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Clinical Trial Results:
A single blinded, randomized, controlled study to evaluate the safety and effectiveness of EVICEL® Fibrin sealant (Human) compared to a Hydrogel sealant as an adjunct to sutured dural repair

Summary
EudraCT number	2014-003954-15
Trial protocol	GB BE
Global end of trial date	12 Oct 2017

Results information
Results version number	v1(current)
This version publication date	26 Oct 2018
First version publication date	26 Oct 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BIOS-14-002

ISRCTN number

US NCT number

NCT02457546

WHO universal trial number (UTN)

Sponsor organisation name

ETHICON Inc

Sponsor organisation address

Route 22 West, Somerville, United States, 08876

Public contact

Heather Paleczny, Principal Research Scientist, Ethicon, Inc., 1 9082182081, hpaleczn@its.jnj.com

Scientific contact

Dr Richard Kocharian, Sr Medical Director , Ethicon, Inc., 1 9082182031, rkochar1@its.jnj.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Nov 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Oct 2017

Global end of trial reached?

Yes

Global end of trial date

12 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

The objective of this study was to evaluate the safety and efficacy of EVICEL® Fibrin Sealant (Human) for use as an adjunct to sutured dural repair in cranial surgery

Protection of trial subjects

The protocol and consent form were provided to the appropriate ethics committee for review and approval.

Background therapy

Not applicable.

Evidence for comparator

The comparator for this trial was DuraSeal™ Dural Sealant System. The efficacy and safety of DuraSeal™ Dural Sealant System as an adjunct to sutured dural repair to obtain watertight closure during cranial surgery was demonstrated in a prospective multicenter study of 111 patients. DuraSeal™ was 100% effective in obtaining watertight closure. Efficacy was also demonstrated in another multicenter single-blind prospective randomized trial in 237 patients exhibiting non-watertight dural closure during cranial surgery which showed the safety profile of DuraSeal™ to be similar to other commonly used dural closure techniques. DuraSeal™ Dural Sealant System is a commercially available synthetic sealant intended for use as an adjunct to sutured dural repair during cranial surgery to provide watertight closure. The product is a synthetic absorbable sealant composed of a polyethylene glycol (PEG) ester solution and a rilysine amine solution. DuraSeal™ Dural Sealant is approved in the US (since 2005), in EU (since 2003) and in numerous countries world-wide.

Actual start date of recruitment

01 Jun 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 71

Country: Number of subjects enrolled

Belgium: 44

Country: Number of subjects enrolled

Australia: 21

Country: Number of subjects enrolled

New Zealand: 23

Country: Number of subjects enrolled

United States: 75

Worldwide total number of subjects

234

EEA total number of subjects

115

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

171

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The first patient was recruited on 7th July 2015 and the last patient, last visit was 12th October 2017.

Screening details

Prospective patients were screened within 30 days prior to surgery. Prior to any study specific procedures, subjects were fully informed of all aspects of the study, and the consenting process was documented.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Blinding implementation details

This was a single-blinded study where the subject was blinded to treatment. Subjects remained blinded throughout the trial.

Are arms mutually exclusive

Yes

EVICEL® Fibrin Sealant (Human)

Arm description

EVICEL® is a human plasma-derived fibrin sealant consisting of two components: Human Fibrinogen (also named Biologically Active Component 2 (BAC2), and Human Thrombin containing Calcium (EVICEL® Fibrin Sealant (Human).

Arm type

Experimental

Investigational medicinal product name

DuraSeal™ Dural Sealant

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Topical use

Dosage and administration details

For subjects randomized to DuraSeal™, the assigned product was applied to the entire length of the suture line, including all suture holes, according to the manufacturer’s instruction for use. No patient received more than 10ml.

Investigational medicinal product name

EVICEL® Fibrin Sealant (Human)

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Topical use

Dosage and administration details

For each subject, at least one kit of EVICEL® (2ml each of BAC2 and Thrombin [total 4ml]) was pre-prepared in the applicator kit prior to randomization. EVICEL® was to be applied to the surgical site by either spraying or dripping onto the dural suture line. If necessary, a second layer of EVICEL® could be applied. No patient received more than 2 kits (8ml)

DuraSeal™ Dural Sealant

Arm description

DuraSeal™ Dural Sealant System is a synthetic absorbable sealant composed of a polyethylene glycol (PEG) ester solution and a rilysine amine solution used as an adjunct to sutured dural repair during cranial surgery to provide watertight closure.

Arm type

Synthetic Sealant

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	EVICEL® Fibrin Sealant (Human)	DuraSeal™ Dural Sealant
Started	114	120
Completed	105	116
Not completed	9	4
Adverse event, serious fatal	3	2
Physician decision	1	-
Subject refusal to attend further visits	1	1
Lost to follow-up	4	1

Baseline characteristics

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Reporting group title

EVICEL® Fibrin Sealant (Human)

Reporting group description

Reporting group title

DuraSeal™ Dural Sealant

Reporting group description

Reporting group values	EVICEL® Fibrin Sealant (Human)	DuraSeal™ Dural Sealant	Total
Number of subjects	114	120	234
Age categorical
Units: Subjects
Adults (18-64 years)	86	85	171
From 65-84 years	27	33	60
85 years and over	1	2	3
Gender categorical
Units: Subjects
Female	59	59	118
Male	55	61	116

Subject analysis set title

Intent to Treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

Consists of all randomized subjects

Subject analysis set title

Per Protocol

Subject analysis set type

Per protocol

Subject analysis set description

Consists of all ITT subjects who have data available for primary effectiveness endpoint and have no major protocol deviations

Subject analysis set title

Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who receive a study treatment.

Subject analysis sets values	Intent to Treat	Per Protocol	Safety Set
Number of subjects	234	208	234
Age categorical
Units: Subjects
Adults (18-64 years)	171	153	171
From 65-84 years	60	53	60
85 years and over	3	2	3
Age continuous
Units:
	( )	( )	( )
Gender categorical
Units: Subjects
Female	118	102	118
Male	116	106	116

End points

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Reporting group title

EVICEL® Fibrin Sealant (Human)

Reporting group description

Reporting group title

DuraSeal™ Dural Sealant

Reporting group description

Subject analysis set title

Intent to Treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

Consists of all randomized subjects

Subject analysis set title

Per Protocol

Subject analysis set type

Per protocol

Subject analysis set description

Consists of all ITT subjects who have data available for primary effectiveness endpoint and have no major protocol deviations

Subject analysis set title

Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who receive a study treatment.

Primary: Primary Endpoint

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End point title

Primary Endpoint

End point description

The primary endpoint was the proportion of subjects that did not have a CSF leak during surgery and up to the 30 (-/+7)-day post-operative period.

End point type

Primary

End point timeframe

30 days +/- 7 days

End point values	EVICEL® Fibrin Sealant (Human)	DuraSeal™ Dural Sealant	Per Protocol
Number of subjects analysed	102 ^[1]	106 ^[2]	208
Units: Number of successes
Number of successes	95	92	187

Notes
[1] - Per protocol
[2] - Per protocol

Primary Endpoint

Statistical analysis description

The statistical hypothesis for testing the treatment difference is presented as follows:  H0: Δ ≤ ‐0.10 tested against the alternative hypothesis  Ha: Δ > ‐0.10. where:  Δ is the difference between the success rates of Experimental and Control (Experimental minus Control)  ‐0.10 is the non‐inferiority difference  The assumed proportion of successes for Control is 0.95

Comparison groups

EVICEL® Fibrin Sealant (Human) v DuraSeal™ Dural Sealant

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Wald CI

Parameter type

non-inferiority

Point estimate

0.063

Confidence interval

level

97.5%

sides

1-sided

lower limit

-0.018

upper limit

Variability estimate

Standard deviation

Notes
[3] - The study is one-sided, non-inferiority, using the 97.5% level (one sided significance level of 0.025). The primary endpoint is CSF leak to 30 days post-surgery.

Adverse events

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Timeframe for reporting adverse events

AEs were recorded as they were reported, whether spontaneously, volunteered, or in response to questioning about well-being. AEs were collected from the start of randomization during the procedure, through the hospital admission, and until completion

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

EVICEL® Fibrin Sealant

Reporting group description

EVICEL® is a human plasma-derived fibrin sealant. EVICEL® consists of two components: a concentrate of Human Fibrinogen (referred to as Biological Component 2; BAC2) and a solution of Human Thrombin, which incorporates calcium.

Reporting group title

DuraSeal™ Dural Sealant

Reporting group description

DuraSeal™ Dural Sealant is a synthetic absorbable sealant composed of a polyethylene glycol (PEG) ester solution and a rilysine amine solution.

Serious adverse events	EVICEL® Fibrin Sealant	DuraSeal™ Dural Sealant
Total subjects affected by serious adverse events
subjects affected / exposed	32 / 114 (28.07%)	37 / 120 (30.83%)
number of deaths (all causes)	3	3
number of deaths resulting from adverse events	3	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
recurrence of glioblastoma
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
residual right front brain tumor
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
worsening of glioblastoma
subjects affected / exposed	1 / 114 (0.88%)	3 / 120 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
carcinomatosis meningitis
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
glioblastoma disease progression
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
progression of non-small cell lung cancer
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
progression of melanoma brain metastasis
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
recurrence of fronto-parietal tumor
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
residual brain tumor
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
malignant melanoma disease progression
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 114 (0.00%)	2 / 120 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Subgaleal haematoma
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
uncontrolled high blood pressure
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
shortness of breath
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
upper airway edema
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
bilateral pulmonary embolism
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
altered mental status
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
mental status decline
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
raised white cell count
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Pseudomeningocele
subjects affected / exposed	2 / 114 (1.75%)	9 / 120 (7.50%)
occurrences causally related to treatment / all	2 / 2	9 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
right subdural haemorrhage
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
intra-parenchimal haemmorrhage
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
left subdural haemorrhage
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
subcutaneous fluid collection
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
chronic subdural hematoma
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial flutter
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	1 / 114 (0.88%)	5 / 120 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
atypical syncopal episode
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CSF leakage
subjects affected / exposed	3 / 114 (2.63%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
metastatic melanoma L5 compression
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
middle cerebral artery infarct
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
severe headache
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
worsening of dysphasia post operatively
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
headache post-op
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hemorrhagic stroke due to ICH/IVH
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Subdural hygroma
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral oedema
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
grand mal seizures
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MCA divisional infarct
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
worsening headache
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
stroke
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
blind in left eye
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
esophageal bleed
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
small bowel obstruction
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
perforated sigmoid colon
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
kidney stone
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
epidural empyema
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
hospital acquired pneumonia
subjects affected / exposed	1 / 114 (0.88%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonia
subjects affected / exposed	1 / 114 (0.88%)	2 / 120 (1.67%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
post craniotomy deep surgical site infection
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
propionibacterium acnes extradural surgical site infection
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
superficial wound infection
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
post operative wound infection
subjects affected / exposed	0 / 114 (0.00%)	2 / 120 (1.67%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
deep wound infection
subjects affected / exposed	1 / 114 (0.88%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
health care associated pneumonia
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
sepsis unknown origin
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
surgical wound infection [mrsa]
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
multilobar pneumonia
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Lactic acidosis
subjects affected / exposed	0 / 114 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 114 (0.88%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	EVICEL® Fibrin Sealant	DuraSeal™ Dural Sealant
Total subjects affected by non serious adverse events
subjects affected / exposed	103 / 114 (90.35%)	109 / 120 (90.83%)
Injury, poisoning and procedural complications
incisional site pain
subjects affected / exposed	11 / 114 (9.65%)	12 / 120 (10.00%)
occurrences all number	13	12
Procedural pain
subjects affected / exposed	19 / 114 (16.67%)	19 / 120 (15.83%)
occurrences all number	19	20
Wound secretion
subjects affected / exposed	6 / 114 (5.26%)	8 / 120 (6.67%)
occurrences all number	9	9
Vascular disorders
Hypertension
subjects affected / exposed	11 / 114 (9.65%)	12 / 120 (10.00%)
occurrences all number	12	12
Hypotension
subjects affected / exposed	6 / 114 (5.26%)	8 / 120 (6.67%)
occurrences all number	6	9
Cardiac disorders
Tachycardia
subjects affected / exposed	5 / 114 (4.39%)	6 / 120 (5.00%)
occurrences all number	5	6
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 114 (4.39%)	10 / 120 (8.33%)
occurrences all number	5	10
Hemiparesis
subjects affected / exposed	7 / 114 (6.14%)	3 / 120 (2.50%)
occurrences all number	7	3
Headache
subjects affected / exposed	35 / 114 (30.70%)	53 / 120 (44.17%)
occurrences all number	45	62
General disorders and administration site conditions
chest pain
subjects affected / exposed	5 / 114 (4.39%)	6 / 120 (5.00%)
occurrences all number	5	6
Fatigue
subjects affected / exposed	4 / 114 (3.51%)	6 / 120 (5.00%)
occurrences all number	4	6
Pyrexia
subjects affected / exposed	3 / 114 (2.63%)	10 / 120 (8.33%)
occurrences all number	3	11
Gastrointestinal disorders
Nausea
subjects affected / exposed	32 / 114 (28.07%)	29 / 120 (24.17%)
occurrences all number	35	30
Vomiting
subjects affected / exposed	19 / 114 (16.67%)	14 / 120 (11.67%)
occurrences all number	20	15
Constipation
subjects affected / exposed	32 / 114 (28.07%)	29 / 120 (24.17%)
occurrences all number	35	31
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 114 (0.00%)	7 / 120 (5.83%)
occurrences all number	0	7
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	3 / 114 (2.63%)	7 / 120 (5.83%)
occurrences all number	3	7
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	6 / 114 (5.26%)	1 / 120 (0.83%)
occurrences all number	7	1

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Were there any global substantial amendments to the protocol? Yes

12 Feb 2015

Up-dated to clarify inclusion/exclusion criteria. Craniotomy edge up-dated to be based on surgeon's standard practice. Exclusion of radio therapy within 2 years of procedure was removed. Clarified signs/symptoms of systemic infection. Additional text add to provide clarity on subjects with hydrocephalus. Occlusive hydrocephalus patients were originally excluded. Up-dated to "Hydrocephalus, except occlusive hydrocephalus caused by posterior fossa pathology or incompletely open cerebrospinal fluid pathways, to be treated during surgical procedure. Cuff of native dura along craniotomy edge was defined as >=10mm wide was up-dated to remove width and be based on surgeon's standard practice. Typographical error regarding tip size. Corrected from 6cm to 4cm. Laboratory/Coagulation/Pregnancy evaluations moved from screening to baseline. Up-dated to clarify must be conducted within 24 hours of surgery. Up-date to contact list

17 Nov 2015

Introduction Clarify that the referenced clinical studies were multicentre, prospective, controlled, randomized Clarify that the potential neurotoxic effects have been demonstrated in experimental in-vivo studies for QUIXIL/CROSSEAL. Information from clinical studies indicated no particular safety concerns Reference to "Dural repair site" added to paragraph for clarity Introduction stated "for use in tissue adhesion/sealing and suture support in neurosurgery". The word "adhesion" was removed as this is a sealing study only Procedure Section Clarify EVICEL® application + to be more consistent with standard surgical practice. Removal of text defining 5mm margin was required. Cure time between layers was up-dated from allowing polymerization to "allow for the EVICEL® clot formation + stabilization" Clarify that patients treated with EVICEL® could not receive DuraSeal™ or any other PEG based or fibrin sealants Add "cranial" before dural lesion for clarity Refer to OR/theatre rather sterile field Confirm that DuraSeal™ must be removed from OR/theatre (originally referred to as sterile field) Incl/Excl No chemotherapy or radiation therapy within 30 days prior to enrollment. Time frame added to be more consistent with surgical practice Traumatic head injuries up-dated to include “penetrating” traumatic injuries to the head with damage to the dura Included "cranial". Two or more separate "cranial" dural defects Other Up-dated contact list(s) Typographical up-date. Added word "maneuver" after valsalva Reference to unopened vials being stored at 25 days in EU/ANZ removed Lab evaluations up-dated to be within 7 days of procedure Removal of coagulation sample Data analysis up-dated to include two-sided 5% significance Definition of inpatient hospitalization up-dated Source for assessing SUSARs up-dated to include product labelling

16 May 2016

Incl/Excl Up-dated to state that approved fibrin sealants may be used for haemostasis if not in contact with dura Two or more separate cranial dural defects up-dated to include the text “including defects from ventricular cannulation and ventriculo-peritoneal shunting” Procedure Up-dated to confirm that the use of onlays is not allowed if watertight closure is achieved for EVICEL®/DuraSeal™ Up-dated to confirm DuraSeal™ patients should not receive EVICEL® in the study treatment area. Other Number of sites increased from 25 to 30 Up-dates to contact list

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Limitations : None Caveats : As lower limit of two-sided 95% CI for difference in proportions of success (Evicel® minus Duraseal™) (-0.018) is greater than non-inferiority margin (-0.10), the non-inferiority of Evicel® to Duraseal™ is demonstrated.

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Clinical Trial Results: A single blinded, randomized, controlled study to evaluate the safety and effectiveness of EVICEL® Fibrin sealant (Human) compared to a Hydrogel sealant as an adjunct to sutured dural repair

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Primary: Primary Endpoint

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A single blinded, randomized, controlled study to evaluate the safety and effectiveness of EVICEL® Fibrin sealant (Human) compared to a Hydrogel sealant as an adjunct to sutured dural repair