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Randomized Controlled Trial
, 56 (8), 1317-32

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study

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Randomized Controlled Trial

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study

Stephen D Silberstein et al. Headache.

Abstract

Objective: To evaluate non-invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment.

Background: Many patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments.

Methods: One hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15-60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified.

Results: The intent-to-treat population comprised 133 subjects: 60 nVNS-treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS-treated subjects and 15.1% of sham-treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred.

Conclusions: In one of the largest randomized sham-controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well-tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

Keywords: acute treatment; chronic cluster headache; episodic cluster headache; neuromodulation; non-invasive vagus nerve stimulation; randomized controlled trial.

Figures

Figure 1
Figure 1
Non‐invasive vagus nerve stimulation device. Image provided courtesy of electroCore, LLC. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 2
Figure 2
Time to first measurement of response used to define the primary end point. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 3
Figure 3
Subject disposition. AE, adverse event; CH, cluster headache; ITT, intent‐to‐treat; nVNS, non‐invasive vagus nerve stimulation. aSome subjects failed screening for >1 reason.
Figure 4
Figure 4
Response ratea (ITT Population). CH, cluster headache; CI, confidence interval; ITT, intent‐to‐treat; nVNS, non‐invasive vagus nerve stimulation. a Response rate was defined as the proportion of 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 and had no rescue medication use through 60 minutes after treatment initiation for the first CH attack in the double‐blind phase. P values are from Fisher's exact test (if ≥1 cell had an expected frequency of ≤5) or the chi‐square test. bPrimary end point. cPrespecified subanalysis.
Figure 5
Figure 5
Sustained treatment response ratea (ITT Population). CH, cluster headache; CI, confidence interval; ITT, intent‐to‐treat; nVNS, non‐invasive vagus nerve stimulation. a Sustained treatment response rate was defined as the proportion of subjects with a pain intensity score of 0 or 1 without rescue medication use at 15 through 60 minutes after treatment initiation for the first CH attack in the double‐blind phase. P values are from Fisher's exact test (if ≥1 cell had an expected frequency of ≤5) or the chi‐square test. bSecondary end point. cPrespecified subanalysis.

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