Clinical trial NCT03276975
Conditions: Cerebrospinal Fluid Leaks
Keywords: CT fluoroscopy epidural patching spontaneous intracranial hypotension
Sponsor: Duke University
Start date: 2017-12-18; Completion date: 2020-03-19
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this randomized controlled trial (RCT) is to compare the efficacy of CT fluoroscopy-guided targeted epidural patching for treatment of imaging-confirmed spinal CSF leaks to that of a simulated procedure without patching material in patients with spontaneous intracranial hypotension.

Detailed description:
Spontaneous intracranial hypotension (SIH) is a condition caused by non-iatrogenic spinal CSF leaks that classically presents with orthostatic headaches. These headaches, in conjunction with other presenting symptoms such as nausea, diplopia, tinnitus, and cognitive deficits, often result in profound disability. SIH is considerably underreported due to pervasive misdiagnosis. Thus, while the estimated annual incidence is reported to be 5 in 100,000, the actual number is likely considerably greater.

The current standard-of-care treatment for SIH cases that are refractory to conservative measures (i.e. bed rest and hydration) is percutaneous epidural blood patching (EBP) of the spinal CSF leak. Percutaneous EBP can be performed in several ways: 1) with or without imaging guidance, 2) targeted to a site of known or suspected CSF leak or non-targeted, and 3) with or without the addition of fibrin glue sealant.

The leading theory for the mechanism behind percutaneous EBP treatment of SIH is that it creates a durable seal of the CSF leak resulting in normalization of CSF hydrodynamics and a resultant diminution in symptoms. Fibrin glue, a sealant used for treatment of unintended durotomies during neurosurgery, is thought to improve the likelihood of a successful patch over patches containing blood alone. Therefore, imaging-guided targeted delivery of patching material containing both blood and fibrin glue directly to the site of CSF leak, a novel therapy, is presumed to be the optimal therapy. For this reason, this procedure has become standard-of-care at many tertiary-care institutions over the past several years.

Our group has extensive experience with CT fluoroscopy-guided targeted blood and fibrin glue patching of proven CSF leaks in SIH patients. However, significant uncertainty remains with regard to the efficacy of this procedure due to a paucity of outcomes data and the absence of any prospective RCTs. In fact, nearly all of the current evidence for the treatment of SIH is found in the form of retrospective chart reviews. Given the growing recognition of SIH, the fact that a known subset of patients will have spontaneous resolution of symptoms, and the absence of clear evidence to guide treatment, there is a critical need to evaluate the efficacy of targeted patching with blood and fibrin glue with a prospective RCT. Fulfilling this unmet need forms the basis for this proposal. While determining the efficacy of the other types of EBPs is also important, we aim to begin by evaluating the efficacy of the presumed optimal therapy.

Arms: arm 1: CT fluoroscopy-guided blood and fibrin glue patching targeted to the site of CSF leak. arm 2: Instead of injection of blood and fibrin glue patching material through the needles, an equivalent volume of preservative free sterile Elliots B solution will be injected.
Interventions: intervention 1: TISSEEL
Intervention descriptions: intervention 1: TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in adult and pediatric patients (\>1 month of age) undergoing surgery when control of bleeding by conventional surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical. TISSEEL is effective in heparinized patients

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A randomized trial of CT fluoroscopy-guided targeted autologous blood and fibrin glue 
patching for treatment of cerebrospinal fluid leaks in spontaneous intracranial hypotension 
 
NCT ID: NCT03276975 
Version Date: 10/26/2017 
 
 
 


 
RESEARCH DESIGN AND METHODS (see Schema) 
Patient Selection 
 
Inclusion Criteria: Adult patients meeting International 
Classification of Headache Disorders 3rd Edition (ICHD-3) criteria for a 
diagnosis of SIH (Table 1) who have had a contrast-enhanced brain MRI 
and a myelogram confirming the presence of a CSF leak will be recruited 
from the Duke Radiology spine intervention clinic [25]. 
Exclusion Criteria: (a) recent (i.e., < 2 weeks) blood patch, (b) 
contraindication or inability to undergo the procedure, (c) inability to 
provide informed consent, (d) expected inability to complete follow-up 
assessment, (e) a contraindication to receiving contrast material 
(precluding an epidurogram), or (f) contraindication to receiving fibrin glue (i.e., allergy). We aim to recruit 148 
patients over 2 years. This number is based on the historical number of patients with SIH and confirmed CSF 
leaks treated at Duke, our sample size determination (see Statistics), and previously published studies.  
 
CT Fluoroscopy-Guided Blood and Fibrin Glue Patching 
 
We will employ a single-center, parallel, randomized, blinded, prospective design. Enrolled patients will 
be assigned to one of two treatment arms using a block randomization scheme: CT fluoroscopy-guided blood 
and fibrin glue patching targeted to the site of CSF leak or a simulated procedure without patching material. 
Baseline data will be collected including: (a) symptom profile and duration, (b) headache impact test (HIT-6), 
(c) EQ-5D (a measure of overall health status), and (d) work productivity and activity impairment (WPAI) (see 
Outcomes). All procedures will be performed under CT fluoroscopy on the same scanner (see Resources). The 
location of injection for patients in both arms will be targeted to the site of the CSF leak identified on prior 
imaging (e.g., CT or dynamic myelogram). All procedures will be performed by a board-certified radiologist with 
a CAQ in neuroradiology and at least six years of 
experience in CT fluoroscopy-guided spine 
injections. 
 
Patients in both arms of the study will be 
placed supine on the CT gantry table. Intravenous 
(IV) access will be obtained and sterile autologous 
blood will be acquired for the purposes of possible 
patching. A planning CT scan (120 kVp, automatic 
tube current modulation: 100 – 400 mA, 2.5 mm 
section thickness, gantry rotation time 0.5 seconds) 
will be obtained with z-axis limited to the area of 
interest. Acquired images will be used to plan a 
needle trajectory and approach to the location of 
the CSF leak for targeted patching using previously 
described techniques for CT fluoroscopy-guided 
epidural patching (e.g. a lateral approach trajectory 
to the neuroforaminal epidural space, an oblique 
interlaminar trajectory to the dorsal spinal canal 
epidural space, or an approach traversing the 
neuroforamen to reach the ventral epidural space) 
[14, 26-29]. The skin surface will then be marked, 
sterilized, draped, and anesthetized with 2% 
lidocaine.  At this point, a computer generated 
randomized treatment assignment will be delivered 
to the treating physician in an opaque sealed 
envelope, which will determine if the patient is 
treated with targeted blood and fibrin glue patching 
versus the simulated procedure. Patients and 
outcome assessors will remained blinded to the 
treatment assignment throughout the study. The 
treating physicians are unable to be blinded, as 
Table	1:	ICHD-3	SIH	Diagnos c	Criteria	
A)	Any	headache	fulfilling	criterion	C	
B)	Low	CSF	pressure	(<60	mm	H2O)	and	/	or	
evidence	of	CSF	leakage	on	imaging	
C)	Headache	has	developed	in	temporal	
rela on	to	the	low	CSF	pressure	or	CSF	
leakage,	or	has	led	to	its	discovery	
D)	Not	accounted	for	by	another	ICHD-3	
diagnosis	
Spontaneous	Intracranial	
Hypotension	
CT	or	dynamic	myelogram	
posi ve	for	CSF	leak	
Eligible	pa ents	consented	
Baseline:	HIT-6,	EQ-5D,	
WPAI	
Primary	Endpoint:	
HIT-6	at	1	month	
(reduc on	from		
>	56	to	<	49)	
Assess	for		
Adverse	Events	
MAJOR:	
• 
Stroke,	paralysis,	or	
other	permanent	
neurologic	deficit	
• 
Allergic	reac on	
• 
Hospitaliza on	/	ED	
visit	
	
MINOR:	(see	methods)	
Inclusion	Criteria:	
• 
Adult	
• 
Meets	ICHD-3	SIH	criteria	
• 
MRI	Brain	with	contrast	
• 
Definite	CSF	leak	on	
myelography	
• 
Baseline	HIT-6	>	56	
	
Exclusion	Criteria:		
• 
Contraindica on	or	inability	
to	undergo	procedure	
• 
Recent	blood	patch	(<	2	
weeks)	
• 
Inability	to	provide	informed	
consent	
• 
Expected	inability	to	
complete	follow	up	
• 
Contraindica on	to	contrast	
media	or	fibrin	glue	
CT	flu
o
r oscopy-guided	
targeted	blood	and	
fibrin	glue	patch	
CT	flu
o
r oscopy-guided	
targeted	saline	
injec on	
2	weeks:	HIT-6,	PGIC,		
EQ-5D,	WPAI	
1	months:	HIT-6,	PGIC,		
EQ-5D,	WPAI	
4	months:	HIT-6,	PGIC,		
EQ-5D,	WPAI	
Randomiza on	
1	week	
immediate	
2	weeks:	HIT-6,	PGIC,		
EQ-5D,	WPAI	
1	months:	HIT-6,	PGIC,		
EQ-5D,	WPAI	
4	months:	HIT-6,	PGIC,		
EQ-5D,	WPAI	
Pa ent	Crossover	Allowed	
2	months	
Brain	MRI:		
SIH	findings	
Secondary	Endpoints:	
HIT-6	at	2	weeks	and	
4	months	
	
EQ-5D,	PGIC,	WPAI,	
Duke	Ques onnaire	
at	2	weeks,	1	month,	
4	months	


 
they will be aware of the type of patching material used. The effectiveness of patient blinding will be assessed 
using the Bang Blinding Index prior to discharge on the day of the procedure [30]. 
 
Targeted Patching of CSF Leaks with Blood and Fibrin Glue (Experimental Arm) 
 
For patients randomized to targeted patching with blood and fibrin glue, a 22-gauge 3.5 or 5 inch 
Quincke tip spinal needle will be advanced under intermittent CT fluoroscopic-guidance to the epidural space 
at the target location. On reaching the target, gentle aspiration will confirm absence of blood return. 
Approximately 0.2 mL of contrast material (iopamidol 200 mgI/mL; Isovue-M 200, Bracco Diagnostics Inc., 
Princeton, NJ) will then be injected to assess needle tip position and potential future spread of patching 
material. Intravascular injection will be excluded using a “double-tap” technique (i.e., 2 sets of CT fluoroscopic 
images: an initial image immediately after injection and a second image acquired 2-3 seconds later to assess 
for contrast material washout), as previously described [31]. After visual confirmation of correct needle tip 
position, a mixture of autologous blood (~1 mL) and fibrin glue (~1-3 mL) will be slowly injected. This process 
will be repeated for all planned needle placements. The number of needle placements and total volume of 
blood and fibrin glue will be at the discretion of the treating radiologist, but will be based upon: (a) the extent of 
spread of patching material, (b) mass effect on the thecal sac and neural structures, and (c) patient symptoms. 
On completion of the procedure, the patient will be observed for 2 hours in the radiology post-procedural unit. 
 
Simulated Patching Procedure (Control Arm) 
 
Patients randomized to undergo the simulated patching procedure will have the same experience as 
the patients in the experimental arm, as described above. This includes placement of an IV, acquisition of 
sterile blood for potential autologous patching (which will be discarded rather than used), a planning CT, all of 
the same needle placements that would have been performed if the patient were randomized to the 
experimental arm, and contrast injection for the epidurogram. However, instead of injection of blood and fibrin 
glue patching material through the needles, an equivalent volume of preservative free sterile saline will be 
injected (buffered intrathecal electrolyte/dextrose injection; Elliots B Solution, Lukare Medical, Scotch Plains, 
NJ). On completion of the procedure, the patient 
will be observed for 2 hours in the post-
procedural unit. 
 
Adverse Events  
 
Patients will be screened for adverse 
events immediately after the procedure as well 
as via phone call at one week post-procedure. 
While all adverse events will be recorded, the following will be considered major adverse events: stroke, 
paralysis, or other permanent neurologic deficit; allergic reaction; hospitalization or ED visit. Minor adverse 
events will include, but not be limited to: nausea and/or vomiting, symptomatic hypertension, vasovagal 
reaction, temporary weakness or sensory deficit, and urinary retention. 
 
Patient Outcome Measures and Crossover 
Headache Impact Test (HIT-6): A validated headache assessment tool with good internal consistency and test-
retest reliability that is designed to provide a global measure of headache impact in six domains [32]. Scores 
range from 36 (asymptomatic) to 78 (severe headache).  Score ranges: 36-49 (little or no headache impact), 
50-55 (some impact), 56-59 (substantial impact), and >60 (severe impact) [33, 34]. Prior studies have 
determined that the minimally important clinical difference between groups is 1.5 points for the HIT-6 [35]. 
EQ-5D: A standardized measure of health status that provides a simple, generic measure of health for clinical 
appraisal [36].  It is well-validated for health status measurement [37] and for quality-of-life in headache [34]. 
Patient Global Impression of Change (PGIC): A validated 7-point Likert-type scale assessing a patient’s overall 
impression of improvement after intervention [38, 39]. 
Work Productivity and Activity Impairment (WPAI): A validated instrument with good test-retest reliability used 
extensively in health research [40, 41] that quantifies impairment in daily activities and work productivity [42].  
Crossover: Patients will be permitted to crossover to the other treatment arm two months after the procedure. 
 
Statistics 
Patient Outcome Analysis 


 
The change in HIT-6 from a pre-procedural score of > 56 (substantial or severe impact on life) will be 
considered for each group at each time point. Primary Endpoint (HIT-6 at 1 month): We will apply a two-sample 
t test, or in the cases of low counts and non-parametric data a Wilcoxon Rank Sum test, to test the primary 
endpoint. Secondary Endpoints: The same analysis will be employed for all secondary endpoints at each time 
point. 
Sample Size Determination 
Based on previously acquired prospective outcomes data (unpublished), we will conservatively 
estimate a positive response rate of 50% in our experimental arm (see Preliminary Studies). In a meta-analysis 
examining sham procedures, our group found a maximum placebo response of 30% (Gu AP, unpublished). 
Therefore, to obtain a power of 0.8 (alpha 0.05) to detect superiority of the blood and fibrin glue patching 
group, assuming positive response rates of 50% for the patching group and 30% for the control group, we 
would need a total of 148 patients (74 patients in each arm).   
Interim Data Analysis 
 
An interim analysis will be performed of the first 74 patients by the biostatistician. All study participants 
and other personnel will remain blinded. Safety and efficacy will be evaluated using an O’Brien–Fleming 
stopping rule of p < 0.001 in order to evaluate for early evidence of treatment efficacy [43]. 
Crossover, Withdrawal, or Missing Data 
We will employ an intention-to-treat (ITT) analysis for this trial [44]. Patients that crossover between 
study arms, withdraw from the study, or for whom there is missing data will all be handled in the same manner: 
we will conservatively assume that no further benefit will be gained from the initial treatment. As such, the most 
recent available outcomes data will be extrapolated to all later time points for which no data are available.  
 
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