Subarachnoid Hemorrhage, Aneurysmal
Conditions
Brief summary
This is a single site, randomized, sham-controlled, double blinded pilot study assessing the feasibility, safety, tolerability, and efficacy of non-invasive VNS (nVNS), gammaCore, in the treatment of headache in subarachnoid hemorrhage (SAH). 40 participants will be enrolled, 20 in the active device arm and 20 in the sham arm. The primary efficacy outcome is the the difference between the active and sham treatment groups in morphine equivalence dosage.
Detailed description
This is a single site, randomized, sham-controlled, double-blind study assessing the feasibility, safety, tolerability, and efficacy of non-invasive VNS (nVNS) in the treatment of headache in subarachnoid hemorrhage (SAH). The hypothesis is that two-two minute noninvasive stimulations of the cervical branch of the Vagus nerve, every 5 hours, is efficacious in safely reducing headache intensity and frequency in patients with headache due to SAH, during the patient's intensive care unit (ICU) stay. After screening and obtaining informed consent, eligible patients diagnosed with SAH on head scans, admitted to the Neurosurgical Intensive Care Unit (NSCU) at Northshore University Hospital will be randomized to either the treatment (stimulation of the cervical branch of the Vagus nerve) or sham (inactive stimulation) group. Pain intensity will be evaluated every 4 hours. Non-invasive stimulation will be performed every 5 hours. Device related adverse events, mean headache intensity, and mean and peak morphine equivalence dosage during the study period will be compared between the VNS group and the sham group. The primary objective of this study is to examine the safety and effectiveness of nVNS as a treatment for headache in subarachnoid hemorrhage (SAH). The primary safety endpoint for this study is the incidence of device related serious adverse events. The primary outcome measurements for effectiveness is the difference between the active and sham treatment groups in morphine equivalence dosage Secondary endpoints include descriptive comparisons between the active and sham treatment groups in: * The difference between the active and sham treatment groups in the mean daily headache intensity * The difference between total overall morphine equivalence dosage between the active and sham group per subject during study * Opiate related adverse events (such as urinary retention, constipation, sedation, respiratory depression, nausea, vomiting and pruritis) * The difference in CSF and blood inflammatory markers before and after VNS * Difference in vessel diameter during angiogram for cerebral vasospasm before and after VNS Study period is 14 days starting 24-72 hours post successful treatment of the aneurysm and extubation.
Interventions
DEVICEgammaCore
The intervention consists of a transcutaneous non-invasive stimulation of the cervical branch of the vagus nerve (nVNS) using gammaCore, an FDA approved device for the treatment of migraine and cluster headache. This will be compared to the sham device, which is the same device which will not provide stimulation to the nerve. Stimulation frequency will be identical to the frequency used in previous nVNS studies for the treatment of migraine headache.
Sponsors
Northwell Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Established signed and dated informed consent form * CT of the head revealing blood in the subarachnoid space * Subject is male or female, 18 to 80 years of age * Subject alert to be able to verbalize pain level. If alertness improves after placement of an external ventricular drain, or once extubated, and the patient becomes alert , the patient will be enrolled * Subject reports pain of \> =7 on 10 Point Pain numeric rating scale * Female of reproductive age must have a negative pregnancy test (Urine or blood test)
Exclusion criteria
* Use of any concomitant electrostimulation devices (Pacemaker, defibrillator, deep brain stimulation.) * Unsecured aneurysm defined as aneurysm that has not been surgically or endovascularly treated. * Previous carotid surgeries or known history of carotid artery disease * Screws, metals or device in the neck * History of secondary or tertiary heart blocks, ventricular tachycardia, Supra-Ventricular Tachycardia (including atrial fibrillation) * Alcoholics (CAGE scale of 2 or greater). If patients are on Clinical Institute Withdrawal Assessment for Alcohol (CIWA) protocol for alcohol withdrawal, the patient will be excluded from the study. * Drug addicts or chronic opioid users confirmed by history or with urine toxicology showing opiates or cocaine * small traumatic SAH
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Difference Between the Active and Sham Treatment Groups in Morphine Equivalence Dosage PER DAY | up to 14 days of admission | Daily morphine equivalence dosage will be calculated and compared between the active and Sham group |
| Overall Difference in MED at 7 Days | baseline and 7 days | difference in mean morphine equivalent dosage at 7 days between active and sham group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Difference Between the Active and Sham Treatment Groups in the Mean Daily Headache Intensity Pre and Post Stimulation | up to 14 days of admission | Headache intensity is measured every 4 hours per standard of care. The pain intensity is reported using a 0 to 10 numeric rating scale, o being no pain, and 10 being severe pain. least mean square difference between the 2 groups between the pre and post stimulation pain score |
| The Difference in Device Related Heart Rate Change Before and After Stimulation | up to 14 days of admission | difference in change in Heart rate between the 2 groups from before to after stimulation |
| Change in SBP Between Active and Sham Group | before and after stimulation, up to 14 days | difference between pre and post stimulation SBP between the 2 groups |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active active VNS group | 19 |
| Sham sham group ( no real stimulation) | 21 |
| Total | 40 |
Baseline characteristics
| Characteristic | Sham | Active | Total |
|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 11 | 54 years STANDARD_DEVIATION 13 | 52.5 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 9 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 7 Participants | 13 Participants |
| HHS hhs1 | 7 participants | 5 participants | 12 participants |
| HHS hhs2 | 11 participants | 10 participants | 21 participants |
| HHS hhs3 | 2 participants | 2 participants | 4 participants |
| HHS hhs4 | 1 participants | 2 participants | 3 participants |
| mfs MFS1 | 2 participants | 4 participants | 6 participants |
| mfs MFS2 | 2 participants | 1 participants | 3 participants |
| mfs MFS3 | 9 participants | 8 participants | 17 participants |
| mfs MFS4 | 8 participants | 6 participants | 14 participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 21 | 0 / 19 |
| other Total, other adverse events | 5 / 21 | 9 / 19 |
| serious Total, serious adverse events | 0 / 21 | 0 / 19 |
Outcome results
Primary
Overall Difference in MED at 7 Days
difference in mean morphine equivalent dosage at 7 days between active and sham group
Time frame: baseline and 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Device | Overall Difference in MED at 7 Days | 21.99 mg | Standard Deviation 21.41 |
| Sham | Overall Difference in MED at 7 Days | 24.29 mg | Standard Deviation 14.5 |
Primary
The Difference Between the Active and Sham Treatment Groups in Morphine Equivalence Dosage PER DAY
Daily morphine equivalence dosage will be calculated and compared between the active and Sham group
Time frame: up to 14 days of admission
Population: 4O PARTICIPANTS , 19 IN ACTIVE GROUP AND 21 IN SHAM GROUP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Device | The Difference Between the Active and Sham Treatment Groups in Morphine Equivalence Dosage PER DAY | 0.058 mg | Standard Deviation 0.31 |
| Sham | The Difference Between the Active and Sham Treatment Groups in Morphine Equivalence Dosage PER DAY | 0.24 mg | Standard Deviation 0.29 |
Secondary
Change in SBP Between Active and Sham Group
difference between pre and post stimulation SBP between the 2 groups
Time frame: before and after stimulation, up to 14 days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Device | Change in SBP Between Active and Sham Group | -2.20 millimeters of mercury | Standard Error 0.88 |
| Sham | Change in SBP Between Active and Sham Group | -1.64 millimeters of mercury | Standard Error 1.05 |
Secondary
The Difference Between the Active and Sham Treatment Groups in the Mean Daily Headache Intensity Pre and Post Stimulation
Headache intensity is measured every 4 hours per standard of care. The pain intensity is reported using a 0 to 10 numeric rating scale, o being no pain, and 10 being severe pain. least mean square difference between the 2 groups between the pre and post stimulation pain score
Time frame: up to 14 days of admission
Population: 40, 19 ACtIVE AND 21 SHAM
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Device | The Difference Between the Active and Sham Treatment Groups in the Mean Daily Headache Intensity Pre and Post Stimulation | -0.59 units on a scale | Standard Error 0.11 |
| Sham | The Difference Between the Active and Sham Treatment Groups in the Mean Daily Headache Intensity Pre and Post Stimulation | -0.13 units on a scale | Standard Error 0.11 |
Secondary
The Difference in Device Related Heart Rate Change Before and After Stimulation
difference in change in Heart rate between the 2 groups from before to after stimulation
Time frame: up to 14 days of admission
Population: between sham and active hear rate
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Device | The Difference in Device Related Heart Rate Change Before and After Stimulation | -1.73 beats per min | Standard Error 1.13 |
| Sham | The Difference in Device Related Heart Rate Change Before and After Stimulation | -0.76 beats per min | Standard Error 1.18 |