Trial Outcomes & Findings for RCT of Non-Invasive Vagus Nerve Stimulation (nVNS) With gammaCore®, for the Acute Treatment of Migraine Attacks (NCT NCT02686034)

Last Updated: 2019-08-02

Results Overview

The primary objective is to compare the treatment response for nVNS and Sham therapies at two hours post-treatment, for the first treated migraine attack during study Period 2. Treatment response is defined as no pain at 2 hours post-treatment and no rescue medication use by 2 hours post-treatment.

Recruitment status

COMPLETED

Study phase

Target enrollment

285 participants

Primary outcome timeframe

2 hours post-treatment

Results posted on

2019-08-02

Participant Flow

37 patients were excluded from the study at the end of the 4-week Run-In/Observational period because they did not continue to meet the study eligibility criteria, were lost to follow-up, or they chose not to continue in the study.

Participant milestones

Participant milestones
Measure	gammaCore-S Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Run-In Period 1 STARTED	142	143
Run-In Period 1 COMPLETED	122	126
Run-In Period 1 NOT COMPLETED	20	17
Randomized Controlled Period 2 STARTED	122	126
Randomized Controlled Period 2 COMPLETED	117	122
Randomized Controlled Period 2 NOT COMPLETED	5	4
Open Label Period 3 STARTED	117	122
Open Label Period 3 COMPLETED	117	121
Open Label Period 3 NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	gammaCore-S Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Run-In Period 1 Eligibility	12	10
Run-In Period 1 Withdrawal by Subject	4	3
Run-In Period 1 Lost to Follow-up	4	4
Randomized Controlled Period 2 Lost to Follow-up	1	2
Randomized Controlled Period 2 Withdrawal by Subject	3	0
Randomized Controlled Period 2 Adverse Event	0	2
Randomized Controlled Period 2 Spontaneous reduction in migraines	1	0
Open Label Period 3 Lost to Follow-up	0	1

Baseline Characteristics

RCT of Non-Invasive Vagus Nerve Stimulation (nVNS) With gammaCore®, for the Acute Treatment of Migraine Attacks

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.	Total n=243 Participants Total of all reporting groups
Age, Continuous	38.8 Years STANDARD_DEVIATION 11.00 • n=5 Participants	39.6 Years STANDARD_DEVIATION 11.78 • n=7 Participants	39.2 Years STANDARD_DEVIATION 11.38 • n=5 Participants
Sex: Female, Male Female	95 Participants n=5 Participants	91 Participants n=7 Participants	186 Participants n=5 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	32 Participants n=7 Participants	57 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	120 Participants n=5 Participants	123 Participants n=7 Participants	243 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Italy	120 Participants n=5 Participants	123 Participants n=7 Participants	243 Participants n=5 Participants
Age of Onset of Migraine Attacks	29.42 years STANDARD_DEVIATION 11.20 • n=5 Participants	28.51 years STANDARD_DEVIATION 11.52 • n=7 Participants	28.96 years STANDARD_DEVIATION 11.35 • n=5 Participants
Migraine with Aura Diagnosis	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Number of Migraine Attacks Per Month in Last 6 Months	5.4 Attacks per month STANDARD_DEVIATION 1.51 • n=5 Participants	5.4 Attacks per month STANDARD_DEVIATION 1.48 • n=7 Participants	5.4 Attacks per month STANDARD_DEVIATION 1.49 • n=5 Participants
Days Per Month Acute Migraine Medication Taken	5.6 Days per month STANDARD_DEVIATION 1.69 • n=5 Participants	5.3 Days per month STANDARD_DEVIATION 1.66 • n=7 Participants	5.5 Days per month STANDARD_DEVIATION 1.68 • n=5 Participants
Currently Taking Migraine Prevention Medication	42 Participants n=5 Participants	35 Participants n=7 Participants	77 Participants n=5 Participants

PRIMARY outcome

Timeframe: 2 hours post-treatment

Population: Sensitivity analysis, Intent to Treat population

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Participants With Treatment Response - No Pain	36 Participants	26 Participants

SECONDARY outcome

Timeframe: 2 hours post-treatment study - period 2 (each study period was 4 weeks)

Population: Intent to treat population

Presence or absence of nausea/vomiting, photophobia and phonophobia for nVNS and sham therapies for the first treated migraine attack at 120 minutes during study Period 2.

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia No Nausea at 120 minutes	83 Participants	86 Participants
Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia No Vomiting at 120 minutes	110 Participants	109 Participants
Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia No Photophobia at 120 minutes	76 Participants	72 Participants
Number of Participants With Absence of Nausea/Vomiting, Photophobia, Phonophobia No Phonophobia at 120 minutes	75 Participants	74 Participants

SECONDARY outcome

Timeframe: 2 hours post-treatment

Population: Intent to Treat

Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Results show count of participants with a response of no pain (score = 0) or mild pain (score = 1) on the 4-point headache pain scale for the nVNS and sham therapies at 2 hours post-treatment and no rescue medication use by 2 hours post-treatment for the first treated migraine attack during study Period 2.

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Participants With Treatment Response - No Pain or Mild Pain	62 Participants	50 Participants

SECONDARY outcome

Timeframe: 24 and 48 hours post-treatment

Population: Intent to Treat

Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Results show count of participants with a response of no pain or mild pain on the 4-point headache pain scale at 24, and 48 hours post-treatment (and no rescue medication use) for nVNS and sham therapies for the first treated migraine attack during study Period 2.

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. 24 Hours	46 Participants	37 Participants
Number of Participants With Treatment Response no Pain or Mild Pain at 24 and 48 Hours. 48 Hours	43 Participants	33 Participants

SECONDARY outcome

Timeframe: 30, 60, 120 minutes; Study Period 2 (each study period was 4 weeks)

Population: Intent to Treat

Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Results show % Treatment response 'No pain' for the nVNS and sham therapies at 30, 60 and 120 minutes calculated for all treated attacks during study Period 2.

Outcome measures

Outcome measures
Measure	gammaCore-S n=373 Attacks Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=347 Attacks Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks 30 Minutes	43 Attacks	28 Attacks
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks 60 Minutes	69 Attacks	41 Attacks
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 2 All Attacks 120 Minutes	93 Attacks	66 Attacks

OTHER_PRE_SPECIFIED outcome

Timeframe: 30, 60, 120 minutes; Period 3 (each study period was 4 weeks)

Population: Intent to Treat Period 2 373/347 attacks treated Period 3 286/309 attacks treated

Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Number of migraine attacks with treatment response 'no pain' for the nVNS and sham therapies at 30, 60 and 120 minutes calculated for all treated attacks during study Period 3.

Outcome measures

Outcome measures
Measure	gammaCore-S n=286 Attacks Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=309 Attacks Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 30 Minutes	35 Attacks	41 Attacks
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 60 Minutes	47 Attacks	61 Attacks
Number of Migraine Attacks With Treatment Response 'No Pain' in Study Period 3 120 Minutes	63 Attacks	83 Attacks

OTHER_PRE_SPECIFIED outcome

Timeframe: 30, 60, 120 minutes; Study Periods 2 and 3 (each study period was 4 weeks)

Population: Intent to Treat Period 2 373/347 attacks treated Period 3 286/309 attacks treated

Response to treatment was assessed by the subjects using the 4 point headache scale, where 0 = No pain, 1 = Mild pain, 2 = Moderate pain and 3 = severe pain. Number of migraine attacks with treatment response 'no pain' or 'mild pain' on the 4-point headache pain scale for the nVNS and sham therapies at 30, 60 and 120 minutes calculated for all treated attacks during study Periods 2 and 3 (separately)

Outcome measures

Outcome measures
Measure	gammaCore-S n=373 Attacks Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=347 Attacks Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Migraine Attacks With Treatment Response no Pain or Mild Pain Period 2 30 Minutes	149 Attacks	123 Attacks
Number of Migraine Attacks With Treatment Response no Pain or Mild Pain Period 2 60 Minutes	160 Attacks	130 Attacks
Number of Migraine Attacks With Treatment Response no Pain or Mild Pain Period 2 120 Minutes	165 Attacks	136 Attacks
Number of Migraine Attacks With Treatment Response no Pain or Mild Pain Period 3 30 Minutes	105 Attacks	122 Attacks
Number of Migraine Attacks With Treatment Response no Pain or Mild Pain Period 3 60 Minutes	117 Attacks	140 Attacks
Number of Migraine Attacks With Treatment Response no Pain or Mild Pain Period 3 120 Minutes	124 Attacks	147 Attacks

OTHER_PRE_SPECIFIED outcome

Timeframe: Study Periods 2 and 3 (each study period was 4 weeks)

Population: Intent to Treat population Period 2 373/347 attacks treated Period 3 286/309 attacks treated

Number of Attacks with Absence of Nausea, Vomiting, Photophobia and Phonophobia at 120 minutes for nVNS and sham therapies calculated for all treated attacks during study Periods 2 and 3 (separately).

Outcome measures

Outcome measures
Measure	gammaCore-S n=373 Attacks Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=347 Attacks Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Nausea Period 2	253 Attacks	228 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Vomiting Period 2	342 Attacks	312 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Photophobia Period 2	233 Attacks	202 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Phonophobia Period 2	223 Attacks	203 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Nausea Period 3	195 Attacks	226 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Vomiting Period 3	268 Attacks	288 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Photophobia Period 3	158 Attacks	195 Attacks
Number of Migraine Attacks With Absence of Nausea, Vomiting, Photophobia and Phonophobia No Phonophobia Period 3	154 Attacks	203 Attacks

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 and 48 hours; Study Periods 2 and 3 (each study period was 4 weeks)

Population: Intent to treat Period 2 373/347 attacks treated Period 3 286/309 attacks treated

Number of migraine attacks with sustained treatment response (mild or no pain at 24 and 48 hours post-treatment) for nVNS and sham therapies calculated for all treated attacks during study Periods 2 and 3 (separately).

Outcome measures

Outcome measures
Measure	gammaCore-S n=373 Attacks Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=347 Attacks Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Attacks With Sustained Treatment Response 24 Hours, Period 2	132 Attacks	103 Attacks
Number of Attacks With Sustained Treatment Response 48 Hours, Period 2	121 Attacks	95 Attacks
Number of Attacks With Sustained Treatment Response 24 Hours, Period 3	100 Attacks	117 Attacks
Number of Attacks With Sustained Treatment Response 48 Hours, Period 3	96 Attacks	111 Attacks

OTHER_PRE_SPECIFIED outcome

Timeframe: Study Periods 2 and 3 (each study period was 4 weeks)

Population: Intent to Treat

Consistency of response, defined as the number of subjects who achieve no pain or mild pain in 50% or greater of their attacks, in subjects treating at least two attacks, for nVNS and sham therapies for all treated attacks during study Periods 2 and 3 (separately).

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Number of Subjects With Consistency of Response Period 2	57 participants	46 participants
Number of Subjects With Consistency of Response Period 3	44 participants	44 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: End of each study period (each study period was 4 weeks)

Population: Intent to treat

Treatment effect on quality of life: EQ-5D-5L is assessed at end of the run-in period and at the end of each 4-week period for nVNS and sham therapies. EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1 = no problems, 2 = slight problems, 3= moderate problems, 4 = severe problems and 5 = extreme problems. Subjects indicate health state by ticking choosing appropriate statement in each dimension. The 5 dimensions scores are combined into a score, where a lower score indicates less problems. Scores across all 5 dimensions are averaged resulting in a total theoretical score of 1 to 5 with lower scores indicating less problems

Outcome measures

Outcome measures
Measure	gammaCore-S n=142 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=143 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) EQ5D5L - Visit 1 Start of run-in period	0.885 Score Standard Deviation 0.1028	0.912 Score Standard Deviation 0.0969
Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) EQ5D5L - Visit 3 End of run-in period	0.896 Score Standard Deviation 0.0903	0.917 Score Standard Deviation 0.0980
Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) EQ5D5L -Visit 5 End of randomised period	0.911 Score Standard Deviation 0.0980	0.926 Score Standard Deviation 0.0951
Quality of Life Measured by EuroQol-5D-5L (EQ-5D-5L) EQ5D5L - Visit 7 End of open label period	0.923 Score Standard Deviation 0.0924	0.931 Score Standard Deviation 0.0910

OTHER_PRE_SPECIFIED outcome

Timeframe: Study Period 2 (4 weeks)

Population: Intent to treat

After the first treated attack and at the end of the double blind period (period 2) subjects were asked to guess if they were had received 'gammaCore-S', ''sham' or 'do not know'. Bang blinding index estimated are presented for the gammaCore-S and sham. Bang Blinding Index shows the success of blinding. The blinding index proposed is scaled to an interval of -1 to 1, 1 being complete lack of blinding, 0 being consistent with perfect blinding and -1 indicating opposite guessing which may be related to unblinding. A score of one means they guess correctly, -1 incorrectly. If the bang index includes 0 it indicates that the guesses were consistent for the sham and active and the study was appropriately blinded

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Bang Blinding Index Scores First Treated Attack	0.07 Bang Blinding Index Score Interval -0.037 to 0.173	0.00 Bang Blinding Index Score Interval -0.106 to 0.106
Bang Blinding Index Scores End of Period 2	-0.03 Bang Blinding Index Score Interval -0.143 to 0.075	0.23 Bang Blinding Index Score Interval 0.125 to 0.334

OTHER_PRE_SPECIFIED outcome

Timeframe: End of Study Periods 2 and 3 (each study period was 4 weeks long)

Population: Intent to treat

Subject satisfaction with the study devices Subjects were asked to rate their satisfaction with the device from the following options: Extremely satisfied, Very satisfied, Satisfied, A little satisfied or Not at all satisfied

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Subject Satisfaction Visit 5 Extremely Satisfied	7 Participants	8 Participants
Subject Satisfaction Visit 5 Very Satisfied	18 Participants	12 Participants
Subject Satisfaction Visit 5 Satisfied	27 Participants	22 Participants
Subject Satisfaction Visit 5 A Little Satisfied	33 Participants	36 Participants
Subject Satisfaction Visit 5 Not at All Satisfied	33 Participants	44 Participants
Subject Satisfaction Visit 7 Extremely Satisfied	10 Participants	12 Participants
Subject Satisfaction Visit 7 Very Satisfied	19 Participants	18 Participants
Subject Satisfaction Visit 7 Satisfied	23 Participants	34 Participants
Subject Satisfaction Visit 7 A Little Satisfied	32 Participants	26 Participants
Subject Satisfaction Visit 7 Not at All Satisfied	31 Participants	28 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 120 minutes, Study Period 2 (each study period was 4 weeks long)

Population: Intent to Treat

Subjects rated pain at onset of migraine attack (baseline) and at 120 minutes using a 4 point headache pain scale where 0 = no pain, 1 = mild pain, 3 = moderate pain and 4 = severe pain. A lower score indicates less pain. Mean change in pain score from baseline to 120 minutes for all attacks in study period 2

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Mean Change in Pain Score From Baseline to 120 Minutes	-0.4954 score on a scale Interval -0.6509 to -0.3399	-0.2769 score on a scale Interval -0.4392 to -0.1146

OTHER_PRE_SPECIFIED outcome

Timeframe: End of Study Periods 2 and 3 (each study period was 4 weeks long)

Population: Intent to treat

Ease of use of the study devices - Subjects were asked to rate the ease of use of the device from the following options: Very easy, somewhat easy, difficult, very difficult.

Outcome measures

Outcome measures
Measure	gammaCore-S n=120 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=123 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Ease of Use Visit 5 Very Easy	90 Participants	97 Participants
Ease of Use Visit 5 Easy	23 Participants	20 Participants
Ease of Use Visit 5 Difficult	5 Participants	4 Participants
Ease of Use Visit 5 Very Difficult	0 Participants	1 Participants
Ease of Use Visit 7 Very Easy	92 Participants	98 Participants
Ease of Use Visit 7 Easy	18 Participants	17 Participants
Ease of Use Visit 7 Difficult	5 Participants	3 Participants
Ease of Use Visit 7 Very Difficult	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: End of each study period (each study period was 4 weeks)

Population: Intent to treat

The HIT-6 measures impact of headaches on ability to function at work, at home and in social situations. Subjects answer 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. Higher score is worse and lower score is better quality of life

Outcome measures

Outcome measures
Measure	gammaCore-S n=142 Participants Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=143 Participants Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Quality of Life Measured by Headache Impact Test (HIT-6) HIT6 - Visit 5 End of randomised period	61.897 Score Standard Deviation 5.5900	60.959 Score Standard Deviation 5.6604
Quality of Life Measured by Headache Impact Test (HIT-6) HIT6 - Visit 1 Start of run-in period	63.250 Score Standard Deviation 5.0581	63.179 Score Standard Deviation 5.2977
Quality of Life Measured by Headache Impact Test (HIT-6) HIT6 - Visit 3 End of run-in period	63.275 Score Standard Deviation 5.4618	61.894 Score Standard Deviation 5.5704
Quality of Life Measured by Headache Impact Test (HIT-6) HIT6 - Visit 7 End of open label period	61.128 Score Standard Deviation 5.5871	60.750 Score Standard Deviation 5.7149

Adverse Events

gammaCore-S

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

gammaCore-S Sham

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Clinical Affairs

electroCore INC

Phone: +1 973 355 6683

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	gammaCore-S n=122 participants at risk Treatment of up to 5 migraine attacks with the Active gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment, or take their usual rescue medication.	gammaCore-S Sham n=126 participants at risk Treatment of up to 5 migraine attacks with the Sham gammaCore-S non-invasive vagus nerve stimulator device which delivers a mild electrical signal in the vicinity of the vagus nerve gammaCore-S Sham: At onset of migraine pain, the subject self-administers a bilateral treatment with the gammaCore nVNS Sham device (2 minutes on the right side, and 2 minutes on the left side). If their headache pain has not improved after 15 minutes, they administer another bilateral treatment with the Sham device. If they are not pain-free at 2 hours, they have the option to administer a third bilateral treatment with the Sham device, or take their usual rescue medication.
Cardiac disorders Tachycardia	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Ear and labyrinth disorders Ear Pain	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Ear and labyrinth disorders Vertigo	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Gastrointestinal disorders Dysphagia	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Gastrointestinal disorders Salivary hypersecretion	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Gastrointestinal disorders Toothache	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Adverse drug reaction	0.82% 1/122 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Application site discomfort	2.5% 3/122 • Number of events 3 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Application site erythema	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	2.4% 3/126 • Number of events 5 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Application site hyperaesthesia	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Application site pain	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	2.4% 3/126 • Number of events 4 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Application site paraesthesia	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Application site rash	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Chest pain	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Hypothermia	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
General disorders Pyrexia	1.6% 2/122 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Acute sinusitis	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Bronchitis	1.6% 2/122 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Cystitis	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Infection	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Influenza	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	2.4% 3/126 • Number of events 3 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Nasopharyngitis	1.6% 2/122 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	2.4% 3/126 • Number of events 3 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Tooth abscess	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Infections and infestations Urinary tract infection	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Investigations Blood pressure	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Musculoskeletal and connective tissue disorders Groin pain	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Musculoskeletal and connective tissue disorders Muscle spasms	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Musculoskeletal and connective tissue disorders Neck pain	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Musculoskeletal and connective tissue disorders Pain in extremity	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Balance disorder	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Dizziness	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	2.4% 3/126 • Number of events 4 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Migraine	1.6% 2/122 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Migraine with aura	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Paraesthesia	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Sciatica	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Nervous system disorders Status migrainosus	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Respiratory, thoracic and mediastinal disorders Epistaxis	1.6% 2/122 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Respiratory, thoracic and mediastinal disorders Hyperventilation	0.00% 0/122 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.79% 1/126 • Number of events 2 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)
Surgical and medical procedures Varicocele repair	0.82% 1/122 • Number of events 1 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)	0.00% 0/126 • 12 weeks - Period 1 (4 weeks), Period 2 (4 weeks) and Period 3 (4 weeks)