Safety and Efficacy of NPS 1776 in the Acute Treatment of Migraine Headaches

• Pain-free rate at 2 hours post-dose
• Response rate up to 48 (±24) hours post-dose
• Recurrence rate of migraine headache within 24 hours post dose
• Time to recurrence of migraine within 24 hours post-dose
• Area under the migraine pain curve in visual analogue scale (VAS) 0 4 hours post-dose
• VAS pain reduction: peak pain reduction in VAS score 0-4 hours post-dose
• Presence of nausea/vomiting, sensitivity to sound/light, skin sensitivity (cutaneous allodynia), intracranial sensitivity
• Brush allodynia
• Muscle tenderness
• Functional disability
• Use of rescue medication
• Time to meaningful pain relief
• Global Subject Impression (GSI)

The purpose of this study was to evaluate the effectiveness and safety of a single oral dose of NPS 1776 in the acute treatment of migraine pain and associated symptoms.

Migraine, the most common cause of recurrent severe or disabling headache, is diagnosed on the basis of a clinical history of intermittent headache with autonomic, constitutional, and neurologic disturbances.

Many antiepileptic drugs (AEDs) have demonstrated efficacy as acute and/or prophylaxis therapy for migraine, even though the mechanism of action of the various AEDs is poorly understood.

NPS 1776, isovaleramide, is a neutral aliphatic amide. The mechanism by which NPS 1776 exerts its therapeutic actions in nonclinical animal models of disease is unclear. The same is true for many antiepileptics on the market today. NPS 1776 does not appear to bind directly to various CNS receptor centers, although it shows a broad range of anticonvulsant activity in multiple animal models of seizures. This broad profile of anticonvulsant activity is similar to that of valproic acid (VPA), and may also predict NPS 1776 efficacy in the treatment of migraine.

Inclusion Criteria:

1. Diagnosis of migraine for at least a year prior to screening.
2. Experiences 2-10 migraine headaches per month (with at least 24 hours between episodes) and no more than 15 headache days per month in the 3 months prior to screening.
3. Ability and willingness to arrive at the investigator's center within 1 hour (±5 min) of migraine pain onset (defined as pain that is consistent with the subject's usual migraine and is of at least moderate severity).
4. Ability and willingness to abstain from taking medications not allowed by the protocol and to meet phone and check-in criteria.
5. Ability and willingness to undergo a comprehensive urine toxicology screen for both licit and illicit drugs.
6. Ability and willingness to complete a migraine-history diary from screening to treatment with study drug and a migraine-treatment diary from discharge through the remainder of the 24-hour period following study-drug treatment.

Exclusion Criteria:

1. Unstable or uncontrolled significant metabolic, hepatic, renal, hematological, pulmonary, gastrointestinal, urological, neurological (except migraine headaches), or psychiatric disorders.
2. Severe or acute cardiovascular or cerebrovascular disease, uncontrolled hypertension, or basilar or hemiplegic migraines.
3. History of hypersensitivity, allergies, or nonresponse to valproic acid.
4. Have taken VPA or other AED in the 30 days prior to screening, or are taking a migraine prophylaxis treatment other than a stable dose of propranolol or tricyclic antidepressant.
5. Migraine attacks that in the investigator's opinion are associated with intractable nausea and/or vomiting.
6. Any acute or chronic condition that in the investigator's opinion would limit the subject's ability to complete and/or participate in this clinical study or would place the subject at increased risk.
7. Have newly started or changed the dose of either feverfew or magnesium (above 200 mg, the amount in common daily supplements) within 3 months prior to screening.