Migraine With Aura
Conditions
Keywords
Migraine, aura
Brief summary
NXN-188 Dihydrochloride is being developed as an immediate release oral product for the treatment of acute migraine. This study is being conducted to evaluate NXN-188 in subjects with a migraine history of aura.
Detailed description
This was a multicenter, double-blind, parallel group, active and placebo-controlled, three arm study of a single oral dose of NXN-188 for the treatment of acute migraine headache with aura. After study eligibility was confirmed, subjects were randomized to NXN-188 600 mg, sumatriptan 100 mg, or placebo in a 1:1:1 ratio. Subjects left the clinic to self-administer the treatment at home at the onset of moderate to severe headache in a suitable dosing environment. Treatment was not to exceed 42 days from Randomization. If the subject did not have a headache within 42 days of randomization (s)he did not take the study medication and returned it to the site. If the subject experienced a qualifying headache (s)he recorded the symptoms in a diary, dosed with the study drug, and called the IVRS to record assessments all adverse events and to report dosing. If the study drug provided insufficient relief 2 hours post dosing (s)he was permitted to use non-triptan rescue medication recommended by the investigator.
Interventions
DRUGNXN-188
NXN-188 hard gelatin capsules, 600 mg administered as three 200 mg capsules
DRUGplacebo
administered as 3 placebo hard gelatin capsules
administered in a hard gelatin capsule with 2 capsules of placebo
Sponsors
NeurAxon Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female migraineurs between 18 and 65 years old. 2. Subjects must have a headache history of migraine with aura as defined by: * Aura consisting of at least one of the following, but no muscle weakness or paralysis: * Fully reversible visual symptoms * Fully reversible sensory symptoms * Fully reversible dysphasia * Aura has at least two of the following characteristics: * Visual symptoms affecting only one side of the field of vision and/or sensory symptoms affecting only one side of the body * At least one aura symptom that develops gradually over more than 5 minutes and/or different aura symptoms occur in succession over more than 5 minutes * Each symptom lasts from 5-60 minutes * Headache begins during the aura or follows aura within 60 minutes * Headache not attributable to another disorder 3. Migraine pain following aura in at least 75% of occurrences 4. Headache frequency of at least 1 migraine attack (with or without aura) per month for the past 3 months but not more than 8 migraines in any 30 day period. Subjects must have at least 1 migraine headache with aura per month • Each migraine attack should last at least 4 hours (without treatment) and not longer than 72 hours. 5. At the time of the study migraine, prior to dosing with study medication, the headache severity, as judged and documented by the subject, is either moderate or severe (on a 4-point categorical scale) 6. Body mass index (BMI) range of 18 to 35 7. The subject is in general good health. • ALT cannot be above 1.5x upper limit of normal; creatinine and urea must be within normal limits 8. Speak, read, and understand English, French, or Spanish sufficiently to understand the nature of the study, to provide written informed consent, and complete all study assessments 9. The subject is willing and able to comply with all testing requirements defined in the protocol 10. All females will avoid pregnancy at least 10 days before randomization, and up until 3 months after dosing. 11. All subjects/partners must use a double-barrier method of birth control during the study and for 3 months after dosing.
Exclusion criteria
1. A diagnosis of headaches that is not consistent with migraine with aura. 2. Presence of any risk factors that would preclude the use of triptans: 3. Known allergy or hypersensitivity to triptans or history of any serious side effect with a triptan which would preclude further dosing with a triptan 4. Presence of any clinically significant condition that would preclude study participation, as evaluated by the investigator 5. Pregnancy or lactation 6. History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, rheumatologic, autoimmune, or metabolic disease 7. Use of the following if taken for migraine prevention: * Cardiovascular drugs (acceptable if reason for use is for treatment of cardiovascular disease and the subject has been on a stable dose for 3 months) * Valproate, topiramate, cyproheptadine, montelukast, or botulinum toxin. 8. Use of monoamine oxidase inhibitors within 30 days of randomization 9. Initiation of therapy with SSRIs or SNRIs for depression or other approved indication within 90 days of randomization (subjects on stable dose for \>3 months for treatment of depression or other approved indication may be included) 10. Are known to or suspected to be currently abusing alcohol or drugs, or have a history (within the past 12 months) of active alcohol or drug abuse 11. Participation in another drug or biologic study within 30 days of randomization into this study or during participation in this study 12. Subjects who are unable or unwilling, in the opinion of the Investigator, to comply with all study procedures and cooperate fully with study center staff
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time (Hours) to First Use of Rescue Medication | 24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Headache Relief and Recurrence (Observed Cases) | 2, 4 and up to 24 hours | Headache relief is defined as a ≥ 1-point reduction from baseline in Headache Severity Score. The Headache Severity Score is a four-point scale: 0=no pain; 1 = mild pain; 2 = moderate pain; and 3 = severe pain. Headache recurrence is defined as any subject that experiences headache relief within 4 hours, who did not use rescue medication, and who experienced a worsening of their headache to moderate or severe within 24 hours following study drug administration. |
| 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | 2 hours | Complete headache relief is defined as reduction of headache severity from moderate or severe to absent. Presence of Photophobia and Phonophobia measured on a 2-point scale: 0 = absent; 1 = present Nausea was measured on a 4-point scale: 0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea |
| 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | 4 hours | Complete headache relief is defined as reduction of headache severity from moderate or severe to absent. Presence of Photophobia and Phonophobia measured on a 2-point scale: 0 = absent; 1 = present Nausea was measured on a 4-point scale: 0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea |
| 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | 24 hours | Complete headache relief is defined as reduction of headache severity from moderate or severe to absent. Presence of Photophobia and Phonophobia measured on a 2-point scale: 0 = absent; 1 = present Nausea was measured on a 4-point scale: 0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea |
Countries
United States
Participant flow
Recruitment details
First Patient Screened: 17 June 2009 Last Patient: 17 December 2009
Pre-assignment details
Subjects meeting eligibility requirements at Screening were randomized at Visit 1 to NXN-188 600 mg, sumatriptan 100 mg or placebo in a 1:1:1 ratio. Randomized subjects were instructed to take study drug when they experienced a mild to moderate migraine headache with aura. Sunbjects not meeting the dosing criteria were discontinued from the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 3 x 0 mg capsules | 63 |
| NXN-188 600 mg 3 x 200 mg capsules | 60 |
| Sumatriptan Succinate 100 mg 1 x 100 mg, 2 x 0 mg capsules | 62 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 | 1 |
| Overall Study | Study drug dosing criteria not met | 17 | 19 | 12 |
Baseline characteristics
| Characteristic | NXN-188 600 mg | Placebo | Sumatriptan Succinate 100 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 13.02 | 37.2 years STANDARD_DEVIATION 10.9 | 41.2 years STANDARD_DEVIATION 12.03 | 39.9 years STANDARD_DEVIATION 12.1 |
| Applicable Aura Symptoms for Qualifying Migraine Dysphasia (speech disturbance) | 6 Participants | 7 Participants | 7 Participants | 20 Participants |
| Applicable Aura Symptoms for Qualifying Migraine Flickering lights | 40 Participants | 33 Participants | 39 Participants | 112 Participants |
| Applicable Aura Symptoms for Qualifying Migraine Lines | 12 Participants | 13 Participants | 11 Participants | 36 Participants |
| Applicable Aura Symptoms for Qualifying Migraine Loss of Vision | 18 Participants | 22 Participants | 22 Participants | 62 Participants |
| Applicable Aura Symptoms for Qualifying Migraine Numbness | 10 Participants | 7 Participants | 11 Participants | 28 Participants |
| Applicable Aura Symptoms for Qualifying Migraine Pins and needles | 15 Participants | 11 Participants | 9 Participants | 35 Participants |
| Applicable Aura Symptoms for Qualifying Migraine Spots | 43 Participants | 43 Participants | 43 Participants | 129 Participants |
| Body Mass Index (BMI) | 27.0 kg/m^2 STANDARD_DEVIATION 5.31 | 26.5 kg/m^2 STANDARD_DEVIATION 4.54 | 26.9 kg/m^2 STANDARD_DEVIATION 4.48 | 26.8 kg/m^2 STANDARD_DEVIATION 4.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 3 Participants | 3 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 60 Participants | 59 Participants | 173 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.8 cm STANDARD_DEVIATION 8.67 | 169.5 cm STANDARD_DEVIATION 9.01 | 166.3 cm STANDARD_DEVIATION 8.82 | 167.9 cm STANDARD_DEVIATION 8.89 |
| Number of Previous Migraines per month | 1.5 migraines per month STANDARD_DEVIATION 0.5 | 1.6 migraines per month STANDARD_DEVIATION 0.59 | 1.5 migraines per month STANDARD_DEVIATION 0.5 | 1.5 migraines per month STANDARD_DEVIATION 0.53 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 9 Participants | 8 Participants | 27 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 53 Participants | 54 Participants | 154 Participants |
| Sex: Female, Male Female | 49 Participants | 43 Participants | 9 Participants | 101 Participants |
| Sex: Female, Male Male | 11 Participants | 20 Participants | 53 Participants | 84 Participants |
| Type of Migraine With Aura | 59 Participants | 61 Participants | 62 Participants | 182 Participants |
| Type of Migraine Without Aura | 31 Participants | 35 Participants | 29 Participants | 95 Participants |
| Weight | 76.3 kg STANDARD_DEVIATION 16.61 | 76.6 kg STANDARD_DEVIATION 16.95 | 74.2 kg STANDARD_DEVIATION 14.5 | 75.7 kg STANDARD_DEVIATION 16 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 63 | 17 / 60 | 13 / 62 |
| serious Total, serious adverse events | 0 / 63 | 0 / 60 | 0 / 62 |
Outcome results
Primary
Time (Hours) to First Use of Rescue Medication
Time frame: 24 hours
Population: The Full Analysis Set included all those subjects randomized who had dosed with study drug and had at least one (1) post study drug administration observation for headache severity. The Efficacy Evaluable Analysis Set, included all subjects with an imputed (LOCF) HSS at both the 2 hour time point and the 4 hour time point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time (Hours) to First Use of Rescue Medication | NA hours |
| NXN-188 | Time (Hours) to First Use of Rescue Medication | NA hours |
| Sumatriptan Succinate | Time (Hours) to First Use of Rescue Medication | NA hours |
p-value: 0.6407Log Rank
Secondary
24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea
Complete headache relief is defined as reduction of headache severity from moderate or severe to absent. Presence of Photophobia and Phonophobia measured on a 2-point scale: 0 = absent; 1 = present Nausea was measured on a 4-point scale: 0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea
Time frame: 24 hours
Population: Number of subjects with headache relief at 24 hours.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 37 Participants |
| Placebo | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 39 Participants |
| Placebo | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 47 Participants |
| Placebo | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Overall Eval-Study Medication-(Good/Excellent) | 24 Participants |
| Placebo | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 51 Participants |
| NXN-188 | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 40 Participants |
| NXN-188 | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 35 Participants |
| NXN-188 | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 49 Participants |
| NXN-188 | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 41 Participants |
| NXN-188 | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Overall Eval-Study Medication-(Good/Excellent) | 30 Participants |
| Sumatriptan Succinate | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 48 Participants |
| Sumatriptan Succinate | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 44 Participants |
| Sumatriptan Succinate | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 38 Participants |
| Sumatriptan Succinate | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Overall Eval-Study Medication-(Good/Excellent) | 35 Participants |
| Sumatriptan Succinate | 24 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 38 Participants |
Secondary
2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea
Complete headache relief is defined as reduction of headache severity from moderate or severe to absent. Presence of Photophobia and Phonophobia measured on a 2-point scale: 0 = absent; 1 = present Nausea was measured on a 4-point scale: 0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea
Time frame: 2 hours
Population: Number of subjects with headache relief at 2 hours.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 12 Participants |
| Placebo | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 16 Participants |
| Placebo | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 18 Participants |
| Placebo | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 18 Participants |
| NXN-188 | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 17 Participants |
| NXN-188 | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 6 Participants |
| NXN-188 | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 30 Participants |
| NXN-188 | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 14 Participants |
| Sumatriptan Succinate | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 23 Participants |
| Sumatriptan Succinate | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 30 Participants |
| Sumatriptan Succinate | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 22 Participants |
| Sumatriptan Succinate | 2 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 12 Participants |
Secondary
4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea
Complete headache relief is defined as reduction of headache severity from moderate or severe to absent. Presence of Photophobia and Phonophobia measured on a 2-point scale: 0 = absent; 1 = present Nausea was measured on a 4-point scale: 0 = no nausea; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea
Time frame: 4 hours
Population: Number of subjects with headache relief at 4 hours.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 21 Participants |
| Placebo | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 31 Participants |
| Placebo | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 25 Participants |
| Placebo | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 23 Participants |
| NXN-188 | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 26 Participants |
| NXN-188 | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 19 Participants |
| NXN-188 | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 25 Participants |
| NXN-188 | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 29 Participants |
| Sumatriptan Succinate | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Nausea Score-Improvement from Baseline | 29 Participants |
| Sumatriptan Succinate | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Photophobia-Shift from Baseline (present-absent) | 30 Participants |
| Sumatriptan Succinate | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Phonophobia-Shift from Baseline (present-absent) | 21 Participants |
| Sumatriptan Succinate | 4 Hours Post Administration - Incidence of Complete Headache Relief, Photophobia, Phonophobia and Nausea | Complete Headache Relief-Observed Cases | 22 Participants |
Secondary
Headache Relief and Recurrence (Observed Cases)
Headache relief is defined as a ≥ 1-point reduction from baseline in Headache Severity Score. The Headache Severity Score is a four-point scale: 0=no pain; 1 = mild pain; 2 = moderate pain; and 3 = severe pain. Headache recurrence is defined as any subject that experiences headache relief within 4 hours, who did not use rescue medication, and who experienced a worsening of their headache to moderate or severe within 24 hours following study drug administration.
Time frame: 2, 4 and up to 24 hours
Population: Number of subjects who experienced headache relief within 4 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Headache Relief and Recurrence (Observed Cases) | Headache Relief - 4 hours | 73.5 percentage of participants |
| Placebo | Headache Relief and Recurrence (Observed Cases) | Headache Relief - 2 hours | 59.6 percentage of participants |
| Placebo | Headache Relief and Recurrence (Observed Cases) | Headache Recurrence | 5.6 percentage of participants |
| NXN-188 | Headache Relief and Recurrence (Observed Cases) | Headache Relief - 4 hours | 81.1 percentage of participants |
| NXN-188 | Headache Relief and Recurrence (Observed Cases) | Headache Relief - 2 hours | 62.0 percentage of participants |
| NXN-188 | Headache Relief and Recurrence (Observed Cases) | Headache Recurrence | 11.1 percentage of participants |
| Sumatriptan Succinate | Headache Relief and Recurrence (Observed Cases) | Headache Relief - 2 hours | 69.1 percentage of participants |
| Sumatriptan Succinate | Headache Relief and Recurrence (Observed Cases) | Headache Recurrence | 13.9 percentage of participants |
| Sumatriptan Succinate | Headache Relief and Recurrence (Observed Cases) | Headache Relief - 4 hours | 81.8 percentage of participants |