Table 3.

Summary of clinical studies addressed to non-invasive cervical vagal nerve stimulation (nVNS) for the treatment of episodic and chronic cluster headache

Year, study design	Headache disorder	Primary treatment	Patient no.	Outcome/parameter	Follow-up	Cyclic stimulation paradigm	Efficacy	Safety/tolerability
2015, pCS23 Class IV	ECH CCH	Acute Prevention	19 8 ECH 11 CCH	Severity/frequency Safety/tolerability	12 months	120 sec dose at a 15 min interval applied two times (prevention) 120 sec dose at a 3 min interval applied unilaterally two to three times/day (acute) Unilateral vagus nerve Predominant head pain	48% overall improvement in 15 patients 47% overall abortive rate within 11±1 min 55% oxygen reduction in 10 patients 48% triptan intake reduction in nine patients Significant attack frequency reduction (4.5/24 vs. 2.6/24 h) p<0.0005	No SAE Mild AE (two patients) Skin reaction Side shift of attacks
2015, pCS24 Class IV	CTS	Acute Prevention	1	Severity/frequency Functional impairment (MIDAS, BDI)	12 weeks	90 sec dose at a 15 min interval applied two times (prevention) 90 sec dose at a 15 min interval applied at attack onset (acute) Unilateral vagus/right sided	45% overall improvement 53% significant MIDAS improvement	No SAE
2016, RCT25 ACT-1 study 1-month double- blind, sham- controlled phase 3-month open- label phase Class I	ECH CCH Subgroup analysis	Acute	Randomized phase 150 73 nVNS 77 sham Open-label phase 128 59 nVNS 69 sham	Primary endpoint (response rate at 15 min treatment) Secondary endpoint (sustained response rate at 15–60 min treatment) ECH vs. CCH subtype analysis	4 months	Three to five doses of 120 sec duration at premonitory symptoms or pain onset Unilateral vagus nerve Right sided	Primary endpoint ITT analysis p=0.1 nVNS-ECH vs. sham-ECH p=0.008 Secondary endpoint ITT analysis p=0.04 nVNS-ECH vs sham-ECH p=0.008	Randomized phase ≥1 AE in 72/150 (48%) ADE in 35/150 (23%) Open-label phase ≥1 AE in 42/128 (33%) ADE in 18/128 (14%) No SDAE
2017, RCT26 ACT-2 study 2-week double- blind, sham- controlled phase 2-week open-label phase Class I	ECH CCH Subgroup analysis	Acute	Randomized phase 102 50 nVNS 52 sham Open-label phase 83 45 nVNS 38 sham	Primary endpoint (pain free at 15 min treatment) Secondary endpoint (pain-relief rate + pain-free rate + mean change in pain intensity at 30 min treatment) ECH vs. CCH subtype analysis	4 weeks	Three to six doses of 120 sec duration at premonitory symptoms or pain onset Unilateral vagus nerve Predominant head pain	Primary endpoint ITT analysis p=0.71 nVNS-ECH vs. sham-ECH p<0.01 Secondary endpoint pain relief ITT analysis p=0.05 nVNS-ECH vs sham-ECH p=0.07 nVNS-CCH vs sham-CCH p=0.34	Randomized phase ≥1 AE in 34/102 (33%) ≥1 ADE 18% Open-label phase ≥1 AE in 23/83 (27%) ≥1 ADE 12% No SDAE
2015, RCT27 PREVA study 4-week randomized phase 4-week extension phase Class III	CCH	Prevention Acute nVNS+SoC vs. SoC alone	Randomized phase 97 48 nVNS+SoC 49 SoC alone Extension phase 92 nVNS+SoC	Primary endpoint (reduction in mean of CH attacks/week) Secondary endpoint (≥50% response rate, acute medication use, duration/intensity of CH attacks)	8 weeks	Three doses of 120 sec duration at a 5 min interval twice per day plus three additional doses for acute use Unilateral vagus nerve Right sided	Primary endpoint ITT analysis p=0.02 nVNS+SoC (−5.9) vs. SoC (−2.1) Secondary endpoint ≥50% response rate nVNS+SoC (40%) vs. SoC (8.3%) p<0.001	Randomized phase ≥1 AE 38% (nVNS+SoC) ≥1 AE 27% (SoC) Extension phase ≥1 AE 25% (nVNS+SoC) ≥1 AE 24%(SoC) No SDAE
2017, RCT28 PREVA study post hoc analysis 4-week randomized phase 4-week extension phase Class III	CCH	Prevention Acute nVNS+SoC vs. SoC alone	Randomized phase 97 48 nVNS+SoC 49 SoC alone Extension phase 92 nVNS+SoC	Primary endpoint (reduction in mean of CH attacks/week + global changes) Secondary endpoint (response rates at cut-offs of ≥25%, ≥50%, ≥75%, ≥100% frequency reduction)	8 weeks	Three doses of 120 sec duration at a 5 min interval twice per day plus three additional doses for acute use Unilateral vagus nerve Right sided	Primary endpoint ITT analysis p<0.02 nVNS+SoC vs. SoC at all study time points Secondary endpoint ≥25%, ≥50% (p<0.001) ≥75% (p=0.009) nVNS+SoC vs. SoC	Randomized phase ≥1 AE 38% (nVNS+SoC) ≥1 AE 27% (SoC) Extension phase ≥1 AE 25% (nVNS+SoC) ≥1 AE 24% (SoC) No SDAE
2016, RCT21 Cost-effectiveness analysis PREVA data	Pharmacoeconomic model using PREVA data nVNS+SoC vs. SoC alone	1-year cost- effectiveness analysis CCH	Preventive treatment	Health care cost Short-/long-term response QALY Abortive medication use Adjunctive therapies	12 months	-------------	nVNS=7,096 Euro SoC=7,511 Euro nVNS+SoC vs. SoC 23% reduction in abortive use nVNS (QALY) 0.607 vs. SoC (QALY) 0.522	Adjunctive nVNS more effective and cost saving than SoC alone
201622 Cost-effectiveness analysis	Pharmacoeconomic nVNS+SoC vs. SoC alone	1-year cost- effectiveness analysis ECH	Acute treatment	Health care cost QALY Adjunctive therapies	12 months	-------------	nVNS=$9,510 SoC=$10,040 nVNS (QALY) 0.83 vs. SoC (QALY) 0.74	Adjunctive nVNS more effective and cost saving than SoC alone

Abbreviations: ADE, adverse device effect; AE, adverse event; BDI, Beck Depression Inventory; CCH, chronic cluster headache; CH, cluster headache; CTS, cluster tic syndrome; ECH, episodic cluster headache; ITT, intent-to-treat; MIDAS, Migraine Disability Scale; nVNS, noninvasive vagus nerve stimulation; pCS, prospective observational cohort studies, QALY, quality-adjusted life years; RCT, randomized controlled trial; SAE, serious adverse event; SDAE, serious device-related adverse event; SoC, standard of care.