A Study of a Melatonin Receptor Agonist to Prevent Migraine

The purpose of this study is to see if ramelteon will reduce the number of migraine headaches over a 12 week period. The safety and tolerability of ramelteon will also be evaluated. Ramelteon has been approved by the U.S. Food and Drug Administration (FDA) for insomnia (trouble sleeping); however; ramelteon has not been approved for the prevention of migraines.

Sleep has played an important role in migraine. Younger migraine sufferers usually report relief of migraine after sleep. In older migraine sufferers migraine is sometimes triggered with sleep changes. Occurrence of migraine in the early morning is very common. Therefore in these individuals regulation of sleep may improve the frequency of migraine. Recent PET studies done during migraine demonstrated activation of hypothalamus during migraine. In light of this new data and the known action of ramelteon on the melatonin receptors it may theoretically provide an insight on a possible mechanism of action in migraine.

• Migraine
• Migraine With Aura
• Migraine Without Aura

• Drug: Ramelteon
  8 mg tablet, oral, once daily
  Other Name: Rozerem
• Drug: Placebo
  Placebo tablet, oral, once daily

• Active Comparator: Active Treatment
  Ramelteon once daily (double-blind assignment)
  Intervention: Drug: Ramelteon
• Placebo Comparator: Placebo
  Placebo tablet, once daily (double-blind assignment)
  Intervention: Drug: Placebo

Inclusion Criteria:

• Male or female, ages 18 to 65 years, inclusive.
• An established history of migraine, with or without aura and probable migraine, conforming to the revised IHS criteria (2004) for at least 1 year before screening, sufficient to establish the diagnosis.
• To be randomized, during the prospective 4-week baseline period (approximately 28 days before Visit 2), subjects must have more than 4 migraine/probable migraine attacks per month (using the 24-hour rule).
• Must have been less than 50 years of age at the time of initial migraine onset.
• Must have no clinically significant and relevant abnormalities on physical or neurologic examinations
• Must have completed a washout of all prophylactic medications for migraine before the start of the 4-week prospective baseline period (ie, 28 days before Visit 2, when randomization occurs).
• Female subjects must be at least 1 of the following:
• postmenopausal, or
• surgically incapable of being children, or
• practicing a highly effective method of birth control

Exclusion Criteria:

• Most frequent type of headache does not meet the revised IHS diagnostic criteria for migraine with aura or without aura or probable migraine.
• Pregnant or lactating women, or sexually active women of childbearing potential who are not using an appropriate method of contraception.
• Failed adequate trials of prophylactic agents with demonstrated or possible efficacy in the prophylaxis of migraine. These agents include beta-blockers, tricyclic antidepressants, valproate, topiramate, and methysergide.
• Unable to complete the diary in a timely and accurate manner after each migraine headache attacks, either independently or with assistance.
• Overuse of analgesics or specific agents for abortive treatment of migraine attacks, which makes the investigator suspect medication overuse headache.
• Receiving non-pharmacological prophylactic treatments such as acupuncture, chiropractic, or massage, if these were started less than 1 month before the screening visit (Day -28). These therapies may be continued if started before that time.
• Currently abusing alcohol or other drugs.
• Have a central nervous system neoplasm or infection, demyelinating disease, degenerative or progressive central nervous system disease, or active epilepsy.
• History of serious systemic disease, including hepatic insufficiency, renal insufficiency, a malignant neoplasm, any disorder in which prognosis for survival is less than 3 months, or any disorder which in the judgment of the investigator will place the subject at excessive risk by participation in a controlled trial.
• Have a significant psychiatric disorder, such as acute psychosis, schizophrenia, severe bipolar disorder, or severe unipolar mood disorder, of sufficient severity to preclude safe and effective participation of the subject in the study.
• Require continued use of any of protocol-defined prohibited medications during the study
• Have any recent or remote history of suicide attempt or ideation
• Known or strongly suspected to be non-compliant in administering daily medications.
• Received an experimental drug or used an experimental device within 30 days before the Screening Visit.
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator
• Any reason for which the investigator, upon her evaluation, feels that it is in the subject's best interest not to continue on in the study.