Nuedexta for the Prevention and Modification of Disease Progression in Episodic Migraine

This is a double-blind, placebo-controlled, randomized, multi-center study to be conducted at the Headache Care Center in Springfield, MO and two other clinics in the United States. Approximately 45 subjects, 18 to 65 years of age, with frequent episodic migraine (6-14 days per month), with (1.2) or without aura (1.1) as defined by ICHD-3beta, will enter a 1-month baseline period to confirm the migraine diagnosis, as well as establish baseline characteristics. At Visit 1, subjects must not have a history of utilization of acute treatment greater than 14 days per month in the preceding 3 month period. Subjects must have a current history of ICHD-3beta migraine with 6-14 migraine days per month in the 3 months prior to the study enrollment. Eligible subjects will be randomly assigned to one of two groups in a 1:1 ratio. Randomization will occur using a computer-generated allocation schedule. Subjects meeting entrance criteria as determined both at screening and through the review of the baseline headache diary will be given the lowest available allocation number for that site. Migraine preventative use is permitted if the subject has been on a stable does for at least 2 months prior to screening and has not failed more than 3 migraine preventatives due to lack of efficacy. The study will consist of 5 office visits per subject: Visit 1 - screening, Visit 2 - randomization, and Visits 3 to 5 - three-month treatment period. During the baseline period, the subject will treat migraines with their current preferred acute treatment of choice.

Inclusion criteria

• male or female, in otherwise good health, 18 to 65 years of age.
• history of frequent episodic migraine for at least 3 months as defined by 6-14 migraine days per month with or without aura according to the ICHD-3beta or a migraine treated with an ergot or triptan which resulted in relief.
• onset of migraine before age 50.
• stable history of headache at least 3 months prior to screening.
• if using daily migraine preventive medications for migraine or for other medical conditions (e.g. propranolol being used for hypertension) and has been on a stable dose and regimen for at least 2 months prior to beginning the baseline period.
• female, of childbearing potential, and agrees to maintain true abstinence or use (or have their partner use) one of the listed methods of birth control for the duration of the study: hormonal contraceptive, intrauterine device (IUD), condoms, diaphragm, and/or vasectomy. The use of barrier contraceptive (condom or diaphragm) should always be supplemented with the use of a spermicide. Note: To be considered not of childbearing potential, subject must be 6 weeks post-surgical bilateral oophorectomy, hysterectomy, or bilateral tubal ligation, or postmenopausal for at least one year.

Exclusion criteria

• unable to understand the study requirements, the informed consent, or complete headache records as required per protocol.
• pregnant, actively trying to become pregnant, or breast-feeding.
• female of childbearing potential not using adequate contraceptive measures.
• experienced the following migraine variants: basilar migraine, aura without headache, familial hemiplegic migraine, complicated migraine, ophthalmoplegic migraine and retinal migraine.
• history of Medication Overuse Headache (Appendix II) in the 3 months prior to study enrollment or during the baseline phase.
• history of acute migraine treatment greater than 14 days per month in 3 months prior to screening.
• history of 3 or more failed preventative medications due to lack of efficacy for prophylactic treatment of migraine after an adequate therapeutic trial.
• received onabotulinumtoxinA injections within 3 months prior to screening and/or will receive onabotulinumtoxinA injections during the study.
• abused, in the opinion of the Investigator, any of the following drugs, currently or within the past 1 year: opioids, alcohol, barbiturates, benzodiazepine, cocaine.
• taken, or plans to take: a monoamine oxidase inhibitor (MAOI) including herbal preparations containing St. John's wort (Hypericum perforatum) within 14 days of Visit 1, concomitant medications and/or foods containing dextromethorphan, quinidine, quinine, mefloquine, paxil, dicyclomine, digitalis, thioridazine or pimozide (medications that prolong QT interval) anytime within the 2 weeks prior to screening through 2 weeks post final study treatment.
• history of hypersensitivity to medications containing dextromethorphan.
• history of hypersensitivity to medications or foods containing quinidine.
• at an increased risk of developing serotonin syndrome, in the opinion of the investigator.
• history of impaired hepatic or renal function that, in the investigator's opinion, contraindicates participation in this study.
• unstable neurological condition or a significantly abnormal neurological examination with focal signs or signs of increased intracranial pressure.
• cardiovascular disease (ischemic heart disease, including angina pectoris, myocardial infarction, documented silent ischemia, or with Prinzmetal's angina); has symptoms of ischemic heart disease, ischemic abdominal syndromes, peripheral vascular disease or Raynaud's Syndrome.
• ECG results outside normal limits (> 470 msec), prolonged QT interval, congenital long QT syndrome, torsades de pointes, or complete AV block.
• has uncontrolled hypertension (≥ 140/90mmHg in either the systolic or diastolic measurements in 2 out of 3 BP readings at screening).
• serious illness, or an unstable medical condition, one that could require hospitalization, or could increase the risk of adverse events, in the opinion of the investigator.
• any psychiatric disorder with psychotic features and any other psychiatric disorder not stable or well controlled, that would interfere in their ability to complete study activities.
• received any investigational agents within 30 days prior to Visit 1.
• plans to participate in another clinical study at any time during this study.