Cerebrospinal Fluid LeaksPhase 2NCT03276975
A Randomized Trial of CT Fluoroscopy-guided Targeted Autologous Blood and Fibrin Glue Patching for Treatment
A Phase 2 study testing TISSEEL in people with Cerebrospinal Fluid Leaks, run by Duke University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cerebrospinal Fluid Leaks
- What is being tested?
- TISSEEL
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- 18 Dec 2017to 19 Mar 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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]
Who cannot join
- recent (i.e., < 2 weeks) blood patch
- contraindication or inability to undergo the procedure
- inability to provide informed consent
- expected inability to complete follow-up assessment
- a contraindication to receiving contrast material (precluding an epidurogram)
- contraindication to receiving fibrin glue (i.e., allergy).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized Trial of CT Fluoroscopy-guided Targeted Autologous Blood and Fibrin Glue Patching for Treatment of Cerebrospinal Fluid Leaks in Spontaneous Intracranial Hypotension.
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.
Read the 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.
- Conditions
- Cerebrospinal Fluid Leaks
- Being tested
- TISSEEL
- Keywords
- CT fluoroscopy, epidural patching, spontaneous intracranial hypotension
- Medical subject headings
- Cerebrospinal Fluid Leak, Intracranial Hypotension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TISSEELDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Patching of CSF Leaks with Autologous Blood and Fibrin | Active comparator | CT fluoroscopy-guided blood and fibrin glue patching targeted to the site of CSF leak. Receives: Drug: TISSEEL |
| Simulated Patching Procedure | Placebo comparator | 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. Receives: Drug: TISSEEL |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Median (Headache Impact Test-6) HIT-6 Score From Baseline
Absolute change in median HIT-6 score from pre-procedural baseline to 1 month post procedure for each group. The HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: "never", "rarely", "sometimes", "very often", or "always". These responses are summed to produce a total HIT-6 score that ranges from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the respondent.
Measured: Baseline, 1 month
Secondary outcomes (6)
Change in Median HIT-6 Score From Baseline
Absolute change in median HIT-6 score from pre-procedural baseline to 2 weeks and 4 months post procedure for each group. The HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: "never", "rarely", "sometimes", "very often", or "always". These responses are summed to produce a total HIT-6 score that ranges from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the respondent.
Measured: Baseline, 2 weeks, 4 months
Reduction in Median Migraine Disability Assessment (MIDAS) Score From Baseline
The MIDAS questionnaire assesses headache-related disability. Patients answer five questions, scoring the number of days, in the past 3 months, where their activity was limited due to headache. A higher score indicates greater headache-related disability. This tool has been shown to be internally consistent, highly reliable, valid, and correlates with physicians' clinical judgment. MIDAS Scale Range: 0 - 270
Measured: Baseline, 2 weeks, 1 month, 4 months
Change in Median NRS Score From Baseline
The pain numerical rating scale (NRS) is a well-validated tool for quantitatively assessing patients' pain. The NRS asks patients to rate their current pain intensity on an 11-point scale ranging from 0 ("no pain") to 10 ("worst possible pain"). It has been found to be a valid measure of pain intensity with minimum clinically important difference noted to be a change of 2 points. The investigators will use NRS averaged over the past 24 hours for all time points in this trial. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement indicates that an NRS reduction of 30% (or 2 points) is associated with a meaningful or moderately important improvement in pain. Further, IMMPACT also indicates that an NRS reduction of 50% (or 4 points) is associated with a substantial improvement in pain. The investigators will follow their consensus recommendations and explicitly report these two categories of pain relief.
Measured: Baseline, 2 weeks, 1 month, 4 months
Change in Median EQ-5D (European Quality of Life-5 Dimensions) Score From Baseline
The EQ-5D is a standardized measure of health status that provides a simple, generic measure of health for clinical appraisal. It is well-validated for health status measurement and for quality-of-life in headache. Scores on the EQ-5D were calculated using the United States 3L, time trade off (TTO) valuation technique. Scores range from 0 to 1, with 1 indicating perfect health.
Measured: Baseline, 2 weeks, 1 month, 4 months
Change in Median WPAI (Work Productivity and Activity Impairment) Score From Baseline
The WPAI is a validated instrument with good test-retest reliability used extensively in health research that quantifies impairment in daily activities and work productivity. Scores on the WPAI range from 0 - 100% with higher percentages indicating greater impact on work productivity and more severe activity impairment.
Measured: Baseline, 2 weeks, 1 month, 4 months
Change in PGIC (Patient Global Impression of Change) Score From Baseline
PGIC is a validated 7-point Likert-type scale assessing a patient's overall impression of improvement after intervention. Scores range from 1 - 7 (1: no change or worsening of condition; 2: almost the same, hardly any change at all; 3: a little better, but no noticeable change; 4: somewhat better, but the change has not made any real difference; 5: moderately better, and a slight but noticeable change; 6: better and a definite improvement that has made a real and worthwhile difference; 7: a great deal better, and a considerable improvement that has made all the difference) with higher scores indicating greater improvement.
Measured: Baseline, 2 weeks, 1 month, 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Sep 2017
- Study start18 Dec 2017
- Primary completion19 Mar 2020
- Study completion19 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Cerebrospinal Fluid LeaksStudies of the same condition, open and under way.
- More trials run by Duke UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Duke University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03276975
- Sponsor's protocol ID
- Pro00083991
- Status last verified
- May 2021
- First submitted
- 7 Sep 2017
- Last updated
- 18 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Trial of CT Fluoroscopy-guided Targeted Autologous Blood and Fibrin Glue Patching for Treatment of Cerebrospinal Fluid Leaks in Spontaneous Intracranial Hypotension.
- ClinicalTrials.gov ID
- NCT03276975
- Acronym / sponsor ID
- Pro00083991
- Conditions
- Cerebrospinal Fluid Leaks
- Keywords
- CT fluoroscopy, epidural patching, spontaneous intracranial hypotension
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Duke UniversityUniversity, hospital or other
- Study start
- 18 Dec 2017 (actual)
- Primary completion
- 19 Mar 2020 (actual)
- Study completion
- 19 Mar 2020 (actual)
- First posted
- 8 Sep 2017 (actual)
- Results
- Posted 18 Jun 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patching of CSF Leaks with Autologous Blood and Fibrin | Active comparator | Drug: TISSEELCT fluoroscopy-guided blood and fibrin glue patching targeted to the site of CSF leak. |
| Simulated Patching Procedure | Placebo comparator | Drug: TISSEELInstead 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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]
Key exclusion criteria (6 listed)
- recent (i.e., < 2 weeks) blood patch
- contraindication or inability to undergo the procedure
- inability to provide informed consent
- expected inability to complete follow-up assessment
- a contraindication to receiving contrast material (precluding an epidurogram)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TISSEELTISSEEL 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 | Drug | Patching of CSF Leaks with Autologous Blood and Fibrin, Simulated Patching Procedure |
Primary outcome
Change in Median (Headache Impact Test-6) HIT-6 Score From Baseline
Time frame: Baseline, 1 month
Absolute change in median HIT-6 score from pre-procedural baseline to 1 month post procedure for each group. The HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: "never", "rarely", "sometimes", "very often", or "always". These responses are summed to produce a total HIT-6 score that ranges from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the respondent.
6 secondary outcomes
Change in Median HIT-6 Score From Baseline
Time frame: Baseline, 2 weeks, 4 months
Reduction in Median Migraine Disability Assessment (MIDAS) Score From Baseline
Time frame: Baseline, 2 weeks, 1 month, 4 months
Change in Median NRS Score From Baseline
Time frame: Baseline, 2 weeks, 1 month, 4 months
Change in Median EQ-5D (European Quality of Life-5 Dimensions) Score From Baseline
Time frame: Baseline, 2 weeks, 1 month, 4 months
Change in Median WPAI (Work Productivity and Activity Impairment) Score From Baseline
Time frame: Baseline, 2 weeks, 1 month, 4 months
Change in PGIC (Patient Global Impression of Change) Score From Baseline
Time frame: Baseline, 2 weeks, 1 month, 4 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing TISSEEL in people with Cerebrospinal Fluid Leaks, run by Duke University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jun 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Median (Headache Impact Test-6) HIT-6 Score From Baseline (time frame: Baseline, 1 month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2021.