Trial Outcomes & Findings for A Randomized, Sham-controlled Study of gammaCore ® (nVNS) for Prevention of Episodic Migraine (NCT NCT02378844)

Last Updated: 2019-08-19

Results Overview

Change in number of migraine days (as reported in subject diary), comparing the 4 week run-in period to the last 4 weeks in the randomized period.

Recruitment status

COMPLETED

Study phase

Target enrollment

477 participants

Primary outcome timeframe

last 4 weeks of the randomized/controlled period compared to the subject's own 4-week run-in period.

Results posted on

2019-08-19

Participant Flow

Participant milestones

Participant milestones
Measure	gammaCore®-R Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized
Run-in Period STARTED	169	172	136
Run-in Period COMPLETED	165	167	0
Run-in Period NOT COMPLETED	4	5	136
Randomized Period (Double Blind) STARTED	165	167	0
Randomized Period (Double Blind) COMPLETED	142	135	0
Randomized Period (Double Blind) NOT COMPLETED	23	32	0
Open Label Period STARTED	142	135	0
Open Label Period COMPLETED	99	87	0
Open Label Period NOT COMPLETED	43	48	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Randomized, Sham-controlled Study of gammaCore ® (nVNS) for Prevention of Episodic Migraine

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Total n=332 Participants Total of all reporting groups
Age, Continuous	43.5 years STANDARD_DEVIATION 11.11 • n=5 Participants	41.4 years STANDARD_DEVIATION 12.26 • n=7 Participants	42.4 years STANDARD_DEVIATION 11.73 • n=5 Participants
Sex: Female, Male Female	142 Participants n=5 Participants	138 Participants n=7 Participants	280 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	29 Participants n=7 Participants	52 Participants n=5 Participants
Race/Ethnicity, Customized Race · Caucasian	160 Participants n=5 Participants	154 Participants n=7 Participants	314 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	4 Participants n=5 Participants	8 Participants n=7 Participants	12 Participants n=5 Participants
Region of Enrollment Greece	15 participants n=5 Participants	16 participants n=7 Participants	31 participants n=5 Participants
Region of Enrollment Netherlands	15 participants n=5 Participants	16 participants n=7 Participants	31 participants n=5 Participants
Region of Enrollment Belgium	11 participants n=5 Participants	11 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Norway	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Denmark	17 participants n=5 Participants	16 participants n=7 Participants	33 participants n=5 Participants
Region of Enrollment United Kingdom	43 participants n=5 Participants	48 participants n=7 Participants	91 participants n=5 Participants
Region of Enrollment Germany	36 participants n=5 Participants	32 participants n=7 Participants	68 participants n=5 Participants
Region of Enrollment Spain	22 participants n=5 Participants	22 participants n=7 Participants	44 participants n=5 Participants

PRIMARY outcome

Timeframe: last 4 weeks of the randomized/controlled period compared to the subject's own 4-week run-in period.

Population: Randomized population, Intention to Treat (ITT)

Change in number of migraine days (as reported in subject diary), comparing the 4 week run-in period to the last 4 weeks in the randomized period.

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Change in the Number of Migraine Days	-1.98 Days Standard Deviation 3.031	-1.53 Days Standard Deviation 3.090	—	—

SECONDARY outcome

Timeframe: The last four weeks in the randomization period compared to the four week run-in period.

Population: Randomized population, Intention to Treat (ITT)

The number of subjects with a reduction of 50% or more in number of migraine days (as reported in the subject diary) from the run-in period to the last 4 weeks of the double-blind period.

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Number of Participants With 50% Responder Rate	47 Participants	38 Participants	—	—

SECONDARY outcome

Timeframe: The last four weeks in the randomization period compared to the four week run-in period.

Population: Randomized population, Intention to Treat (ITT)

The mean change in number of headache days (as reported in the subject diary) from the run-in period to the last 4 weeks of the double-blind period.

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Mean Change in Number of Headache Days	-2.28 Days Standard Deviation 3.623	-1.72 Days Standard Deviation 3.732	—	—

SECONDARY outcome

Timeframe: The last four weeks in the randomization period compared to the four week run-in period.

Population: Randomized population, Intention to Treat (ITT)

The mean change in number of acute medication days (as reported in the subject diary) from the run-in period to the last 4 weeks of the double-blind period

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Change in Number of Acute Medication Days	-1.65 acute medication days Standard Deviation 3.310	-1.02 acute medication days Standard Deviation 3.310	—	—

SECONDARY outcome

Timeframe: From four week run-in period to last four weeks in the randomization period

Population: Randomized population, Intention to Treat (ITT) In the active group 23 subjects had missing data, in the sham group 32 subjects had missing data at the end of the randomized period

Change in headache disability from the 4 week run-in period to the last 4 weeks of the randomized period as measured using the Headache Impact Test-6 (HIT-6). The HIT-6 measures the impact if a subject's headaches on their ability to function at work, at home and in social situations. Subjects are presented with 6 questions about ability to function and normal daily life and for each question they rate the impact of their headaches as 'never' (6 points) or 'rarely' (9 points) or 'sometimes' (10 points) or 'very often' (11 points) or 'always' (13 points). Minimum score = 36, maximum score = 78. A higher score indicates more impact.

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Change in Headache Disability Using Headache Impact Test-6 HIT-6 score Run-in perio	63.442 units on a scale Interval 49.0 to 74.0	64.263 units on a scale Interval 44.0 to 76.0	—	—
Change in Headache Disability Using Headache Impact Test-6 HIT-6 score end of Randomized period	60.234 units on a scale Interval 42.0 to 76.0	60.992 units on a scale Interval 40.0 to 78.0	—	—

SECONDARY outcome

Timeframe: 3 months - end of run-in period to end of randomized period

Population: Randomized population, Intention to Treat (ITT) At randomisation (visit 2) subject numbers are 165 gammaCore-R and 167 gammaCore-R Sham. At visit 6 the numbers are lower due to early subject discontinuation: 141 gammaCore-R and 132 gammaCore-R Sham

Migraine Disability Assessment (MIDAS) score from the end of run-in period to the end of randomized period. The MIDAS assessment measures the effect of headaches on a subject's daily functioning. It takes into account the past 3 months and is comprised of five questions. A lower score indicated less disability, a higher score indicates more disability. The scores are graded: 0-5, MIDAS Grade I, little disability 6-10, MIDAS Grade II, mild disability 11 to 20 MIDAS Grade III, moderate disability 21+ MIDAS Grade IV, severe disability

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 0 of Randomized Period (Visit 2) Grade I	11 participants	11 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 0 of Randomized Period (Visit 2) Grade II	15 participants	15 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 0 of Randomized Period (Visit 2) Grade III	23 participants	32 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 0 of Randomized Period (Visit 2) Grade IV	116 participants	109 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 12 (Visit 6) Grade I	22 participants	24 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 12 (Visit 6) Grade II	19 participants	17 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 12 (Visit 6) Grade III	37 participants	27 participants	—	—
Number of Participants According to Grade on the Migraine Disability Assessment (MIDAS) Before and After Randomized Period Week 12 (Visit 6) Grade IV	63 participants	64 participants	—	—

SECONDARY outcome

Timeframe: From four week run-in period to last four weeks in the randomization period

Population: Randomized population, Intention to Treat (ITT) In the active group 24 subjects had missing data, in the sham group 35 subjects had missing data at the end of the randomized period

The descriptive system comprises five dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels (5L): no problems (1) , slight problems (2), moderate problems (3), severe problems (4) and extreme problems (5). Minimum score is 5 (no problems) and maximum score is 25 (extreme problems) An overall health question is asked using a visual analogue scale(VAS) from 0-100 where 0 is bad health and 100 good health

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Selfcare run-in period	1.02 scores on a scale Interval 1.0 to 4.0	1 scores on a scale Interval 1.0 to 1.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Visual analogue scale )VAS) run-in period	80.97 scores on a scale Interval 5.0 to 100.0	80.3 scores on a scale Interval 8.0 to 100.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Mobility run-in period	1.10 scores on a scale Interval 1.0 to 4.0	1.10 scores on a scale Interval 1.0 to 3.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Mobility randomized period	1.09 scores on a scale Interval 1.0 to 3.0	1.07 scores on a scale Interval 1.0 to 3.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Selfcare randomized period	1.02 scores on a scale Interval 1.0 to 3.0	1.02 scores on a scale Interval 1.0 to 3.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Usual activities run-in period	1.27 scores on a scale Interval 1.0 to 5.0	1.23 scores on a scale Interval 1.0 to 4.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Usual activities randomized period	1.24 scores on a scale Interval 1.0 to 3.0	1.22 scores on a scale Interval 1.0 to 3.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Pain/discomfort run-in period	1.56 scores on a scale Interval 1.0 to 5.0	1.59 scores on a scale Interval 1.0 to 5.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Pain/discomfort randomized period	1.50 scores on a scale Interval 1.0 to 4.0	1.48 scores on a scale Interval 1.0 to 4.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Anxiety/depression run-in period	1.35 scores on a scale Interval 1.0 to 4.0	1.4 scores on a scale Interval 1.0 to 5.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Anxiety/depression randomized period	1.32 scores on a scale Interval 1.0 to 3.0	1.41 scores on a scale Interval 1.0 to 5.0	—	—
Compare Changes in Quality of Life EuroQol Questionnaire 5 Dimensions and 5 Levels (EQ-5D-5L) Visual analogue scale (VAS) randomized period	82.46 scores on a scale Interval 38.0 to 100.0	76.35 scores on a scale Interval 30.0 to 100.0	—	—

SECONDARY outcome

Timeframe: The 6 month open-label period compared to the four week run-in period

Population: Randomized population (Intent to treat)

Change in number of migraine days (as reported in subject diary) during the 6 month open label period compared to the baseline run-in period.

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Change in Migraine Days in the Open Label Period (Adjusted ANCOVA) Migraine days run in period	7.94 Days Interval 3.0 to 15.0	7.9 Days Interval 3.0 to 12.9	—	—
Change in Migraine Days in the Open Label Period (Adjusted ANCOVA) Migraine days open label period	5.75 Days Interval 0.0 to 20.0	5.7 Days Interval 0.0 to 17.0	—	—

SECONDARY outcome

Timeframe: up to Week 36

Population: Safety population

Adverse Effects were collected for all subjects for the duration of the study.

Outcome measures

Outcome measures
Measure	gammaCore®-R n=169 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=172 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized n=136 Participants Subjects that were screen failures and were not randomized.	Open Label n=277 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Number of Participants With Adverse Events Serious adverse events	2 Participants	1 Participants	0 Participants	2 Participants
Number of Participants With Adverse Events Adverse events (non-serious)	74 Participants	91 Participants	13 Participants	118 Participants

SECONDARY outcome

Timeframe: The 6 month open-label period compared to the four week run-in period

Population: Randomized population (Intent to treat)

The mean change in number of headache days (as reported in the subject diary) during the open label period compared to the base-line run-in period

Outcome measures

Outcome measures
Measure	gammaCore®-R n=165 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=167 Participants Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomized Subjects that were screen failures and were not randomized.	Open Label Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Change in Headache Days in the Open Label Period	-0.55 Days Interval -1.08 to -0.02	-0.51 Days Interval -1.02 to 0.0	—	—

Adverse Events

gammaCore®-R

Serious events: 2 serious events

Other events: 74 other events

Deaths: 0 deaths

gammaCore®-R Sham

Serious events: 1 serious events

Other events: 91 other events

Deaths: 0 deaths

Not Randomised

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Open Label

Serious events: 2 serious events

Other events: 118 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	gammaCore®-R n=169 participants at risk Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	gammaCore®-R Sham n=172 participants at risk Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side). gammaCore®-R Sham: Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).	Not Randomised n=136 participants at risk Subjects that were screen failures and were not randomized.	Open Label n=277 participants at risk Subjects will be instructed to treat three times per day, 2 consecutive bilateral stimulations, upon waking, six to eight hours following the first daily treatment, and six to eight hours following the second daily treatment (one stimulation on the right side immediately followed by a second stimulation on the left side).
Gastrointestinal disorders Admitted because of suspecion of appendicitis	0.00% 0/169 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.58% 1/172 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/277 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal Cell Cancer	0.00% 0/169 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.58% 1/172 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/277 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Gastrointestinal disorders Gastric Ulcer	0.59% 1/169 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/172 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/277 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Nervous system disorders Migraine attack	0.00% 0/169 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/172 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.36% 1/277 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Infections and infestations Pneumonia	0.59% 1/169 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/172 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/277 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Reproductive system and breast disorders Surgery for removal cyste and twisted fallopian tube left	0.59% 1/169 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/172 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/277 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Congenital, familial and genetic disorders carrier BRCA2 gene, prophylactic surgery: adnex extirpation	0.00% 0/169 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/172 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.36% 1/277 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)
Gastrointestinal disorders obstructive syndrom with dyspnea	0.59% 1/169 • Number of events 1 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/172 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/136 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)	0.00% 0/277 • 40 weeks (run-in 4 weeks, double blind/randomized 12 weeks, open label 24 weeks)

Other adverse events

Additional Information

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electroCore INC

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