CompletedNCT01701245Updated Apr 25, 2016Results posted

Prevention and Acute Treatment of Chronic Cluster Headache Compared to Standard of Care

A Phase 2 interventional study of GammaCore in Chronic Cluster Headache, sponsored by ElectroCore INC. Completed at 10 sites in 4 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2016-04-25.

Sponsored by ElectroCore INC · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 97
Allocation: Randomized
Ages: 18 Years to 70 Years
Sex: All

Study summary

Subjects enrolled into this 10 week study will for the first two weeks document the number of cluster headaches and the means of treating (medication) of these attacks. Subjects will then be randomized to into either two groups. The first group is continuing with standard of care and the second group is treatment with the investigational device (GammaCore) for a period of 4 weeks. After this 4 week period, all subjects will treat with the GammaCore for another 4 week period. It is hypothesized the the treatment group will have a reduction in mean cluster headaches per week by 50% compared to the standard of care group.

Read the detailed description

The study is a prospective randomized controlled multi-center investigation designed for comparison of two parallel groups, GammaCore® (active treatment) and Standard of Care, SoC, (control). The study period begins with a 2 week run-in period, followed by a 4 week comparative period when the subjects are randomized to either active treatment or control 1:1. The comparative period will be followed by a period where all subject will receive GammaCore® for 4 weeks.After the subject signed the Consent Form for participation the baseline (visit1) data will be collected. Subject will be informed how to complete the 2 week diary during the run-in period During the run-in period, all subjects will use stable SoC according to their individual prescriptions. The subject will record as CH attack regarding duration and frequency and the use of medication and oxygen.

Once subjects have finalized the run-in period, they are randomized to continue in 4 weeks comparative period. During this period, the control group continues with stable SoC and the active group is provided with a GammaCore® device for prophylactic and acute treatment in addition to the stable SoC Subjects stimulate 3 x 2 times daily as part of the prophylactic treatment regimen (cervical vagal nerve). Three 90 second stimulations are self-administered by the subject with 5 minutes between each stimulation on the right side of the neck.

This preventive stimulation regimen is performed:

First Daily Treatment - within 1 hour of waking
Second Daily Treatment - 7-10 hours following the first daily treatment

Acute CH attack:

3 x 90 second treatments consecutively at the onset of pain or symptoms. If the attack is not aborted within 15 minutes the subject should be informed to take SOC abortive medication.
If an acute cluster headache attack is treated with the GammaCore® device, the subject will try to work within the preventive treatment window to avoid a preventive treatment in the 2-hour refractory period following the acute treatment.

A total of minimally 6 stimulations for the preventive part and as needed for the acute attacks. The active group also continues with the stable SoC during the entire 4 weeks period. Both groups record all CH attacks in the diary together with medication and oxygen use. All adverse events shall also be recorded in the diary.

The end of the 4 week comparative period marks the completion of the randomized part of the study, however all subjects are provided the option to continue to a 4 week GammaCore® treatment with the same stimulation parameter as during the 4 week randomization period. All subjects randomized to the SoC group will receive training.

During the entire study period, subjects are allowed to take rescue medication including oxygen inhalation for abortion of CH attacks. The amount and doses of the medication and oxygen are recorded in the diary.

Conditions studied

Chronic Cluster Headache

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Keywords

vagus nerve stimulation
vagal nerve stimulation
nVNS
VNS
cluster headache
chronic
non invasive
gammacore

In context

Cluster Headache

116 studies on the registry are indexed under Cluster Headache; 27 are open to participants now.

This study's enrollment of 97 is above the median of 42 across 86 interventional studies indexed under Cluster Headache.

Browse Cluster Headache studies →

Lead sponsor

ElectroCore INC is the lead sponsor of 19 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 70 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Signed Informed Consent Form 2. Subjects between the age of 18-70, both genders 3. Subjects diagnosed with chronic cluster headache for at least 1 year, without remission periods or with remission periods lasting \<1 month, in accordance with the ICHD-II classification criteria (2ndEd):

a. At least 5 attacks fulfilling the following criteria: i. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 minutes if untreated ii. Headache is accompanied by at least 1 of the following:

Ipsilateral conjunctival injection and/or lacrimation
Ipsilateral nasal congestion and/or rhinorrhea
Ipsilateral eyelid oedema
Ipsilateral forehead and facial sweating
Ipsilateral miosis and/or ptosis
A sense of restlessness or agitation iii. Attacks have a frequency from 1 every other day to 8 per day and are not attributed to another disorder iv. Attacks recur over > 1 year without remission periods or with remission periods lasting \< 1 month.

Has minimum mean attack frequency of 4 CH attacks per week. 5. Is able to distinguish CH from other headaches (i.e. tension-type headaches).

Is capable of completing headache pain self-assessments. 7. Agrees to use the GammaCore® device as intended and follow all of the requirements of the study, including follow-up visit requirements.

Is willing to keep all concomitant medication stable during the entire study period.

Women of child-bearing potential must use 2 methods of contraceptive i.e. hormones and condom.

Exclusion criteria

Exclusion Criteria:

Is currently taking CH prophylactic medication for indications other than CH which in the opinion of the clinician may interfere with the study
Has had a change in type or dosage of prophylactic headache medications \< 1 month prior to enrollment
Has a history of intracranial or carotid aneurysm, intracranial hemorrhage, brain tumors or significant head trauma.
Has a lesion (including lymphadenopathy), dysaesthesia, previous surgery or abnormal anatomy at the GammaCore® treatment site.
Has other significant pain problem that might confound the study assessments in the opinion of the investigator.
Has known or suspected severe atherosclerotic cardiovascular disease, severe carotid artery disease (e.g. bruits or history of TIA or CVA), congestive heart failure (CHF), known severe coronary artery disease or recent myocardial infarction (within 5years).
Has had a previous unilateral or bilateral vagotomy.
Has uncontrolled high blood pressure.
Is currently implanted with an electrical and/or neurostimulator device, including but not limited to cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant.
Has a history of carotid endarterectomy or vascular neck surgery on the right side.
Has been implanted with metal cervical spine hardware or has a metallic implant near the GammaCore® stimulation site.
Has a history, the last 12 month, of syncope.
Has a history, the last 12 month of seizures.
Has a known history or suspicion of substance abuse or addiction, or overuse of acute headache medication for headaches other than CH.
Has psychiatric or cognitive disorder and/or behavioral problems which in the opinion of the investigator may interfere with the study
In the opinion of the investigator the subject is incapable of operating the GammaCore® device as intended and performing the data collection procedures.
Is participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days.
Woman who are pregnant or lactating.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 97 participants (actual)

Study arms

No intervention
Standard of care
No intervention, standard of care
Active comparator
GammaCore
Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.
Device: GammaCore

Interventions

DeviceGammaCore
vagal stimulation

What researchers measure

Primary outcomes

A Change in the Frequency of Cluster Headache Attacks Per Week
The primary endpoint is the reduction in mean number of CH attacks per week. The number of CH attacks will be calculated as the sum of all attacks over the days in the run-in period and divided by the number of weeks, respectively for the last 14 days of treatment during the randomised phase. The reduction will then be the number of CH attacks during treatment period (last 14 days of the randomized treatment period) - number of CH attacks during run-in.
Time frame: 4 weeks

Secondary outcomes

Pain Relief of Headache Attacks
The median pain during baseline (2 weeks) will be compared with the last 14 days of the treatment period Scale 0-4 0= no pain 1. mild pain 2. moderate pain 3. severe pain 4. very severe pain
Time frame: baseline (2 weeks) and random period(last 2 weeks)
Adverse Events
The frequency of device effects will be compared between the two treatment groups. Only effects which are new after baseline or have increased severity after baseline will be used in the comparison.
Time frame: 10 weeks
EQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)
The EQ-5D-3L (EuroQoL 5 questions and 3 answering levels) during the run-in period will be compared with the EQ-5D-3L during the treatment period. And treatment period will be compared to open label. Rating of questions Level 1 no problems Level 2 some problems Level 3 Significant problems Worst case is 15 points and best case is 5 points using index Visual analogue scale VAS 0-100 where 0 is the worst imaginable health state and 100 the best imaginable health state
Time frame: 10 weeks (baseline 2 weeks, random 4 weeks and open label 4 weeks)

Results

Posted Apr 25, 2016

Participant flow

Participant flow — Overall Study
Milestone	Standard of Care	GammaCore
Started	49	48
Fas unmatched data	48	45
Fas matched data	42	32
Completed	37	33
Not completed	12	15
Withdrew: Protocol violation	1	3
Withdrew: Did not complete the open label period	11	12

Outcome measures

PrimaryA Change in the Frequency of Cluster Headache Attacks Per Week

The primary endpoint is the reduction in mean number of CH attacks per week. The number of CH attacks will be calculated as the sum of all attacks over the days in the run-in period and divided by the number of weeks, respectively for the last 14 days of treatment during the randomised phase. The reduction will then be the number of CH attacks during treatment period (last 14 days of the randomized treatment period) - number of CH attacks during run-in.

Time frame:: 4 weeks
Reported as:: Mean · CH attacks per week

A Change in the Frequency of Cluster Headache Attacks Per Week
CH attacks per week	Standard of Care	GammaCore
A Change in the Frequency of Cluster Headache Attacks Per Week	-2.0 ± 7.6	-7.6 ± 6.4

SecondaryPain Relief of Headache Attacks

The median pain during baseline (2 weeks) will be compared with the last 14 days of the treatment period Scale 0-4 0= no pain 1. mild pain 2. moderate pain 3. severe pain 4. very severe pain

Time frame:: baseline (2 weeks) and random period(last 2 weeks)
Reported as:: Number · participants

Pain Relief of Headache Attacks
participants	Standard of Care	GammaCore
Mild baseline	2	1
Mild random	3	1
Moderate baseline	16	8
Moderate random	15	11
Severe baseline	16	15
Severe random	16	12
Very severe baseline	8	8
Very severe random	8	8

SecondaryAdverse Events

The frequency of device effects will be compared between the two treatment groups. Only effects which are new after baseline or have increased severity after baseline will be used in the comparison.

Time frame:: 10 weeks
Reported as:: Number · participants

Adverse Events
participants	Standard of Care	GammaCore
Mild	6	9
Moderate	2	1
Severe	0	1

SecondaryEQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)

The EQ-5D-3L (EuroQoL 5 questions and 3 answering levels) during the run-in period will be compared with the EQ-5D-3L during the treatment period. And treatment period will be compared to open label. Rating of questions Level 1 no problems Level 2 some problems Level 3 Significant problems Worst case is 15 points and best case is 5 points using index Visual analogue scale VAS 0-100 where 0 is the worst imaginable health state and 100 the best imaginable health state

Time frame:: 10 weeks (baseline 2 weeks, random 4 weeks and open label 4 weeks)
Reported as:: Mean · units on a scale

EQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)
units on a scale	Standard of Care	GammaCore
Baseline vs. Randomized period	-0.049 (-0.837 to 0.856)	0.145 (-0.532 to 0.807)
Randomized period vs. Open label perios	0.078 (-0.601 to 1.01)	0.155 (-0.568 to 1.01)
VAS Baseline vs. Randomized period	0.27 (-81.0 to 40.0)	9.20 (-20.0 to 40.0)
VAS Randomized period vs. Open label	4.36 (-50.0 to 48.0)	10.79 (-26.0 to 55.0)

Adverse events

Collected over 18 months. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Standard of Care	—	2/49 (4.1%)	3/49 (6.1%)
GammaCore	—	2/48 (4.2%)	3/48 (6.3%)

Most frequent serious events

Most frequent serious events
Event	Standard of Care	GammaCore
CholecystitisHepatobiliary disorders	0/49	1/48
Scrotal HaematomaInjury, poisoning and procedural complications	0/49	1/48
Genital herpes simplexInfections and infestations	1/49	0/48
Cluster headacheNervous system disorders	1/49	0/48

Most frequent other events

Most frequent other events
Event	Standard of Care	GammaCore
DizzinessNervous system disorders	3/49	3/48

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Standard of Care	GammaCore	Total
Mean	42.3 ± 11.0	45.4 ± 11.0	43.8 ± 11.1

Sex: Female, Male
Sex: Female, Male(Participants)	Standard of Care	GammaCore	Total
Female	16	14	30
Male	33	34	67

Region of Enrollment
Region of Enrollment(participants)	Standard of Care	GammaCore	Total
Belgium	5	4	9
Germany	28	29	57
United Kingdom	13	11	24
Italy	3	4	7

Study locations

10 sites

University Department of Neurology CHR
Liège, B-4000, Belgium
Westdeutsches Kopfschmerzzentrum
Hufelandstr. 26, Essen D-45147, Germany
Neurologische Klinik und Poliklinik
Berlin, D-10117, Germany
Krankenhaus Lindenbrunn, Department of Neurology
Coppenbrügge, D-31863, Germany
Migräne- und Kopfschmerzklinik Königstein
Königstein im Taunus, D-61462, Germany
Department of Neurology, University of Munich
Munich, D-813 77, Germany
Regional Referral Headache Centre Sant' Andrea Hospital
Rome, IT-00189, Italy
The Southern Hospital, Neurology Department
Glasgow, Scotland G51 4TF, United Kingdom
Hull Royal Infirmary, Neurology Department
Hull, HU3 2JZ, United Kingdom
The Walton Centre, Neurology Department
Liverpool, L9 7LJ, United Kingdom

References and documents

Publications

Morris J, Straube A, Diener HC, Ahmed F, Silver N, Walker S, Liebler E, Gaul C. Cost-effectiveness analysis of non-invasive vagus nerve stimulation for the treatment of chronic cluster headache. J Headache Pain. 2016;17:43. doi: 10.1186/s10194-016-0633-x. Epub 2016 Apr 22. PubMed 27102120 ↗

Individual participant data

Plan to share: No — Not planned to share individual data

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Apr 25, 2016, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01701245
Lead sponsor: ElectroCore INC
Responsible party: Sponsor
First posted: Oct 5, 2012
Start date: Oct 2012
Primary completion: Mar 2014
Completion: Oct 2014
Results posted: Apr 25, 2016
Last update: Apr 25, 2016

Study contacts

Charly Gaul, Dr med

principal investigator · Migräne- und Kopfschmerzklinik Königstein

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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