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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.
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:
Study period is 14 days starting 24-72 hours post successful treatment of the aneurysm and extubation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sham arm | Sham Comparator | gammaCore sham device which will not provide stimulation of the vagus nerve |
|
| Treatment group | Active Comparator | Active gammaCore device that supplies non-invasive stimulation of the cervical branch of the Vagus nerve |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| gammaCore | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | up to 14 days of admission |
| Overall Difference in MED at 7 Days | difference in mean morphine equivalent dosage at 7 days between active and sham group | baseline and 7 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Northshore University Hospital | Manhasset | New York | 11030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23808965 | Background | Magalhaes JE, Azevedo-Filho HR, Rocha-Filho PA. The risk of headache attributed to surgical treatment of intracranial aneurysms: a cohort study. Headache. 2013 Nov-Dec;53(10):1613-23. doi: 10.1111/head.12165. Epub 2013 Jun 28. | |
| 29107164 | Background | Rumalla K, Smith KA, Arnold PM, Mittal MK. Subarachnoid Hemorrhage and Readmissions: National Rates, Causes, Risk Factors, and Outcomes in 16,001 Hospitalized Patients. World Neurosurg. 2018 Feb;110:e100-e111. doi: 10.1016/j.wneu.2017.10.089. Epub 2017 Oct 26. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sham Arm | gammaCore sham device which will not provide stimulation of the vagus nerve gammaCore: 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. |
| FG001 | Treatment Group | Active gammaCore device that supplies non-invasive stimulation of the cervical branch of the Vagus nerve gammaCore: 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Active | active VNS group |
| BG001 | Sham | sham group ( no real stimulation) |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 4O PARTICIPANTS , 19 IN ACTIVE GROUP AND 21 IN SHAM GROUP | Posted | Least Squares Mean | Standard Deviation | mg | up to 14 days of admission |
|
through study completion, up to 14 days
Difference in Heart rate, SBP, DBP between the active and sham between before and after stimulation rate of VNS related side effects: skin irritation, hoarseness, dyspepsia, shortness of breath , arrhythmia between the two groups
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sham Arm | gammaCore sham device which will not provide stimulation of the vagus nerve gammaCore: 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| site discomfort | General disorders | other | Non-systematic Assessment | discomfort during stimulation |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| northwell health | northwell health | 5165620100 | trebeiz@northwell.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 12, 2023 | Jul 6, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 1, 2022 | Sep 15, 2023 | SAP_002.pdf |
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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|
| up to 14 days of admission |
| 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 | up to 14 days of admission |
| Change in SBP Between Active and Sham Group | difference between pre and post stimulation SBP between the 2 groups | before and after stimulation, up to 14 days |
| 26932915 | Background | Glisic EK, Gardiner L, Josti L, Dermanelian E, Ridel S, Dziodzio J, McCrum B, Enos B, Lerwick P, Fraser GL, Muscat P, Riker RR, Ecker R, Florman J, Seder DB. Inadequacy of Headache Management After Subarachnoid Hemorrhage. Am J Crit Care. 2016 Mar;25(2):136-43. doi: 10.4037/ajcc2016486. |
| 27704534 | Background | Morad AH, Tamargo RJ, Gottschalk A. The Longitudinal Course of Pain and Analgesic Therapy Following Aneurysmal Subarachnoid Hemorrhage: A Cohort Study. Headache. 2016 Nov;56(10):1617-1625. doi: 10.1111/head.12908. Epub 2016 Oct 5. |
| 19828484 | Background | Dorhout Mees SM, Bertens D, van der Worp HB, Rinkel GJ, van den Bergh WM. Magnesium and headache after aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2010 May;81(5):490-3. doi: 10.1136/jnnp.2009.181404. Epub 2009 Oct 13. |
| 24530613 | Background | Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014 May;155(5):1037-1042. doi: 10.1016/j.pain.2014.02.009. Epub 2014 Feb 14. |
| 28286178 | Background | Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis. 2017 Jun;102:96-104. doi: 10.1016/j.nbd.2017.03.004. Epub 2017 Mar 9. |
| 28104084 | Background | Frangos E, Komisaruk BR. Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: fMRI Evidence in Healthy Humans. Brain Stimul. 2017 Jan-Feb;10(1):19-27. doi: 10.1016/j.brs.2016.10.008. Epub 2016 Oct 20. |
| 20437558 | Background | Bosche B, Graf R, Ernestus RI, Dohmen C, Reithmeier T, Brinker G, Strong AJ, Dreier JP, Woitzik J; Members of the Cooperative Study of Brain Injury Depolarizations (COSBID). Recurrent spreading depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex. Ann Neurol. 2010 May;67(5):607-17. doi: 10.1002/ana.21943. |
| 26645547 | Background | Chen SP, Ay I, Lopes de Morais A, Qin T, Zheng Y, Sadeghian H, Oka F, Simon B, Eikermann-Haerter K, Ayata C. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016 Apr;157(4):797-805. doi: 10.1097/j.pain.0000000000000437. |
| 14571320 | Background | Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003 May-Aug;9(5-8):125-34. |
| 30943885 | Background | Suzuki T, Takizawa T, Kamio Y, Qin T, Hashimoto T, Fujii Y, Murayama Y, Patel AB, Ayata C. Noninvasive Vagus Nerve Stimulation Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice. Stroke. 2019 May;50(5):1216-1223. doi: 10.1161/STROKEAHA.118.023928. |
| 20633378 | Background | George MS, Ward HE Jr, Ninan PT, Pollack M, Nahas Z, Anderson B, Kose S, Howland RH, Goodman WK, Ballenger JC. A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders. Brain Stimul. 2008 Apr;1(2):112-21. doi: 10.1016/j.brs.2008.02.001. Epub 2008 Mar 28. |
| 29593576 | Background | Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Front Psychiatry. 2018 Mar 13;9:44. doi: 10.3389/fpsyt.2018.00044. eCollection 2018. |
| 30214271 | Background | Lendvai IS, Maier A, Scheele D, Hurlemann R, Kinfe TM. Spotlight on cervical vagus nerve stimulation for the treatment of primary headache disorders: a review. J Pain Res. 2018 Aug 27;11:1613-1625. doi: 10.2147/JPR.S129202. eCollection 2018. |
| Total |
Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| mfs | MODIFIED RANKIN SCALE IS A RANK FROM 1-4
| Number | participants |
|
| HHS | Hunt Hess Scale Is a prognostic scale, how the patient presented on admission, the higher the scare the poorer the prognosis HHS1. no/mild headache HHS2, mod/seve headache, CN palsy HHS3, drowsy, min neuron deficit HHS4 Stupor,mod/sev hemiparesis HHS5- Deep coma, decerebrate | 40 overall , 21 in sham and 19 in active | Number | participants |
|
| Units | Counts |
|---|
| Participants |
|
|
| Primary | Overall Difference in MED at 7 Days | difference in mean morphine equivalent dosage at 7 days between active and sham group | Posted | Mean | Standard Deviation | mg | baseline and 7 days |
|
|
|
| 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 | 40, 19 ACtIVE AND 21 SHAM | Posted | Least Squares Mean | Standard Error | units on a scale | up to 14 days of admission |
|
|
|
| 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 | between sham and active hear rate | Posted | Least Squares Mean | Standard Error | beats per min | up to 14 days of admission |
|
|
|
| Secondary | Change in SBP Between Active and Sham Group | difference between pre and post stimulation SBP between the 2 groups | Posted | Least Squares Mean | Standard Error | millimeters of mercury | before and after stimulation, up to 14 days |
|
|
|
| 1 |
| 21 |
| 0 |
| 21 |
| 5 |
| 21 |
| EG001 | Treatment Group | Active gammaCore device that supplies non-invasive stimulation of the cervical branch of the Vagus nerve gammaCore: 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. | 0 | 19 | 0 | 19 | 9 | 19 |
|
| tingling sensation | General disorders | other | Systematic Assessment | tingling during stimulation |
|
| pain at stimulation | General disorders | other | Non-systematic Assessment | pain during stimulation |
|
| muscle twitching | General disorders | other | Non-systematic Assessment | twitching during stimulation |
|
| transient facial droop | General disorders | other | Systematic Assessment | during stimulation |
|
| dizziness | Nervous system disorders | other | Systematic Assessment | dizziness during stimulation |
|
| hoarseness | Ear and labyrinth disorders | other | Systematic Assessment | transient hoarseness during stimulation |
|
| dysgusia | General disorders | other | Systematic Assessment | dysgusia during stimulation |
|
| dyspnea | General disorders | other | Systematic Assessment | transient dyspnea during stimulation |
|
| nausea | Gastrointestinal disorders | other | Systematic Assessment | nausea during stimulation |
|
| coughing | Respiratory, thoracic and mediastinal disorders | other | Systematic Assessment | coughing during stimulation |
|
| hoarseness | Ear and labyrinth disorders | other | Systematic Assessment | hoarseness during stimulation |
|
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| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |