Theramine® in the Prevention of Migraine Headache

The purpose of this study is to evaluate the efficacy of Theramine® as a preventative for migraine headaches.

This randomized double blind placebo-controlled study will enroll approximately 80 otherwise healthy subjects with a diagnosis of migraine headache. All subjects will be medically stable at enrollment and be on a stabilized dosage of daily medications.

The study duration will be approximately four months and the study will be divided into 3 phases (described below). Participants will complete daily headache diaries throughout all phases of the study, which will assess the presence or absence of headache as well as its characteristics (e.g. unilateral vs. bilateral, worse with exertion, moderate to severe intensity, throbbing quality, presence of associated symptoms \[nausea, vomiting, photophobia, phonophobia\]. The peak severity of the headaches will also be rated on a 0-10 scale each day. The characteristics of the headaches will enable us to classify headache days into those with migraine and non-migraine headaches. A migraine day will be considered any day with a moderate to severe headache that has one of the following two associated symptoms: 1) both photophobia and phonophobia or 2) nausea or vomiting. A headache day will be defined as the presence of any headache regardless of its characteristics.

Migraine preventative medications will be permitted, but no changes in dosage will be allowed during the four month study. Migraine abortive meds will be permitted and will be administered per their standard routine.

Phase 1: During this phase, participants will complete daily headache diaries for 30 days, but no study medication will be given. This phase will last approximately 1 month and will establish a baseline for the frequency of migraine in the absence of study medication.

Phase 2: Phase 2 will last for 1 month and represents the time period of initiation of the study medication. Participants will be randomized to either 2 capsules of Theramine® BID (Group A) or matching placebo (Group B) in a 1:1 treatment allocation. Subjects will take the study medications (Theramine® or placebo) for the duration of this phase and complete daily headache diaries. Participants will also complete a Headache Impact Questionnaire (HIT-6), which is a validated questionnaire to assess headache related disability in the last month. This phase will not be included in the data analysis as it may take 1 month to see a treatment effect after starting a preventative.

Phase 3: Phase 3 will last 2 months and represents the time period during which the efficacy of Theramine® will be determined. Participants will continue to complete headache diaries and will continue to Theramine® or placebo during this phase. They will also complete a HIT-6 questionnaire.

There will be four study visits, which will be described below.

Office Visit 1: Following informed consent, a physical and neurological exam and vital signs will be completed. A urine or serum pregnancy test will be collected by all female subjects of childbearing potential. Routine labs (electrolyte panel with creatinine, liver enzyme profile and CRP), will be collected. Eligible participants will be trained during the visit to complete daily headache diaries. It is anticipated that this visit will last for 2 hours.

Office Visit 2: At Visit 2, research staff will review the diary information completed during phase 1. Subjects who complete a minimum of 25 out of 30 days of their daily headache diary will be asked to continue participation with Phase 2 of the study. They will receive 268 capsules of study medication (enough for 67 days) and will be instructed to record any adverse events experienced from taking the study medication. During the office visit, subjects will complete the HIT-6 questionnaire. It is anticipated that this visit will last for 1 hour.

Office Visit 3: At Visit 3, research staff will review the diary information completed during phase 1. Subjects who complete a minimum of 50 out of 60 days of their daily headache diary and took 80% of their study medication will be asked to complete the last month of the study. They will receive 134 capsules of study medication (enough for 33 days) and will be instructed to record any adverse events experienced from taking the study medication. During the office visit, subjects will complete the HIT-6 questionnaire. It is anticipated that this visit will last for 1 hour.

Office Visit 4: At Visit 4, medical and medication history will be updated and adverse events collected. A urine or serum pregnancy test will be collected by any subjects of childbearing potential if study medication was taken and a blood test for CRP will be done. Pregnancy testing and CRP may be completed at Visit 3 if subjects will not be returning for a Visit 4. Study medication accountability and compliance will be assessed by counting all the pills that had been returned by the study participant. Subjects will complete the HIT-6 questionnaire. It is anticipated that this visit will last for 1 hour.

The study coordinator will contact participants by phone, email, mail or texting at least one time per month to schedule appointments and discuss any questions. This study is minimal risk and subjects will not need to return study drug if they withdraw or are withdrawn by the investigator. Information regarding study medication that is not returned for any reason will be documented in the study medication accountability log. Lost to follow up will be defined as any subject who has failed to contact the study coordinator after the coordinator has made six attempts to contact the subject over a 30 day period.

The Investigator will access in a case-by-case basis should a subject request additional days to complete the study or request replacement study medication due to loss. Documentation of such requests and outcomes will be maintained in subject's study file.

Eligibility Criteria:
INCLUSION CRITERIA: The inclusion criteria will be the following:

1. (male and female) 18-65 years of age
2. Women of child-bearing potential, has a negative pregnancy test (urine or serum) at screen, and agrees to one of the following:

   1. Complete abstinence from intercourse from 2 weeks prior to administration of the investigational product, throughout the study, and for a time interval (5 days) after completion or premature discontinuation from the study,
   2. History of bilateral tubal ligation,
   3. Hormonal Contraception (oral, patch, etc.) as approved by the Investigator,
   4. Sterilization of male partner; or,
   5. Any intrauterine device (IUD),
   6. Spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or spermicide plus a female diaphragm); or,
   7. Any other barrier methods (only if used in combination with any of the above acceptable methods);
3. Diagnosis of migraine headache (ICHD 1.1-1.5) as determined by criteria established by the International Classification of Headache Disorder (ICHD-II).
4. 4-14 days per month with migraine averaged over past 3 months, as self reported by subject.
5. Migraines symptoms must have been present for at least one year prior to enrollment in the study.
6. The onset of migraine symptoms must have occurred before age 50.
7. Is medically stable as determined by the Investigator.
8. If taking any concomitant preventative medication(s), is on a stabilized dosage at the discretion of the investigator.
9. Is willing to stay on current preventative medication(s) for the duration of the study.
10. Is able to take oral medication, adhere to the medication regimens and perform study procedures.
11. Is able to understand and communicate intelligibly with the study observer.
12. Is able to read and comprehend written instructions and be willing to complete all procedures and assessments required by this protocol.
13. Is able to demonstrate the willingness to participate by signing and understanding an informed consent after full explanation of the study.

EXCLUSION CRITERIA: The exclusion criteria will be the following:

1. Is pregnant, actively trying to become pregnant, or breast feeding.
2. A diagnosis of medication overuse headaches as determined by the investigator.
3. Chronic medical illnesses (eg. lupus, malignancy, infections, sarcoidosis) that could potentially modulate the frequency of migraine headache.
4. Has evidence of alcohol or substance abuse within the last year or any concurrent medical or psychiatric condition which, in the investigator's judgment, will likely interfere with the study conduct, subject cooperation, or evaluation and interpretation of the study results, or which otherwise contraindicates participation in this clinical trial.
5. Chronic daily headache (≥ 15 days per month with headache of any kind) averaged over past 3 months.
6. Abnormal creatinine, BUN, and/or Liver Function Enzymes will be assessed and exclusion will be at the discretion of the Investigator.
7. Allergy or hypersensitivity to any ingredients in Theramine® including arginine-containing preparations and whey protein (milk).