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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and effectiveness of daily dextromethorphan/quinidine (Nuedexta) in reducing the frequency and progression of episodic migraine.

Detailed Description
-----------------
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.

Official Title
-----------------
A Randomized Pilot Study of Nuedexta for the Prevention and Modification of Disease Progression in Episodic Migraine

Conditions
-----------------
Episodic Migraine

Intervention / Treatment
-----------------
* Drug: Dextromethorphan and quinidine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nuedexta<br>One capsule will be taken (dextromethorphan HB and quinidine sulfate, 20 mg/10 mg) daily for seven days. On the eight day and for the remainder of the study 2 capsule will be taken twice a day. Medication will be taking daily for a total of 3 months. | Drug: Dextromethorphan and quinidine<br> <br> * Other names: Nuedexta;|
| Placebo Comparator: Placebo<br>One capsule will be taken of placebo to match daily for seven days. On the eight day and for the remainder of the study 2 capsule will be taken twice a day. Medication will be taking daily for a total of 3 months. | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache Days in Each Treatment Period Month | The average number of headache days at treatment period months 1, 2, and 3 (28 day periods for each month) for the Nuedexta arm and the Placebo arm. Headache days were defined as any patient reported head pain during the prior 24 hour period. | Treatment Month 1, Treatment Month 2, and End of Treatment Period Month 3 (Day 116) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache Days in Treatment Period Month 3 | The average number of headache days at treatment period month 3 (28 day period) for the Nuedexta arm and the Placebo arm. Headache days were defined as any patient reported head pain during the prior 24 hour period. | End of Treatment Period Month 3 (Day 116) | 
| Migraine Days in Each Treatment Period Month | The average number of migraine days at treatment period months 1, 2, and 3 (28 day periods for each month) for the Nuedexta arm and the Placebo arm. | Treatment Month 1, Month 2, and End of Treatment Period Month 3 (Day 116) | 
| Headache Severity in Each Treatment Period Month | The average headache severity at treatment period months 1, 2, and 3 (28 day periods for each month) for the Nuedexta arm and the Placebo arm. Headache pain severity was measured on a scale from 1 = Mild, to 3 = Severe. Higher numbers indicating more severe headache pain. | Treatment Month 1, Month 2, and End of Treatment Period Month 3 (Day 116) | 
| Headache Duration in Each Treatment Period Month | The average headache duration (time of onset to pain free) at treatment period months 1, 2, and 3 (28 day periods for each month) for the Nuedexta arm and the Placebo arm. Headache duration was measured in hours. | Treatment Month 1, Month 2, and End of Treatment Period Month 3 (Day 116) | 
| 50% Headache Reduction | The number of subjects with at least a 50% reduction in number of headache days comparing baseline to each visit (treatment period months 1, 2, and 3: 28 day for each month) in the Nuedexta arm vs. the placebo arm. | Baseline (Day 0) to Treatment Period Month 3 (Day 116) | 
| Acute Medication Use in Each Treatment Period Month | The average number of doses of acute medication taken at treatment period months 1, 2, and 3 (28 day periods for each month) for the Nuedexta arm and the Placebo arm | Treatment Month 1, Month 2, and End of Treatment Period Month 3 (Day 116) | 
| Migraine Disability Assessment Scale (MIDAS) | MIDAS scores at Visit 2 and Visit 5 (end of treatment period month 3). The MIDAS is a questionnaire consisting of five (5) how many days in the last 3 months... questions. Thus the range for the MIDAS is from, 0 to a maximum possible score 93 (31 days X 3 months). The MIDAS is scored according to the following: 0-5, MIDAS Grade I, Little or No Disability 6-10, MIDAS Grade II, Mild Disability 11-20, MIDAS Grade III, Moderate Disability 21+, MIDAS Grade IV, Severe Disability | Visit 2 (Day 28) to Visit 5 (Day 116) | 
| Headache Health Score | Headache Health Score at Visit 2 (Day 28), Visit 3 (Day 57), Visit 4 (Day 85), and Visit 5 (Day 116) for the Nuedexta arm and the placebo arm. The Headache Health Score is measured using a scale from 0 to 100, with higher scores indicating less headache impact on the subject's life. | Visit 2 (Day 28), Visit 3 (Day 57), Visit 4 (Day 85), and Visit 5 (Day 116) | 
| Adverse Events | Compare the number of adverse events in the Nuedexta arm vs. the placebo arm. | Baseline (Day 0) to Treatment Period Month 3 (Day 116) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Episodic Migraine, Migraine, Headache