Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study

Abstract

Background Clinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for treating cluster headache (CH) attacks. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. Results The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%; p < 0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. Conclusions Combing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirm and extend previous findings regarding the efficacy, safety, and tolerability of nVNS for the acute treatment of eCH.

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

Figure 1.

Subject disposition. Abbreviations: AE: adverse event; cCH: chronic cluster headache; eCH: episodic cluster headache; ITT: intent-to-treat; LTFU: lost to follow-up; nVNS: non-invasive vagus nerve stimulation.

Figure 2.

Proportions of all treated attacks that achieved pain-free status within 15 minutes (ITT population). n Values denote the numbers of treated CH attacks; ORs (95% CIs) are 1.22 (0.42, 3.51) for all CH, 9.19 (1.77, 47.80) for eCH, and 0.41 (0.13, 1.30) for cCH. ORs and p values are from the generalized estimating equations model, which was adjusted for site in the total cohort and cCH subgroups but was not adjusted for site in the eCH subgroup. OR > 1 favors nVNS. 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; OR: odds ratio.

Figure 3.

Proportions of treated attacks per subject that achieved responder (a) or pain-free (b) status within 30 minutes (ITT population). (a) Responder status. Differences (±SE) between treatment groups are 15.1 (7.3) for all CH, 32.0 (15.0) for eCH, and 8.1 (8.1) for cCH. (b) Pain-free status. Differences (± SE) between treatment groups are 7.8 (6.4) for all CH, 23.9 (14.4) for eCH, and 1.3 (6.5) for cCH. nValues denote numbers of patients; p values are from the Wilcoxon rank sum test stratified by study site. Abbreviations: cCH: chronic cluster headache; CH: cluster headache; eCH: episodic cluster headache; ITT: intent-to-treat; nVNS: non-invasive vagus nerve stimulation; SD: standard deviation; SE: standard error.

Figure 4.

Proportions of subjects who achieved pain-free (A) or responder (B) status in ≥50% of treated attacks at 15 minutes (ITT population). (a) Pain-free status. (b) Responder status. p values were determined from the chi-square or Fisher’s exact test, as appropriate. Abbreviations: cCH: chronic cluster headache; CH: cluster headache; eCH: episodic cluster headache; ITT: intent-to-treat; nVNS: non-invasive vagus nerve stimulation.