(546 days)
Not Found
Not Found
No
The device description and performance studies focus on electrical stimulation and clinical trial outcomes, with no mention of AI or ML.
Yes
The device is described as "gammaCore Non-invasive Vagus Nerve Stimulator" which is intended for the "acute treatment of pain associated with episodic cluster headache". This indicates its use for therapeutic purposes (treatment of a medical condition).
No
The device is described as a "Non-invasive Vagus Nerve Stimulator" intended to "provide non-invasive vagus nerve stimulation (nVNS)" for the "acute treatment of pain associated with episodic cluster headache." Its function is therapeutic (stimulation for pain treatment), not diagnostic (identifying or characterizing a condition).
No
The device description explicitly states it is a "hand-held portable device" consisting of physical components like an outer plastic case, battery, electronics, thumbwheel, LED, horn, and stainless steel skin contact surfaces. This indicates it is a hardware device, not software-only.
Based on the provided information, the gammaCore Non-invasive Vagus Nerve Stimulator is not an In Vitro Diagnostic (IVD) device.
Here's why:
- Intended Use: The intended use is for the acute treatment of pain associated with episodic cluster headache. This is a therapeutic purpose, not a diagnostic one.
- Device Description: The device description details a stimulator that applies electrical signals to the body. This is consistent with a therapeutic device, not a device that analyzes samples from the body (which is the hallmark of an IVD).
- Mechanism of Action: The device works by providing non-invasive vagus nerve stimulation, which is a physical intervention, not a test performed on biological samples.
- Clinical Studies: The clinical studies evaluate the device's effectiveness in treating pain, not its ability to diagnose a condition or measure a substance in a biological sample.
In Vitro Diagnostic devices are used to examine specimens taken from the human body, such as blood, urine, or tissue, to provide information for the diagnosis, prevention, or treatment of a disease or condition. The gammaCore device does not perform this function.
N/A
Intended Use / Indications for Use
The gammaCore Non-invasive Vagus Nerve Stimulator is intended to provide non-invasive vagus nerve stimulation (nVNS) on the side of the neck. The gammaCore device is indicated for the acute treatment of pain associated with episodic cluster headache in adult patients.
Product codes (comma separated list FDA assigned to the subject device)
PKR
Device Description
The gammaCore Non-invasive Vagus Nerve Stimulator (hereafter referenced as "gammaCore device") is a hand-held portable device (Figure 1) consisting of an outer plastic case, a battery, signal generating and amplifying electronics, a thumbwheel to power on the device and control stimulation intensity (range 0-5 continuous, relative), LED and horn (indicate device status), and a pair of stainless steel skin contact surfaces (referred to as the "stimulation surfaces"). Electrode conductive gel is applied to the electrode surfaces prior to placement on the skin of the neck over the pathway of the vagus nerve.
The low voltage electric signal applied across the two electrodes generates an electric field in the vicinity of the vagus nerve. The electrical stimulation consists of five cvcles of a 5000 Hz waveform that are repeated at a rate of 25 Hz. The waveform of the electric pulses is approximately a sine wave with a peak voltage limited to 24 volts when placed on the skin and a maximum output current of 60 milliamps. The electrical stimulation passes through the skin of the neck to the vagus nerve. When switched on, the device provides a 120 second period of stimulation. This includes time for the operator to properly place the device and to adjust the stimulation level as well as time for the stimulation. Each device allows for multiple treatments to an individual user.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
side of the neck
Indicated Patient Age Range
Adult patients (age 18-75 in studies)
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical data submitted by gammaCore for the acute treatment of episodic cluster headache is provided from two prospective, double-blind, sham-controlled, randomized clinical trials (referred to as ACT1 and ACT2).
ACT1 Study:
- Study type: Multi-center, prospective, double-blind, randomized, sham controlled pivotal study.
- Sample size: 150 patients with Cluster Headache (101 eCH, 49 cCH). Modified intent to treat group included 60 subjects in treatment arm and 73 in sham arm.
- Key Results:
- Primary End Point (response rate for mild or no pain at 15 minutes post-initiation of treatment of the first treated cluster headache attack of Phase 1, no rescue medication during first hour): Not statistically significant for total population (nVNS 26.7%, sham 15.1%, P=0.1).
- Subgroup analysis showed a higher response rate for the eCH cohort (nVNS 34.2%, sham 10.6%, P=0.008) but not for the cCH cohort (nVNS 13.6%, sham 23.1%, P=0.48).
- Sustained treatment response rates (mild or no pain without rescue medication through 60 minutes after treatment initiation) for total and eCH cohort population were higher with nVNS (total: nVNS 26.7%; sham 12.3%; eCH: nVNS 34.2%; sham 10.6%).
- The proportion of subjects in the eCH cohort (but not cCH or total) who were responders (mild or no pain) at 15 minutes for ≥50% of the total number of treated attacks was statistically significant with nVNS (eCH: nVNS 34.2%; sham 14.9%; P=0.04).
- Change in duration of attacks from baseline significantly favored nVNS in total population (-9.5 minutes; P=0.03) and eCH cohort (-14.4 minutes; P=0.03).
- Safety: No device related serious adverse events. Majority of adverse events were mild and transient, occurring during active treatment.
ACT2 Study:
- Study type: Postmarket clinical study, 3 phases (1-week run-in, 2-week double-blind randomized, 2-week open label).
- Sample size: 102 patients with Cluster Headache.
- Key Results:
- Primary End Point (percentage of total attacks that were pain-free at 15 minutes after initiation of treatment with no rescue medication through 30 minutes): Not statistically significant for total population (nVNS 13.5%, sham 11.5%, P=0.713).
- In the eCH cohort, a higher percentage of attacks were pain free with nVNS than with sham treatment (nVNS 47.5%; sham 6.2%; P
§ 882.5892 External vagal nerve stimulator for headache.
(a)
Identification. An external vagal nerve stimulator for headache is a prescription device used to apply an electrical current to a patient's vagus nerve through electrodes placed on the skin for the treatment of headache.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The technical parameters of the device, including waveform, output modes, maximum output voltage and current (with 500, 2,000, and 10,000 ohm loads), pulse duration, frequency, net charge (µC) per pulse, maximum phase charge at 500 ohms, maximum current density (mA/cm
2 , r.m.s.), maximum average current (mA), maximum average power density (W/cm2 ), and the type of impedance monitoring system shall be fully characterized through non-clinical performance testing.(2) Software verification, validation, and hazard analysis shall be performed.
(3) Biocompatibility evaluation of the patient-contacting components of the device shall be performed.
(4) The device shall be tested for electrical, thermal, and mechanical safety, and for electromagnetic compatibility (EMC).
(5) The labeling must include:
(i) Instructions for proper use of the device, including placement of the device on the patient; and
(ii) Instructions on care and cleaning of the device.
0
DE NOVO CLASSIFICATION REQUEST FOR
gammaCore Non-invasive Vagus Nerve Stimulator
REGULATORY INFORMATION
FDA identifies this generic type of device as:
External vagal nerve stimulator for headache. An external vagal nerve stimulator for headache is a prescription device used to apply an electrical current to a patient's vagus nerve through electrodes placed on the skin for the treatment of headache.
NEW REGULATION NUMBER: 21 CFR 882.8592
CLASSIFICATION: II
PRODUCT CODE: PKR
BACKGROUND
DEVICE NAME: gammaCore® Non-invasive Vagus Nerve Stimulator
SUBMISSION NUMBER: DEN150048
DATE OF DE NOVO: October 15, 2015
CONTACT: electroCore, LLC 150 Allen Road, Suite 201 Basking Ridge, NJ 07920
INDICATIONS FOR USE
The gammaCore Non-invasive Vagus Nerve Stimulator is intended to provide non-invasive vagus nerve stimulation (nVNS) on the side of the neck. The gammaCore device is indicated for the acute treatment of pain associated with episodic cluster headache in adult patients.
LIMITATIONS
For prescription use only.
The request is granted based on a clinical comparison of probable risks and benefits to health and FDA has determined probable benefit to health based on clinical evidence submitted to FDA and patient preference information.
Warnings
The safety and effectiveness of the gammaCore Non-invasive Vagus Nerve Stimulator has not been established in the acute treatment of chronic cluster headache.
1
This device has not been shown to be effective for the prophylactic treatment of chronic or episodic cluster headache.
The long-term effects of the chronic use of the device have not been evaluated.
Safety and efficacy of the gammaCore device has not been evaluated in the following patients, and therefore is NOT indicated for:
- Pediatric patients ●
- Patients with an active implantable medical device, such as a pacemaker, hearing aid . implant, or any implanted electronic device
- Patients diagnosed with narrowing of the arteries (carotid atherosclerosis)
- Patients with a history of surgery to cut the vagus nerve (cervical vagotomy)
- . Pregnant women
- Patients with uncontrolled hypertension
- . Patients with a history of baseline cardiac disease or atherosclerotic cardiovascular disease, including congestive heart failure (CHF), known severe coronary artery disease or recent myocardial infarction (within 5 years).
- . Patients with a history of a prolonged OT interval or arrhythmia
- Patients with a history of an abnormal baseline ECG (e.g. second and third degree . heart block, atrial fibrillation, atrial flutter, recent history of ventricular tachycardia or ventricular fibrillation, or clinically significant premature ventricular contraction)
- Patients with a history of seizures
POTENTIAL ADVERSE REACTIONS
Adverse reactions seen in studies using the device include:
- . Shortness of breath (dyspnea), hoarseness, or change in voice during treatment
- . Muscle twitching, discomfort, or pain during stimulation
- Change in taste (dysgeusia) .
These first three reactions resolved after treatment was completed.
- . Skin irritation/inflammation
- . Progression of headache symptoms
Adverse reactions which were not seen in the studies, but are known to be associated with implanted vagal nerve stimulation devices include:
- . Tingling, pricking, or a feeling of "pins and needles" on the skin where the device is applied (paresthesia or dysaesthesia) lasting beyond the treatment period
- Fainting (syncope), light-headedness, and/or dizziness ●
- Sweating ●
- Fatigue, depressed mood
- Tinnitus ●
- . Diarrhea
2
- . Abnormal heart rhythm
PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The gammaCore Non-invasive Vagus Nerve Stimulator (hereafter referenced as "gammaCore device") is a hand-held portable device (Figure 1) consisting of an outer plastic case, a battery, signal generating and amplifying electronics, a thumbwheel to power on the device and control stimulation intensity (range 0-5 continuous, relative), LED and horn (indicate device status), and a pair of stainless steel skin contact surfaces (referred to as the "stimulation surfaces"). Electrode conductive gel is applied to the electrode surfaces prior to placement on the skin of the neck over the pathway of the vagus nerve.
Image /page/2/Picture/4 description: The image shows a white plastic case with blue caps and a stimulation surface. The device has an LED light and a thumbwheel for operation. The blue caps are removable and cover the stimulation surface. The device appears to be designed for some kind of therapeutic or sensory stimulation.
Figure 1: gammaCore Non-invasive Vagus Nerve Stimulator
The low voltage electric signal applied across the two electrodes generates an electric field in the vicinity of the vagus nerve. The electrical stimulation consists of five cvcles of a 5000 Hz waveform that are repeated at a rate of 25 Hz. The waveform of the electric pulses is approximately a sine wave with a peak voltage limited to 24 volts when placed on the skin and a maximum output current of 60 milliamps. The electrical stimulation passes through the skin of the neck to the vagus nerve. When switched on, the device provides a 120 second period of stimulation. This includes time for the operator to properly place the device and to adjust the stimulation level as well as time for the stimulation. Each device allows for multiple treatments to an individual user.
3
| Output | Specifications |
|---|---|
| Waveform (e.g., pulsed monophasic, biphasic) | Pulsed 5 cycle sinusoidal wave, symmetrical biphasic |
| Shape (e.g., rectangular, spike, rectified sinusoidal) | Full sinusoidal waveform/pulse |
| Maximum Output Voltage (+/- 5%) (@500Ω) (@2000Ω) (@10000Ω) | 23±2V |
| 23±2V | |
| 23±2V | |
| Maximum Output Current (+/- 25%) (@500Ω) (@2000Ω) (@10000Ω) | 2x/week) for indications other than CH), botulinum toxin injections in previous |
6
3 months or nerve blocks in P value | 0.1 | | 180 min were excluded according to International Classification of Headache Disorders criteria.
4Change from the last attack before randomization) to the first attack in the first attack in the double-blind phase (based on objective recording).
Safety
In the blind and open phases of the ACT1 study there were 1772 headaches treated over a period of four months. The greatest number of treatments to any subject was 112. There were no device related serious adverse events in this study. The majority of the adverse events were mild and transient and occurred during the time of active treatment. See Table 5 for complete details.
Table 5. ACT1 Incidence of Adverse Events and Adverse Device Effects (All Treated Subjects) AEs and ADEs
| Double-blind Phase | Open-label Phase | |||
|---|---|---|---|---|
| nVNS | ||||
| (n=73) | Sham | |||
| (n=77) | nVNS | |||
| (n=128) | ||||
| Subjects with ≥1 AE, No. (%) | 18 (24.7) | 31 (40.3) | 42 (32.8) | |
| Subjects with ≥1 serious AE, No. (%) | 1 (1.4)a,b | 0 | 5 (3.9)b,c | |
| Subjects with ≥1 ADE, No. (%) | 11 (15.1) | 24 (31.2) | 18 (14.1) | |
| Device related adverse events in the treatment arm for subjects who used the gammaCore device. Percentages | ||||
| represent highest incidence, whether occurring in randomized or open label phase | ||||
| Myokymia during treatment | 11% | |||
| Neck soreness or tightness | 4.10% | |||
| Application site irritation; erythema at treatment site | 1.60% | |||
| Skin irritation | 0.00% | |||
| Sore or dry throat | 2.40% | |||
| Electrical sensation (stinging/tingling/numbness), | ||||
| paresthesia during treatment | 2.70% | |||
| Myalgia; shoulder muscle tightness | 0.80% | |||
| Dysgeusia during treatment | 1.60% | |||
| Jaw or tooth pain | 1.60% | |||
| Nausea or vomiting | 1.60% |
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| Increased frequency/severity of cluster headache attacks | 1.60% |
|---|---|
| ---------------------------------------------------------- | ------- |
Abbreviations: ADE, adverse device effect; AE, adverse event; nVNS, non-invasive vagus nerve stimulation. ªSerious AE of cluster headache (2 occurrences).
bSerious AEs were not considered related to the study device.
'Serious AEs included cluster headache (1 occurrence: 1 subject); cluster headache as well as multiple left extremity deep
vein thromboses, abdominal aortic aneumonia, anasarca, acute respiratory failure, and urethral trauma (1 occurrence each in the same subject): mesenteric ischemia (1 occurrence: 1 subject): herniated disk (1 occurrence:
1 subject); and ureteral calculus (1 occurrence; 1 subject).
The ACT2 Study: gammaCore for the acute treatment of acute or chronic episodic cluster headache:
This study was conducted in Europe as a postmarket clinical study. The study was conducted in 3 phases. The first phase of the study was a one-week run-in period during which subjects continued to use their standard of care treatments for acutely treating their cluster headaches and recorded the duration, frequency and the use of medication for each attack. During the second phase of the study, subjects were randomized to treatment with either an active gammaCore or sham device and remained blinded to the randomization assignment for the duration of the 2 week phase. The third phase was open label during which all subjects treated their cluster headache attacks with an active gammaCore device for an additional 2 weeks, according to the same instructions for use followed during the second phase.
Each subject enrolled in the study was instructed to treat all cluster headache attacks that are at least six hours apart, as soon as possible after onset over a total period of two weeks. If an attack was not treated with the device, the subject still recorded the attack and the medication/treatment for the attack. Each self-administered treatment consisted of three 120-second stimulation cycles applied consecutively at the onset of the attack. If the attack was not aborted the subject could stimulate with an additional three consecutive 120 second cycles at nine minutes. If the attack was not aborted within 15 minutes from the start of the device treatment, the subject could use their standard of care treatment (medication and/or oxygen). Patients were required to wait at least 6 hours following the treatment of a cluster attack before treating a second attack. If a cluster headache attack was not treated with the gammaCore (within the 6 hour period, or otherwise) the subject still recorded the attack and the medication/treatment used for the attack.
The primary outcome measurement for effectiveness was the fraction of treated headaches that responded with pain freedom (pain intensity of 0 on the 5-point headache pain scale (no pain, mild, moderate, severe, very severe) at 15 minutes for the active treatment group, compared to the sham control group.
In the ACT2 study subjects were asked to refrain from starting new prophylactic treatment or changing the dose of any medication for cluster headache once the run-in period started and agreed to maintain their existing cluster headache treatment regimens during the run-in and double-blind periods. Subjects were allowed to use their usual rescue treatments (prescribed or over the counter) to relieve cluster headache attacks that were not aborted with the study device but were asked to refrain from use of rescue treatments for 15 minutes after initiation of treatment with the study device for an attack.
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In the ACT2 Study, subjects were instructed to treat their cluster headache attack at the onset of pain with three 2-minute stimulations (Figure 3) with stimulation to the neck ipsilateral to the side of the head where the cluster headache originated. If pain was still present at nine minutes the subjects had the option of treating with an additional three 2-minute stimulations.
Image /page/12/Figure/1 description: This image shows a flowchart of a treatment process. The treatment starts with the onset of pain, followed by three 2-minute stimulations. If the patient is pain-free, the process moves to the primary endpoint at 15 minutes. If the patient is not pain-free, an optional second treatment of three 2-minute stimulations is given.
Demographics
The ACT2 study enrolled a total of 102 patients with Cluster Headache. Demographic and baseline characteristics were not statistically different between the treatment and control arms. General Demographics are provided in the following table:
| | By Treatment Group
(N=102) | | By Cohort
(N=102) | |
|-----------------------------------------------------------------|-------------------------------|----------------|----------------------|----------------------|
| Characteristic | nVNS
(n=50) | Sham
(n=52) | eCH Cohort
(n=30) | cCH Cohort
(n=72) |
| Age, mean (SD), y | 43.9 (10.6) | 46.9 (10.6) | 42.9 (12.7) | 46.5 (9.6) |
| Male, No. (%) | 35 (70.0) | 38 (73.1) | 22 (73.3) | 51 (70.8) |
| Ethnic origin, No. (%) | | | | |
| White | 49 (98.0) | 52 (100.0) | 30 (100.0) | 71 (98.6) |
| Black | 0 | 0 | 0 | 0 |
| Asian | 1 (2.0) | 0 | 0 | 1 (1.4) |
| Duration of CH attacks during run-
in period, mean (SD), min | 69.9 (68.7) | 77.4 (76.9) | 69.6 (83.3) | 76.1 (69.0) |
| CH Type, No. (%) | | | | |
Table 6. ACT2 Demographic and Baseline Characteristics (Safety Population)
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| eCH | 15 (30.0) | 15 (28.8) | 30 (100.0) | 0 |
|---|---|---|---|---|
| cCH | 35 (70.0) | 37 (71.2) | 0 | 72 (100.0) |
| Medications used to manage CH, No. (%) | ||||
| Triptans | 37 (74.0) | 34 (65.3) | 19 (63.3) | 52 (72.2) |
| Oxygen | 27 (54.0) | 31 (59.6) | 20 (66.7) | 38 (52.8) |
| Mild analgesics | 7 (14.0) | 6 (11.5) | 2 (6.7) | 11 (15.3) |
| Narcotics | 3 (6.0) | 0 | 1 (3.3) | 2 (2.8) |
| Verapamil | 18 (36.0) | 23 (44.2) | 11 (36.7) | 30 (41.7) |
| Lithium | 4 (8.0) | 4 (7.7) | 1 (3.3) | 7 (9.7) |
| Propranolol | 1 (2.0) | 0 | 0 | 1 (1.4) |
| Tricyclic antidepressants | 2 (4.0) | 1 (1.9) | 1 (3.3) | 2 (2.8) |
| Serotonin receptor antagonists | 2 (4.0) | 2 (3.8) | 1 (3.3) | 3 (4.2) |
| Antiepileptics | 10 (20.0) | 6 (11.5) | 3 (10.0) | 13 (18.1) |
| Corticosteroids | 1 (2.0) | 2 (3.8) | 1 (3.3) | 2 (2.8) |
| Other | 5 (10.0) | 8 (15.4) | 4 (13.3) | 9 (12.5) |
| None | 0 | 5 (9.6) | 1 (3.3) | 4 (5.6) |
Abbreviations: cCH, chronic cluster headache; CH, cluster headache; eCH, episodic cluster headache; nVNS, non-invasive vagus nerve stimulation; SD, standard deviation.
Subject Disposition:
Image /page/13/Figure/3 description: This image is a flowchart that shows the progress of patients through a clinical trial. At the top, 103 patients were enrolled, and after a 1-week run-in period, 102 patients were in the safety population. The patients were then divided into two groups: a gammaCore group and a sham group. The flowchart shows the number of patients in each group at each stage of the trial, as well as the number of patients who were excluded or discontinued from the trial.
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Efficacv
The primary outcome for effectiveness defined in the ACT2 study was the percentage of total attacks that were pain-free at 15 minutes after initiation of treatment with the device with no use of rescue medication through the treatment period (30 minutes).
The results for the primary end point in the total population were 13.5% in the nVNS group and 11.5% in the sham group and the difference between the two was not statistically significant (P=0.713). In the eCH cohort, a higher percentage of attacks were pain free with nVNS than with sham treatment (nVNS 47.5%; sham 6.2%; PP value | 0.71 | | Other end points (all subjects) | | | | | | |
| Subjects who achieved responder
status (pain level 0 or 1 and no
use of rescue med through 30
min.)at 30min for ≥50% of
treated attacks, No. (%)a | 19 (39.6) | 6 (13.6) | 9 (64.3) | 2 (15.4) | 10(29.4) | 4 (12.9) |
| Subjects who achieved responder
status (pain level 0 or 1 and no
use of rescue med through 30
min.) at 15 min for their first
treated attack, No. (%)a | 18 (37.5) | 13 (29.5) | 7 (50.0) | 2 (15.4) | 11 (32.4) | 11 (55.0) |
Table 7. ACT2 Key End Points (mITT Population Unless Otherwise Indicated)
Abbreviations: cCH, chronic cluster headache; CH, cluster headache; CI, confidence interval; eCH, episodic cluster headache; ITT, intent-to-treat; nVNS, non-invasive vagus nerve stimulation; SD, standard deviation.
"No rescue medication use at any point after treatment initiation for the attack; generalized estimating equations model adjusted for site (SAS proc genmod); odds ratio >1 favors nVNS.
bP values were derived from 2-sided t tests.
&P values were derived from the Cochran-Mantel-Haenszel test stratified by site.
Safety
In the ACT2 study there were 1326 headaches treated in 102 subjects over a 4 week period in the blind and open parts of the study. The greatest number of treatments in any individual was 59. There were no device related serious adverse events. The majority of the adverse events were mild and transient and occurred during the time of active treatment. See Table 8 for complete details.
| Table 8. ACT2 Incidence of Adverse Events and Adverse Device Effects (All Treated | |
|---|---|
| Subjects) |
| Double-blind Phase | Open-label Phase | ||
|---|---|---|---|
| AEs and ADEs | nVNS (n=50) | Sham (n=52) | nVNS (n=83) |
| Subjects with ≥1 AE, No. (%) | 23 (46.0) | 22 (42.3) | 28 (33.7) |
| Subjects with ≥1 serious AE, No. (%) | 1 (2.0)a | 1 (1.9)b | 0 |
| Subjects with ≥1 ADE, No. (%) | 13 (26.0) | 13 (25.0) | 14 (16.9) |
| Device related adverse events in the treatment arm for subjects who used the gammaCore device; Percentages represent highest incidence, whether occurring in randomized or open label phase | |||
| Myokymia during treatment | 2.2% | ||
| Neck soreness or tightness | 1.1% | ||
| Application site irritation; erythema at treatment site | 4.0% |
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| Skin irritation | 4.0% |
|---|---|
| Sore or dry throat | 2.0% |
| Electrical sensation (stinging/tingling/numbness), | |
| paresthesia during treatment | 3.3% |
| Myalgia; shoulder muscle tightness | 2.2% |
| Dysgeusia during treatment | 2.0% |
| Jaw or tooth pain | 0.0% |
| Nausea or vomiting | 2.0% |
| Increased frequency/severity of cluster headache attacks | 0.0% |
4 One subject in the gammaCore group reported severe lower abdominal and lower back pain. These events were not considered related to treatment and resolved without intervention.
9 One subject in the sham group reported severe depression and anxiety. These events were not considered by the investigator to be related to the sham device. The subject discontinued from the SAEs resolved.
Additional information on safety comes from a study of 19 patients who were treated with the device both acutely and prophylactically for a period of up to 12 months ( Neurology 84: 1249-1254, Nesbitt et al, 2015). No serious adverse events were reported in this study of cluster headache patients.
Posthoc Analysis of ACT1 and ACT2 Studies
To further examine the therapeutic benefit of gammaCore for the acute treatment of episodic cluster headache the data from each study was analyzed using as close an approximation as was possible to the other study's end point. Because ACT1 defined the use of rescue medication within sixty minutes to be a treatment failure while ACT2 defined use of rescue medication within thirty minutes as a treatment failure and considering other differences in the way the treatment was delivered in ACT1 and ACT2, the comparison is not exact.
Table 9. ACT1 Primary End Point: Mild pain or pain free (score of 0 or 1 on the 5-point headache pain scale) at 15 minutes in response to the first attack in the randomization period
| | nVNS
(n/N (%)) | 95% CI | Sham
(n/N (%)) | 95% CI | P (Chi-
square or
Fishers Exact
Test) |
|-----------------------------------------------------------------------------------------|-------------------|------------|-------------------|------------|-------------------------------------------------------|
| ACT 1 Population, No rescue medication within one hour of the start of an attack | | | | | |
| Total | 16/60 (26.7) | 16.1, 39.7 | 11/73 (15.1) | 7.8, 25.4 | 0.10 |
| Episodic CH | 13/38 (34.2) | 19.6, 51.4 | 5/47 (10.6) | 3.6, 23.1 | P value |
|---|---|---|---|---|---|
| n/Na (%) | GEE Model | ||||
| Adjusted % | |||||
| (95% CI)b | n/Na (%) | GEE Model | |||
| Adjusted % | |||||
| (95% CI)b | GEE modelb | ||||
| ACT 1 Populationc, No rescue medication within one hour of the start of an attack | |||||
| Total | 28/259 (10.8) | 11.5 (7.0,18.4) | 26/319 (8.2) | 8.4 (4.9,14.0) | |
| Episodic CH | 24/158 (15.2) | 15.4 (9.5,24.1) | 13/206 (6.3) | 6.1 (3.0,12.0) | |
| Chronic CH | 4/101 (4.0) | 5.3 (1.1,22.5) | 13/113 (11.5) | 14.6 (6.1,31.0) | |
| ACT 2 Population , No rescue medication within thirty minutes of the start of an attack | |||||
| Total | 67/495 (13.5) | 15.0 (9.0,23.8) | 46/400 (11.5) | 8.7 (4.2,16.9) | 0.20 |
| Episodic CH | 48/101 (47.5) | 35.2 (19.1,55.5) | 5/81 (6.2) | 7.4 (1.6,28.4) | 0.04 |
| Chronic CH | 19/394 (4.8) | 7.4 (3.3,15.9) | 41/319 (12.9) | 9.2 (4.3,18.6) | 0.69 |
4Number of successful responses/number of attacks.
6 Generalized linear mixed effects regression models (SAS proc glimmix) were utilized to estimate the proportion of successful responses allowing for both subject-specific and population-averaged inference in non-normally distributed data. P values for comparison between nVNS and sham are from resulting F-tests.
6 ACT1 analysis is posthoc and multiplicity testing was not performed on this analysis so statistics are not included.
For the ACT2 data the result was statistically significant for the eCH subgroup. The pattern in the ACT1 data for the eCH subgroup are consistent with this result.
LABELING
The labeling for the device is a single user manual for both patients and physicians. It includes instructions for use and satisfies the requirements of 21 CFR § 801.109 for prescription devices. The labeling for the gammaCore Non-invasive Vagus Nerve Stimulator includes:
- Detailed instructions for use ●
- A detailed summary of potential risks and complications
- Instructions for discontinuing use of the device in the event of adverse side effects ●
- Warnings identifying individuals who should not use the device and populations in ● which the device has not been tested
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- A detailed summary of the clinical performance testing, including adverse events, ● complications, and potential side effects
- A warning that the long term effects of chronic use of the device have not been ● evaluated
- A statement that the device is approved based on a comparison of its low risks and probable benefit
- Instructions on proper care of the device ●
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of the external vagal nerve stimulator for headache and the measures necessary to mitigate these risks.
| Identified Risk | Mitigation Measures |
|---|---|
| Adverse tissue reaction resulting from patient contacting components | Biocompatibility evaluation |
| Labeling | |
| Electrical shock injury from device failure | Electrical safety, thermal, and |
| mechanical testing | |
| Software verification, validation, and | |
| hazard analysis | |
| Labeling | |
| Incorrect stimulation resulting from | |
| interference from other electrical devices | Electromagnetic compatibility testing |
| Stimulation side effects such as the following | |
| • Seizure | |
| • Cardiac side effects | |
| • Worsening of headache | Labeling |
| Ineffective therapeutic response due to device | |
| failure | Non-clinical performance testing |
| Software verification, validation and | |
| hazard analysis | |
| Labeling | |
| User error | Labeling |
Table 11 - Identified Risks to Health and Mitigation Measures
SPECIAL CONTROLS:
In combination with the general controls of the FD&C Act, the external vagal nerve stimulator for headache is subject to the following special controls:
-
- The technical parameters of the device, including waveform, output modes, maximum (b) and (b) (4) ohm loads), pulse duration, output voltage and current (with frequency, net charge (µC) per pulse, maximum phase charge at [60] ohms, maximum (b) maximum average current (mA), maximum average current densitv (0) (4), and the type of impedance monitoring system shall be power density characterized through non-clinical performance testing.
-
- Software verification, validation, and hazard analysis shall be performed.
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-
- Biocompatibility evaluation of the patient-contacting components of the device shall be performed.
-
- The device shall be tested for electrical, thermal, and mechanical safety, and for electromagnetic compatibility (EMC).
-
- The labeling must include:
- a) Instructions for proper use of the device, including placement of the device on the patient: and
- b) Instructions on care and cleaning of the device.
BENEFIT/RISK DETERMINATION
The risks of the device are based on the clinical studies described above while considering the patient preference information described below. There were no device related serious adverse events observed in the study. Probable device-related adverse events are mostly mild and selflimited, discontinuing when stimulation was turned off. The most common events were small muscle twitching during treatment; neck soreness or tightness; application site irritation; erythema at the treatment site; and electrical sensation (stinging/ting/ numbness). Other events include sore or dry throat; paresthesia during treatment; myalgia, shoulder muscle tightness, dysgeusia during treatment; jaw or tooth pain; nausea or vomiting; increased frequency/severity of cluster headache attacks.
The risks with long-term stimulation of this device (both frequency of daily use and for how long (months/years)) are unknown. The device was not tested in subjects with cerebral or cardiac disease and thus the risk profile in these subjects is unknown. The sponsor has mitigated these and similar risks through warnings in the labeling.
The probable benefits of the device are based on the randomized controlled clinical studies with a primary endpoint of aborting the first cluster headache (CH) attack treated with the device (ACT1) or the primary endpoint of aborting attacks treated with the device (ACT2) as well as patient preference information. A post hoc subgroup analysis was conducted analyzing separately the episodic and chronic cluster headache subgroups. This analysis demonstrated a clinically meaningful improvement in the treatment of the first attack. specifically in the number of subjects reaching mild pain or pain freedom within 15 minutes of onset and clinically meaningful improvement in the overall number of attacks that could be aborted. While both studies have a degree of uncertainty regarding clinical improvement, the patient preference information collected to date, the posthoc subgroup analyses, and the consistent outcomes in two studies done in different locations with different study designs identifies a clinically meaningful benefit in this patient population. The magnitude of the treatment effect was substantially less for the group of chronic cluster headache individuals studied in both studies and there was no demonstrable benefit shown for this subpopulation.
Additional factors considered in determining probable risks and benefits for the gammaCore device include:
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- . Characterization of the disease - the condition is severe and chronic. Even a small amount of relief can have a large impact on an affected individual.
- . Patient tolerance for risk – Patients are severely incapacitated by the headaches and have a high risk tolerance for effective treatments. The effectiveness and continuing effectiveness of the treatment for a specific individual will be readily apparent so the patient can discontinue using the device if it is not effective.
- . Availability of alternative treatments - while effective, patients express concern (see below) that existing alternative therapies are inconvenient or have more side effects.
- Risk mitigation many risks are mitigated through the labeling to instruct proper use and . to cease stimulation to minimize transient side effects that may occur during stimulation.
The device is readily portable, easily used, and can provide multiple treatments in a 24 hour time window. This makes the device significantly different from the existing therapies of triptans and high flow oxygen. The device does not prevent the use of any other rescue therapies.
Taken in total, these two studies support a clinically meaningful benefit in a portion of the episodic cluster headache population. Patients for whom this device is effective might be expected to feel relatively immediate relief from the intense pain of a cluster headache while individuals for whom it is not effective will rapidly seek other forms of relief.
Patient Perspectives
Clusterbusters, a 501(c)(3) non-profit organization "dedicated to improving the quality of life of those with cluster headache through research, education, and advocacy" conducted an 11 question survey of its community via social media. These survey results are an accurate reflection of the respondents to the survey but it was not a random survey of cluster headache sufferers. It is not known to what extent this responding population is reflective of the overall cluster headache population. Data from 291 responses submitted indicated most patients used oxygen (78%) or triptans (73%) to treat acute attacks. In response to the question, "What proportion of your attacks are you able to effectively treat with your preferred acute treatment", approximately 55% indicated they were successful less than half the time. On a 5 choice scale, 50% responded that they were 'not at all' satisfied with their currently available acute treatment options. 100% of survey responders believed that new acute treatments are needed and 86% indicated that they would try a new device if it worked for a third of their attacks. This can be compared to the data from the ACT1 and ACT2 studies that indicated that 34% (ACT1) and 64% (ACT2) of the subjects responded to over 50% of the treated attacks.
In addition to the patient survey, the sponsor identified several episodic CH patients who participated in the trial who volunteered to speak about their experiences. This group included subjects for whom the treatment was either effective or not effective. Subjects were interviewed over the phone by an FDA clinician. Interviews which lasted 30 minutes to an hour consisted of a patient history and a history of the cluster headache presentation in the individual, a history of treatments tried or in current use and their effectiveness. and a history of the impact that the condition has had on the sufferer's social and work life. The interview also addressed the willingness of the sufferer to try new approaches and to accept risk for an uncertain benefit. Consistent with the survey, these patients reported that the available abortive therapies (oxygen
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and triptans) were useful but that other therapies were needed, even if greater uncertainty existed about a product with minimal risk. Inadequacies reported by the patients for oxygen therapy include this treatment is not portable (high flow oxygen tanks), it is not effective for more severe attacks, and must be delivered at the onset of the attack which requires it to be always nearby. Inadequacies reported for triptans include sometimes not effective, not always available, and limitation of 2 doses per day which can result in 'saving' it for a worse attack when an individual is having several attacks per day.
Benefit/Risk Conclusion
Given that the gammaCore device is low risk, the disease is severe and chronic for the identified patient population, and patient tolerance for risk is high, FDA concludes that the available benefit and risk data for the use of the device for the acute treatment of episodic cluster headache demonstrates that the probable benefits outweigh the probable risks for the gammaCore device. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.
CONCLUSION
The De Novo classification request for the gammaCore Vagus Nerve Stimulator is granted and the device is classified under the following:
Product Code: PKR Device Type: External vagal nerve stimulator for headache Class: II Regulation: 21 CFR 882.8592