Comparing Fibrin Glue (Tisseel®) and a Two-Component Synthetic Polymer Sealant (PEI/PEG, Adherus®) Versus No Sealant for the Prevention of Cerebrospinal Fluid Leak and Promotion of Wound Healing Following Endonasal Skull Base Surgery, Designed in Accordance With the SPIRIT 2025 Guidelines
Phase: NA
Conditions: CerebroSpinal Fluid (CSF) Leak
Sponsor: Maria Sklodowska-Curie National Research Institute of Oncology

 
 
 
 
 
 
 
 
Date of the document 23.07.2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
The NoSeal Trial – Nasal Outcome Study Evaluating Artificial Leak-Sealing: 
A Prospective, Randomized, Controlled, Single-Blinded, Single-Center 
Clinical Trial Comparing Fibrin Glue (Tisseel®) and a Two-Component 
Synthetic Polymer Sealant (PEI/PEG, Adherus®) Versus No Sealant for the 
Prevention of Cerebrospinal Fluid Leak and Promotion of Wound Healing 
Following Endonasal Skull Base Surgery, Designed in Accordance with the 
SPIRIT 2025 Guidelines 
 
 
 
Protocol ID: NIO-NS2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
STUDY PROTOCOL 
The NoSeal Trial – Nasal Outcome Study Evaluating Artificial Leak-Sealing: 
A Prospective, Randomized, Controlled, Single-Blinded, Single-Center 
Clinical Trial Comparing Fibrin Glue (Tisseel®) and a Two-Component 
Synthetic Polymer Sealant (PEI/PEG, Adherus®) Versus No Sealant for the 
Prevention of Cerebrospinal Fluid Leak and Promotion of Wound Healing 
Following Endonasal Skull Base Surgery, Designed in Accordance with the 
SPIRIT 2025 Guidelines 
 
Wojciech Czyżewski1,2, Mateusz Jeżewski1, Barbara Buchalska3, Tomasz Szalniński1, Asta 
Zielińska1, Anna Rzehak1, Klaudia Kus-Budzynska4, Tomasz Mandat1, Jacek Kunicki1 
 
1 Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, ul. W.K. 7 Roentgena 5, 02-
781 Warsaw, Poland 
2 Department of Didactics and Medical Simulation, Medical University of Lublin, 20-954 Lublin, Poland 
3 Student society of Warsaw Medical University 
4 Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, 20-954 Lublin, Poland 
 
 
ABSTRACT 
 
Introduction 
 
Postoperative cerebrospinal fluid (CSF) leak is a significant complication of endoscopic 
endonasal approaches (EEA) to the skull base. The use of tissue sealants such as fibrin glue 
(Tisseel) or synthetic agents (PEI/PEG) is widespread in surgical practice, however, recent 
high-quality evidence challenges their clinical benefit and cost-effectiveness. This study aims 
to investigate whether the routine use of sealants in patient with peri-operatively assessed low 
CSF leak risk, significantly improves outcomes over no sealant use, to guide more cost-
effective, evidence-based closure strategies. To the best of our knowledge, the present study is 
the first randomized clinical trial to evaluate the necessity and comparative effectiveness of 
fibrin and synthetic sealants versus no sealant in preventing postoperative CSF leaks following 
endoscopic endonasal surgery in low-post operative CSF leak risk patients. 
 
 
Materials and Methods 
 
This is a prospective, randomized, controlled, single-center clinical trial conducted at 
the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland. 
Adult patients scheduled for endoscopic endonasal surgery (EES) will first undergo screening 
based on medical history and detailed radiological evaluation. Those who meet all predefined 
inclusion and exclusion criteria will be enrolled and randomized preoperatively using a 
computer-generated allocation sequence into one of three treatment arms: (1) no sealant 
(standard multilayer closure), (2) fibrin glue application (Tisseel®), or (3) synthetic 
polyethylene glycol-based sealant (Adherus®). Following randomization, surgery will be 
performed in accordance with the assigned intervention. The primary endpoint is the incidence 
of postoperative cerebrospinal fluid (CSF) leak within 3 months. Secondary outcomes include 
endoscopic evaluation of mucosal healing at 6 weeks and 3 months, postoperative complication 
rates (e.g., meningitis, pneumocephalus), reoperation rate, patient-reported quality of life, and 
a cost-effectiveness analysis comparing sealant use to standard closure. 

 
The study is designed and will be reported in accordance with the SPIRIT 2025 
(Standard Protocol Items: Recommendations for Interventional Trials) guidelines to ensure 
methodological transparency and reproducibility. 
 
Results 
 
Initial enrollment includes a target of 225 patients (75 per arm). Interim data analysis 
focuses on early healing parameters, safety profiles, and cost metrics. Hypothesis testing will 
determine if either sealant significantly reduces CSF leak rates compared to no sealant and 
whether the marginal benefit justifies routine use in all patients. Exploratory endpoints include 
biomaterial handling characteristics and surgeon-reported usability. 
 
Conclusion 
 
The NoSeal Trial addresses a critical gap in evidence regarding the necessity and 
comparative performance of sealants in skull base reconstruction. By evaluating both clinical 
outcomes and economic impact, the study seeks to optimize surgical protocols and improve the 
safety and efficiency of endonasal neurosurgical procedures. 
 
Keywords 
Endoscopic endonasal surgery – pituitary surgery- CSF leak - Skull base repair - Fibrin glue - 
Synthetic polymer sealant - PEI/PEG - Mucosal healing ·  
 
 
 
1. INTRODUCTION 
 
Postoperative cerebrospinal fluid (CSF) leaks remain a notable complication of 
endoscopic endonasal surgery (EES), contributing to increased risks of meningitis, reoperation, 
and extended hospital stay[1]. Although tissue sealants such as fibrin glue (Tisseel®) and 
synthetic polyethylene glycol-based polymers (e.g., Adherus®) are frequently employed to 
reduce leak rates, evidence suggests that in experienced, high-volume centers, their use may be 
unnecessary. Moreover, comparative data on the effectiveness and clinical utility of these 
sealants remain limited. The NoSeal Trial aims to determine whether adjunctive sealants 
provide measurable benefit over standard multilayer closure without sealants, and to assess their 
overall clinical value and cost-effectiveness. 
 
 
2. MATERIALS AND METHODS 
 
Primary Objective 
 
To compare the incidence of postoperative CSF leaks within 3 months among patients 
receiving: 
1. No sealant (standard multilayer closure- GROUP A)  
2. Fibrin glue (Tisseel® – GROUP B) 
3. Two-component synthetic polymer sealant (PEI/PEG – Adherus® – GROUP C) 
 
Secondary Objectives 
a) Assess mucosal healing at 4 weeks and 3 months postoperatively (endoscopic grading) 
b) Evaluate rates of postoperative complications (e.g., meningitis, pneumocephalus, CSF 
leak) 
c) Analyze cost-effectiveness of each closure strategy 
d) Record revision surgery rate 

e) Assess patient-reported quality of life (VAS, SNOT-22) 
 
Exploratory Analysis: 
 
a) Post hoc stratification by CSF leak occurrence to create subgroups: A1 (leak), A2 (no 
leak), B1, B2, C1, C2 
 
b) Correlation between laboratory results, imaging (pre-op MR and post-op CT), 
intraoperative findings, and outcome 
 
Study Design and Setting 
Prospective, randomized, controlled single-center clinical trial conducted at the National 
Institute of Oncology Maria Skłodowska-Curie, Warsaw, Poland. 
 
Inclusion Criteria 
a) Age ≥ 18 years 
b) Undergoing endoscopic endonasal surgery for skull base pathology 
c) Informed written consent obtained 
d) Hemodynamic and electrolyte stability prior to surgery 
e) Surgery expected to be completed without high-flow intraoperative CSF diversion 
techniques 
 
Exclusion Criteria 
a) Re-do surgery or complex reconstruction techniques (e.g., extended EEA with 
cribriform or clival defects) 
b) Pathology that initially requires extended approach and complexed sella reconstruction 
c) Preoperative hydrocephalus  
d) Allergy to fibrin or polymer sealant components 
e) Active sinus infection or systemic inflammatory condition 
f) Prior radiotherapy to the sellar/parasellar region 
g) Uncontrolled diabetes mellitus (HbA1c > 7.0%) 
h) Participation in another interventional trial interfering with wound healing or CSF 
assessment 
i) Radiologic signs of chronic intracranial hypo/hypertension 
 
 
 
 
 
 
 
 
 
 
 
 
 

Participant timeline: Schedule of enrollment, interventions, and assessments according to 
SPIRIT 2025 Guidelines.  
 
TRIAL PERIOD 
Enrollment 
Post-
randomization 
 
 
 
 
TIME POINT 
-48h to 0 
0 (surgery) 
t₁ = Day 
2 
t₂ = Day 
5-7 
t₃ = Day 
30 
t₄ = Day 
90 
ENROLLMENT: 
 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Baseline data 
collection 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
INTERVENTIONS:  
 
 
 
 
 
Tisseel (Group A) 
 
X 
 
 
 
 
Adherus (Group B) 
 
X 
 
 
 
 
No sealant (Group C) 
 
X 
 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
Demographics, 
medical history 
X 
 
 
 
 
 
Laboratory checklist 
X 
 
X 
 
 
X 
Imaging checklist 
X 
 
X 
 
 
 
Intraoperative 
findings 
 
X 
 
 
 
 
Surgical procedure 
checklist  
 
X 
 
 
 
 
CSF leak observation 
 
X 
X 
X 
X 
X 
Endoscopic healing 
assesment 
 
 
X 
 
X 
X 
SNOT-22 
 
 
X 
X 
X 
X 
VAS 
X 
 
X 
X 
X 
X 
Adverse 
events/infection 
 
 
X 
X 
X 
X 
Reoperation 
 
 
 
 
 
 
 
 
 
 
 
Randomization and Groups 
 
Eligible patients will be initially enrolled in the trial preoperatively based on medical 
history and radiological imaging assessment. Final allocation to treatment arms will be 
performed intraoperatively using a computer-generated randomization sequence via the free 
academic software Randomizer for Clinical Trials (https://www.randomizer.at/). 
 
Group A: No sealant (standard closure) 
Group B: Fibrin glue (Tisseel)  
Group C: Synthetic PEI/PEG sealant (Adherus)  
 
 
Secondary analyses will stratify patients in each arm (A–C) according to the presence 
or absence of postoperative cerebrospinal fluid (CSF) leak, resulting in analytical subgroups 

A1–A2, B1–B2, C1–C2. These subgroups will be used for post hoc analysis of outcomes, 
including mucosal healing, quality of life (SNOT-22), and cost-effectiveness 
 
 
PERIOPERATIVE ASSESSMENT 
 
A) Demographics, medical history 
B) Preoperative Imaging Checklist (MRI-based) of features that predispose to 
CSF leak 
 
MRI Finding 
Clinical Significance 
Tumor size with suprasellar extension 
Increased risk of herniation into subarachnoid 
space 
Diaphragm penetration ('mushroom sign') 
High risk of breaching the CSF compartment 
Absent or atrophic diaphragma sellae 
No anatomical barrier to prevent leakage 
No visible suprasellar cistern (absent 
arachnoid cap) 
Tumor adheres to chiasm or brainstem 
Depressed or absent chiasmatic cistern 
Risk of opening cisternal space during 
resection 
Acute, tapered angle between tumor and 
cistern 
Suggests tension and arachnoid membrane 
vulnerability 
Heterogeneous enhancement, cysts, necrosis 
Tumor collapse after resection → secondary 
leak 
Displaced or obscured pituitary stalk 
Risk of superior structure injury and hormonal 
complications 
Extensive sphenoid sinus pneumatization 
(sellar type) 
Difficult reconstruction due to lack of bony 
support 
Thinned or absent sellar bony floor 
Potential leakage into sphenoid sinus 
Visible CSF cap or persistent fluid spaces 
above tumor 
Evidence of prior or chronic microleaks 
Presence of arachnoid cyst above tumor or 
near chiasm 
Additional risk of CSF compartment violation 
 
C) Postoperative Imaging (CT checklist) 
Assessment Area 
Signs 
Clinical Significance 
Pneumocephalus 
Presence of intracranial air, 
especially in the chiasmatic 
cistern, lateral ventricles, or 
above the tentorium 
Indicates communication with 
CSF space, i.e., an open leak 
Fluid levels in sphenoid or 
ethmoid sinus 
Air-fluid levels or isolated 
fluid in the sphenoid sinus 
May indicate leakage into the 
sinus 
Thickened mucosa of the 
sphenoid sinus 
Edema, exudate, opacification Could be secondary to 
chronic leak or infection 
Presence of reconstructive 
materials 
Fat, sponge, flap – presence 
and position 
Absence or displacement may 
suggest reconstruction failure 
Fluid in the sella 
Hypodense content in the 
sella turcica 
May represent persistent CSF 
leak into the cavity 
Additional CSF collections 
Hypodense areas near the 
tentorium or Sylvian fissure 
Accumulation of CSF due to 
leakage 
Displacement of pituitary, 
stalk, or chiasm 
Downward shift or 
deformation 
May reflect collapsed cistern 
due to CSF leak 
Connection between sphenoid 
sinus and nasal cavity 
Evaluation of possible fluid 
pathway 
May indicate anterior skull 
base leak 

 
D)  Laboratory Assessment: 
 
Test 
Preoperative (Day -1) 
Postoperative (Day 
1–2) 
Follow-up (Day 90) 
CRP 
X 
X 
 
ESR 
X 
 
 
Leukocytes (WBC) 
X 
X 
X 
NLR 
(Neutrophil/Leukocyte 
Ratio) 
X 
X 
X 
Platelets (PLT) 
X 
 
 
INR 
X 
 
 
APTT 
X 
 
 
Fasting glucose 
X 
X 
 
HbA1c 
X 
 
 
Sodium (Na) 
X 
X 
X 
Potassium (K) 
X 
X 
X 
Chloride (Cl) 
X 
X 
 
Serum osmolality 
X 
X 
 
Urine osmolality 
 
X 
 
Daily diuresis 
 
X 
 
Total protein 
X 
 
X 
Albumin 
X 
 
X 
Procalcitonin (PCT) 
X 
X 
 
Cortisol (8:00) 
X 
X 
X 
ACTH 
X 
X 
X 
FT4 
X 
X 
X 
TSH 
X 
X 
X 
Prolactin 
X 
X 
X 
IGF-1 
X 
X 
X 
LH 
X 
X 
X 
FSH 
X 
X 
X 
Estradiol/Testosterone 
X 
X 
X 
 
E) Intraoperative findings 
a) Intraoperative CSF leak observed (Keller, Esposito scale) 
b) Large or irregular sellar floor defect 
c) Tumor adherence to arachnoid/chiasm 
d) Arachnoid herniation into the sella 
e) Invasion of the cavernous sinus 
f) Difficult hemostasis at skull base 
g) Extended surgical time (>3 hours) 
 
F) CSF leak observation  
a) Clinical signs of CSF leak through the whole trial 
b) Endoscopic evaluation (day 2, 30 and 90 post-op) 
G) Endoscopic healing assessment 
a) Endoscopic evaluation (day 2, 30 and 90 post-op) – Lund-Kennedy Scale 
H) Assessment of patient symptoms and quality of life with Sino-Nasal Outcome 
Test (SNOT-22) (day 2, 7, 30 and 90 post-op) 

I) Pain assessment - Visual Analogue Scale (VAS)  (day 0, 2, 7, 30 and 90 post-
op) 
J) Observation for adverse effects 
K) Need for revision surgery 
 
Interventions 
 
All patients will undergo a standard multilayer closure using mucosal flap, and 
haemostatics (Surgicel, Tachosil). Sealants (Tisseel or Adherus) will be applied only in 
intervention arms. Lumbar drainage will not be routinely used. 
 
Outcomes 
 
Primary Endpoint 
 
 
Incidence of postoperative CSF leak within 90 days 
 
Secondary Endpoints 
 
a) Endoscopic mucosal healing score at 4 weeks and 3 months 
b) Occurrence of infectious/inflammatory complications 
c) Hospital length of stay 
d) Need for reoperation 
e) Cost analysis of sealant use 
f) Patient quality of life (VAS and SNOT-22 scores) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Procedures 
 
 
 
Statistical analysis 
 
 
All statistical analyses will be conducted using the Statistica software (ver. 13.3, TIBCO 
Software Inc., Palo Alto, CA, USA). Baseline characteristics will be summarized using 
descriptive statistics. Continuous variables will be presented as means ± standard deviations 
(SD) or medians with interquartile ranges (IQR), depending on distribution assessed by the 
Shapiro–Wilk test. Categorical variables will be expressed as counts and percentages. 
 
Primary Outcome: 
 
 
The incidence of postoperative cerebrospinal fluid (CSF) leak within 90 days will be 
compared among the three groups (no sealant, fibrin glue, synthetic sealant) using the Chi-
square test or Fisher’s exact test, as appropriate. A log-binomial regression with robust error 
variance will be used to calculate relative risk (RR) and 95% confidence intervals (CI), 
adjusting for key baseline covariates (e.g., tumor size, suprasellar extension). 
 
Secondary Outcomes: 
 
 
Mucosal healing (graded endoscopically at weeks 4 and 12) will be analyzed using the 
Kruskal–Wallis test or ordinal logistic regression. 
 
Complication rates (e.g., meningitis, pneumocephalus) will be compared using Chi-
square tests. 

 
Patient-reported outcomes (VAS, SNOT-22) will be analyzed using repeated-measures 
ANOVA or linear mixed-effects models. 
Subgroup Analysis: 
 
A post hoc stratified analysis will be conducted within each treatment group to compare 
outcomes in patients with versus without postoperative CSF leak (e.g., A1 vs A2, B1 vs B2, C1 
vs C2). Interaction effects will be tested using likelihood ratio tests. 
 
Missing Data: 
 
 
Missing data will be handled using multiple imputation by chained equations (MICE) 
under the assumption of missing at random (MAR), with sensitivity analyses to assess the 
impact of missingness. 
 
Statistical Significance: 
 
 
A two-sided p-value <0.05 will be considered statistically significant. No correction for 
multiple comparisons will be applied to exploratory outcomes. 
 
 
Sample Size and Statistical Analysis 
 
Based on published data, the incidence of postoperative cerebrospinal fluid (CSF) leaks 
has been reported to range between 3% and 10%, depending on surgical technique, patient 
selection, and use of adjunctive sealants. 
 
Assuming the following parameters: 
 
Significance level α = 0.05 (two-tailed), 
Statistical power 1–β = 0.80, 
 
An expected absolute difference in CSF leak rate of 7 percentage points (e.g., 10% vs. 
3%), the calculated sample size required to compare two groups using a test for proportions is 
approximately 190 patients per group. 
 
For a comparison across three parallel groups, while accounting for multiple testing and 
maintaining sufficient statistical power, the recommended sample size is approximately 70–80 
patients per group, resulting in a total of 210–240 patients. Thus, the planned sample size will 
include a minimum of 75 patients in each group (225 patients in total). If full recruitment proves 
unattainable, the study may be concluded earlier, and post hoc statistical methods with power 
correction may be applied to ensure valid interpretation of the results. 
 
 
Quality assurance 
 
This clinical trial will be conducted at the Department of Neurosurgery, Maria 
Skłodowska-Curie National Research Institute of Oncology in Warsaw— a tertiary reference 
neurosurgical center in Poland with extensive experience in endoscopic skull base surgery. The 
department is nationally recognized for its excellence in pituitary and anterior skull base 
procedures. All procedures will be carried out by neurosurgeons with high expertise in 
minimally invasive techniques, ensuring consistency, adherence to protocol standards, and 
optimal patient safety. The institution's well-established infrastructure for clinical research and 
postoperative follow-up supports rigorous data collection and quality control throughout the 
trial. 
 

 
Data collection and management 
 
All clinical, radiological, intraoperative, and laboratory data will be collected 
prospectively using standardized electronic case report forms (eCRFs) designed specifically for 
this study. Data will be entered into a secure, password-protected electronic database hosted on 
institutional servers, compliant with GDPR and local data protection regulations. Each 
participant will be assigned a unique study identification number to ensure pseudonymization 
and confidentiality. Source documents, including operative reports, imaging, and laboratory 
results, will be retained for verification and monitoring purposes. 
 
Data entry will be performed by trained study personnel and independently verified by 
a second investigator for accuracy. Quality control procedures will include periodic audits, 
range checks, and logic checks to detect inconsistencies or missing values. Access to the dataset 
will be restricted to authorized study investigators. Any changes to data entries will be tracked 
and documented with audit trails. The final locked dataset will be used for statistical analysis. 
 
Ethics and Registration 
 
This trial was approved by the Bioethics Committee of the National Institute of 
Oncology (33/2025).  
 
It will be conducted in accordance with the Declaration of Helsinki and is planned for 
registration at ClinicalTrials.gov. 
 
3.Discussion 
 
Cerebrospinal fluid (CSF) leakage is one of the most critical and surgeon-dependent 
complications following endoscopic transnasal skull base surgery[2]. Despite advances in 
multilayer reconstruction techniques and vascularized flap design, the occurrence of 
postoperative CSF leak significantly increases the risk of meningitis, prolongs hospitalization, 
and often necessitates reoperation[1]. Various biological and synthetic sealants—such as fibrin 
glue and polymer-based adhesives—are routinely employed in clinical practice to reinforce 
skull base reconstruction[3]. However, their clinical effectiveness in patients with low 
preoperative risk of CSF leak, as compared to standard multilayer closure without sealants, 
remains uncertain and is not well supported by high-quality evidence. 
 
Experimental studies, including animal models, have suggested a potential benefit of 
fibrin sealants in enhancing mucosal graft adhesion strength[4]. Nevertheless, clinical trials 
have yielded conflicting results. Some studies have confirmed the safety profile of synthetic 
sealants like Adherus [5]yet failed to demonstrate a significant reduction in CSF leak rates or 
superiority over conventional techniques. Others, including Mohindra et al. [6] and Ganesh et 
al. [7], reported no statistically significant difference in leak frequency between patients treated 
with and without sealants. Notably, a large prospective cohort study from the University of 
Pittsburgh observed a paradoxically higher CSF leak rate in the sealant group (14%) compared 
to the non-sealant group (6%), further questioning the clinical value of routine sealant use[8]. 
However, they investigated only patients operated diagnosed with CSF leak pre-operatively. 
 
Recent systematic reviews and meta-analyses have reinforced these concerns. Pang et 
al. [3]and Khan et al. [9]independently concluded that the use of sealants does not significantly 
lower CSF leak incidence, while also highlighting the methodological heterogeneity and low 
quality of available evidence. As a result, current surgical practice often relies on institutional 
preferences and individual surgeon experience, rather than on standardized, evidence-based 
guidelines. 
 
The NoSeal Trial addresses a pivotal gap in skull base surgery: whether adjunctive 
sealants provide clinical and economic benefits in patients deemed low-risk for CSF leak. 

Unlike prior studies focused on confirmed intraoperative leaks, our protocol excludes high-risk 
profiles at baseline, aligning with real-world practice in many centers. 
 
Sealants may lead to unintended complications, including foreign body reactions, 
delayed mucosal healing, and tissue necrosis, while also imposing significant additional 
costs [10], [11], [12]. Also, given the lack of clear benefit and the variability in clinical 
outcomes, a cost-effectiveness analysis is warranted. Given the lack of clear benefit and 
variability in reported outcomes, a comprehensive cost-effectiveness analysis is warranted. 
Consequently, the widespread use of sealants in skull base reconstruction requires validation 
through rigorous, high-quality trials. 
 
The absence of demonstrable benefit—and even potential harm—associated with 
sealant use in the Pittsburgh cohort underscores the need for more nuanced, risk-stratified 
trials[8]. By pre-selecting patients without preoperative leaks, we reduce heterogeneity and 
target the true effect of sealants. The randomized comparison between fibrin and synthetic 
sealants, as well as a no-sealant control, addresses limitations in previous head-to-head studies, 
and directly tests whether either sealant offers superior outcomes or is cost-effective compared 
to standard multilayer closure alone. Should our results demonstrate non-inferiority-or 
superiority-of the no-sealant approach, the implications could be practice-changing: promoting 
resource-efficient, evidence-based protocols without undue reliance on adjunct sealants.  
 
Nevertheless, this study has several limitations. As a single-center trial conducted in a 
high-volume, experienced neurosurgical department, the findings may not be generalizable to 
centers with lower surgical caseloads or different levels of expertise. Due to the nature of 
surgical interventions, blinding of the operating surgeons is not feasible, which may introduce 
performance bias. Although patients are randomized preoperatively, actual CSF leak severity 
is determined intra- and postoperatively, potentially resulting in imbalanced distribution of 
high- and low-flow leaks across study arms. Additionally, heterogeneity in tumor pathology, 
size, and invasiveness may influence outcomes despite uniform surgical protocols.  
 
 
Conclusion 
 
The NoSeal Trial addresses a critical evidence gap in the management of cerebrospinal 
fluid (CSF) leaks following endoscopic endonasal skull base surgery. While tissue sealants are 
widely adopted in clinical practice, their routine use has not been supported by high-quality 
comparative data, particularly in low-risk patients undergoing standard multilayer 
reconstruction. By directly comparing fibrin-based and synthetic polymer sealants against no 
sealant, this randomized controlled trial aims to determine whether these adjunctive materials 
confer a meaningful clinical benefit in preventing postoperative CSF leaks and enhancing 
wound healing. 
 
In addition to clinical endpoints, the study evaluates safety, usability, and cost-
effectiveness—key dimensions for guiding evidence-based practice. The revised sample size 
ensures sufficient statistical power to detect clinically significant differences, while the 
standardized surgical protocol enhances the internal validity of findings. Results from the 
NoSeal Trial are expected to establish clinical guidelines, reduce unnecessary healthcare 
expenditures, and contribute to the safe and judicious use of biomaterials in neurosurgical 
reconstruction. 
 
 
 
 
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