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Supplements Considerations in Non-Invasive Vagus Nerve Stimulation: Clinical Data and Expert Panel Recommendations
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Bruce Simon, PhD, and Justyna Blake, MSE
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Review of Non-Invasive Vagus Nerve Stimulation (gammaCore): Efficacy, Safety, Potential Impact on Comorbidities, and Economic Burden for Episodic and Chronic Cluster Headache
Mkaya Mwamburi, MD, PhD (HEOR), MA (Econ); Eric J. Liebler, BA; and Andrew T. Tenaglia, BA
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Review of Non-Invasive Vagus Nerve Stimulation (gammaCore): Efficacy, Safety, Potential Impact on Comorbidities, and Economic Burden for Episodic and Chronic Cluster Headache

Mkaya Mwamburi, MD, PhD (HEOR), MA (Econ); Eric J. Liebler, BA; and Andrew T. Tenaglia, BA
The FDA has cleared gammaCore (non-invasive vagus nerve stimulator [nVNS]) for the treatment of episodic cluster headache (eCH). With the exception of subcutaneous sumatriptan, all other treatments are used off label and have many limitations. The FDA approval process for devices differs from that of drugs. We performed a review of the literature to evaluate new evidence on various aspects of gammaCore treatment and impact. The ACute Treatment of Cluster Headache Studies (ACT1 and ACT2), both double-blind sham-controlled randomized trials, did not meet the primary endpoints of the trials but each demonstrated significant superiority of gammaCore among patients with eCH. In ACT1, gammaCore resulted in a higher response rate (RR) (RR, 3.2; 95% CI, 1.6-8.2; P = .014), higher pain-free rate for >50% of attacks (RR, 2.3; 95% CI, 1.1-5.2; P = .045), and shorter duration of attacks (mean difference [MD], –30 minutes; P <.01) compared with the sham group. In ACT2, gammaCore resulted in higher odds of achieving pain-free attacks in 15 minutes (OR, 9.8; 95% CI, 2.2-44.1; P = .01), lower pain intensity in 15 minutes (MD, –1.1; P <.01), and higher rate of achieving responder status at 15 minutes for ≥50% of treated attacks (RR, 2.8; 95% CI, 1.0-8.1; P = .058) compared with the sham group. The PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) study also demonstrated that gammaCore plus standard of care (SOC) was superior to SOC alone in patients with chronic cluster headache (CH). Medical costs, pharmacy refills, and pharmacy costs were higher in patients coded for CH in claims data compared with controls with nonheadache codes. gammaCore is easy to use, practical, and safe; delivery cannot be wasted; and patients prefer using gammaCore compared with SOC. The treatment improves symptoms and reduces the need for CH rescue medications. Current US reimbursement policies, which predate nVNS and are based on expensive, surgically implanted, and permanent implanted vagus nerve stimulation (iVNS), need to be modified to distinguish nVNS from iVNS. gammaCore, cleared by the FDA in April 2017, provides substantial value to patients and also to payers. There is sufficient evidence to support the need to modify current reimbursement policies to include coverage for gammaCore (nVNS) for eCH.
 
In April 2017, the FDA cleared gammaCore (non-invasive vagus nerve stimulator [nVNS]; electroCore Medical, LLC, Basking Ridge, NJ) for the treatment of pain associated with episodic cluster headache (eCH) in the United States.1 gammaCore has been available in Europe and other world regions since 2013 and is used for multiple indications, including cluster headache (CH) and migraine. CH, which may be episodic or chronic, is a type of primary headache that causes excruciating pain around the eyes that affects approximately 0.1% to 0.4% of individuals in the United States and Europe.2,3 However, the disorder is responsible for a substantial and disproportionate amount of clinical and economic burden.4,5 Only 1 other treatment, subcutaneous sumatriptan, is approved by the FDA for treatment of eCH in the United States. Other treatments for CH, such as intranasal zolmitriptan, ergotamine tartrate, narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and NSAID-based combinations (eg, Excedrin), among others, are used off label.6,7 High-flow oxygen is also used for treatment of acute attacks of CH. No treatment is approved by the FDA for prophylactic treatment of CH. However, similar to treatments used for acute attacks, many prophylactic treatments are used off label, including corticosteroids (eg, prednisone), verapamil, ergotamine tartrate, lithium, and divalproex sodium.6,7 The effectiveness and reliability of previously used treatments for CH have been limited.8

Outside the United States, gammaCore is used for multiple indications. In the United Kingdom, for instance, the National Institute for Health and Care Excellence has provided guidance for gammaCore use for the prevention and acute treatment of migraine and CH.9,10 In the 3 years prior to the FDA clearance of gammaCore in the United States, pivotal studies for gammaCore have cumulatively generated significant research data and new evidence for the efficacy of gammaCore in patients with CH. In addition, observational studies conducted in Europe provide evidence for the clinical and economic burden of CHs.1,4-8,11-18 A review of new evidence, including data from recent pivotal trials, not captured in prior reviews, is critical when evaluating this newly approved treatment for eCHs in order to inform and update practice guidelines and reimbursement policies.

We perfomed a qualitative review of the literature that focused on available evidence regarding the efficacy, safety, and economic impact of gammaCore (nVNS) in episodic and chronic CH. The purpose was to understand the clinical and economic burden of CHs, highlighting the potential for longer-term benefits of adequately managing patients with CH.

Methods

We performed a review of literature, with qualitative analysis of the evidence related to the efficacy and effectiveness of gammaCore, including its safety and impact on quality of life in the treatment of eCH and chronic CH. We also evaluated the burden of illness of CHs.

Sources of Evidence

Evidence from the following sources were reviewed:

Research published before August 31, 2017, in English, that focused on gammaCore for treatment of CH in humans.

The search strategy was defined by search terms in PubMed using key terms and their respective variations and Medical Subject Headings equivalents for:

nVNS or gammaCore

Primary studies were excluded if they were:

Non-CH studies

Focused on other nVNS (nongammaCore)

Mixed-indication populations

Reviews that included clinical applications for gammaCore (nVNS) published within 3 years of search date, including the role of gammaCore in current treatment landscape

Studies identified in bibliographies of qualifying research studies

Recent studies, presented in 2014 to 2016 at conferences, that focused on gammaCore treatment, effectiveness, or burden of illness of CH specifically, or on primary headaches in general. electroCore provided a complete list of publications and abstracts/posters presented at conferences, including those of the American Headache Society, American Academy of Neurology, International Society of Pharmacoeconomics and Outcomes Research, and the Academy of Managed Care Pharmacy.

Study Selection

All publications and conference presentations on gammaCore were reviewed. The search yields from PubMed and from conference proceedings were combined and any duplicate studies were removed. If studies were published as full-text, peer-reviewed journal articles and presented in conference proceedings as well, then the most recent cumulative information of the studies from both sources was included.

Qualitative Analysis

Data were analyzed qualitatively in the following categories:

Randomized trials

Observational studies on the potential impact of gammaCore and the burden of illness of CH specifically or of primary headaches in general

Cost-effectiveness studies of gammaCore treatment

Findings presented in recent reviews

Results

The PubMed search yield was 101 studies, while that from conferences was 8 studies. Of the total of 109 studies, 95 were rejected (4 were duplicate studies and 91 were non-CH studies). Of the 14 qualifying studies, 3 were randomized trials, 3 were observational studies, 2 were cost-effectiveness studies, 1 was a burden-of-illness study, and 5 were reviews or pooled analyses that included the clinical role of gammaCore. Study attrition is shown in the PRISMA diagram (Figure).

Randomized Trials

Three multicenter randomized trials were reported, evaluating efficacy, quality-of-life measures, and safety of gammaCore.1,6,7

Trial Designs

The ACute Treatment of Cluster Headache Studies (ACT1 and ACT2) were prospective, multicenter, double-blind, sham-controlled, randomized trials with optional open-label extension phases. ACT1 and ACT 2 evaluated the superiority of gammaCore acute treatment in patients with both eCH and chronic CH who remained on their current CH medications or standard of care (SOC) (Table 1).1,7 ACT1 was conducted across 20 US centers (ClinicalTrials.gov identifier: NCT01792817). Patients were evaluated in a double-blind randomization phase for 1 month or until 5 CH attacks were treated, and in an open-label phase in which patients who completed the double-blind phase optionally received 3 additional months of gammaCore treatment. ACT2, also a double-blind randomized trial with an open-label extension phase, was conducted in 9 European centers (ClinicalTrials.gov identifier: NCT01958125). A limitation of the ACT trials was that multiple attacks in an individual patient were treated as though they were independent events for 1 of the outcomes reported.

The PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) study evaluated efficacy of gammaCore + SOC in comparison with SOC alone in preventive treatment of patients with chronic CH.6,14 PREVA was a prospective, multicenter, open-label, randomized, controlled trial conducted at 10 European sites (ClinicalTrials.gov identifier: NCT01701245). Patients were evaluated in a 2-week run-in phase in which all participants received only their medications (SOC), followed by an open-label randomization phase for 1 month, followed by an open-label phase of gammaCore + SOC treatment for 1 month.

Trial Results

Study results for ACT1 and ACT2 for the respective primary end points,  as described below for episodic patients, were nonsignificant, but the results were significant for PREVA (Table 2).1,6,7 For all 3 trials, the mean age of patients was between 42 and 49 years, mostly male (at least 67%), who reported, at baseline, the average duration of attack to be between 60 and 105 minutes. In all trials, a significant proportion of patients were on standard treatments including triptans, high-flow oxygen, and prophylactic therapy, including verapamil and corticosteroids.

The ACT1 study sample was composed of two-thirds of patients with eCH and one-third of patients with chronic CH.7 In a prespecified secondary endpoint, the efficacy for patients with eCH in ACT1 receiving gammaCore, the treatment resulted in a response rate (RR) more than 3 times higher compared with sham (RR, 3.2; 95% CI, 1.6-8.2; P = .014), a rate of being pain-free for >50% of attacks that was more than 2 times higher versus sham (RR, 2.3; 95% CI, 1.1-5.2; P = .045), and a difference of more than 30 minutes in duration of attacks, with a mean difference (MD) of –14.4 minutes for gammaCore compared with + 16.3 minutes for sham (P <.01). RR was defined as the proportion of all subjects who achieved a pain intensity score of 0 or 1 on a 5-point scale (0, no pain; 4, very severe pain) at 15 minutes after treatment initiation and who did not require rescue medication.7 The safety profile for gammaCore was similar to sham. All device-related adverse events (AEs) reported were mild and transient with no serious device-related AEs reported. The number of patients (of all study participants) reporting at least 1 AE was 18 (25%) in the gammaCore group compared with 30 (40%) in the sham group. The number of patients reporting at least 1 device-related AE was 11 (15%) in the gammaCore group compared with 24 (31%) in the sham group. One patient in the gammaCore group reported a serious AE not related to the device (deep vein thrombosis), whereas none were reported in the sham group.

The ACT2 data, which have been presented but not published, were based on a study sample of approximately 30% patients with eCH and 70% patients with chronic CH.1,19 Regarding efficacy for patients with eCH in ACT2 receiving gammaCore, compared with sham, the treatment resulted in nearly 10 times higher odds of achieving pain-free attacks with no rescue medication use in 15 minutes (OR, 9.84; 95%; CI, 2.2-44.1; P = .01), reduction in the intensity of attacks within 15 minutes (MD, –1.1; P <.01), and a rate nearly 3 times higher of achieving responder status at 15 min for ≥50% of treated attacks (RR, 2.8; 95% CI, 1.0-8.1; P = .058). Response status was defined as the proportion of all subjects who reported mild or no pain at 15 minutes after treatment initiation, and intensity score was based on a 5-point scale (0, no pain; 4, very severe pain).1 The safety profile for gammaCore was also similar to sham in ACT2. All device-related AEs were mild and transient with no serious device-related AEs reported. The number of patients reporting at least 1 AE was 23 (46%) in the gammaCore group compared with 22 (42%) in the sham group; the AEs were mild and transient, including lip pull, skin irritation, and metallic taste at the time of application. The number of patients reporting at least 1 device-related AE was 13 (26%) in the gammaCore group compared with 13 (25%) in the sham group. One patient in the gammaCore group reported a serious AE (severe lower abdominal and lower back pain), as did 1 in the sham group (severe depression).

 
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