Cognitive Effects of Immediate Release Topiramate vs Extended Release Topiramate in Patients With Migraine

Study Overview
=================
Brief Summary
-----------------
Crossover, randomized, double blind: Q12h dosing in both periods; matching placebo for evening dosing during XR treatment; target dose: 100mg

Detailed Description
-----------------
The primary objective is to compare the effect of treatment with an immediate-release topiramate (IR-TPM), namely Topamax®, to an extended-release topiramate (XR-TPM), namely Trokendi XR®, regimen on cognition in adults with migraine. The secondary objective is to determine the factors that explain inter-individual variability in cognitive response. Pharmacokinetic and demographic factors will be explored. Variability in cognitive response between individuals can be large. A population approach (nonlinear, mixed effects) will be used to determine drug exposure response relationships.

Official Title
-----------------
Cognitive Effects of Immediate Release Topiramate vs Extended Release Topiramate in Patients With Migraine

Conditions
-----------------
Migraine, Headache

Intervention / Treatment
-----------------
* Drug: IR-TPM (Topamax)
* Drug: XR-TPM (Trokendi XR)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Established history of episodic migraine with or without aura, as assessed by International Headache Society criteria, for at least 6 months before screening and frequency of 3 or more headache attacks per month during the past 3 months Male or female, ages 18-65 Women are required to be postmenopausal, surgically incapable of bearing children, or practicing a medically acceptable method of birth control (i.e., double barrier method, IUD, Mirena, etc) for at least 1 month before study entry through 30 days following last dose. If postmenopausal and on hormone replacement therapy (HRT) then must to be on a stable regimen for at least 2 months (continuous stable regimen of cyclic or non-cyclic HRT); negative pregnancy test. Native English speakers (due to speech and language analysis) Montreal Cognitive Assessment (MoCA) score equal to or greater than 26. Exclusion Criteria: Onset of migraine occurred after age 50 years, or overuse of analgesics or migraine specific agents for the acute treatment of migraine episodes; examples of analgesic overuse included the following: more than 8 treatment episodes (episode defined as any calendar day of usage) of ergot containing medications a month; more than 8 treatment episodes of triptans a month; or more than 6 treatment episodes of potent opioids a month. Required, continued use of the following medications for any medical reason during the study: beta-blockers, benzodiazepines, tricyclic antidepressants, antiepileptics, calcium channel blockers, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) daily, opioids, agents for insomnia (e.g., Ambien, diphenhydramine-containing OTC products); corticosteroids, local anesthetics, botulinum toxin within last three months, or herbal preparations such as feverfew or St John's wort. However, subjects will be permitted to be on a stable regimen of a selective serotonin reuptake inhibitor or SNRI for 3 months or more for depression and/or anxiety. A history of nephrolithiasis Have previously taken topiramate Received an experimental drug or used an experimental or approved device for migraine prevention (e.g., TENIS unit) within 30 days of screening

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: Crossover Assignment
Interventional Model Description: a crossover, randomized, double blind design in conjunction with intensive pharmacokinetic sampling and multiple administrations of a neurocognitive test battery to directly compare the effects on cognition of IR-TPM to XR-TPM in adults with migraine. The dose will begin at 25mg and titrated in 25mg increments to reach target dose of 100mg.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IR-TPM (Topamax)<br>IR-TPM (Topamax) | Drug: IR-TPM (Topamax)<br>* XR-TPM (Trokendi XR)<br>Drug: XR-TPM (Trokendi XR)<br>* XR-TPM (Trokendi XR)<br>|
| Active Comparator: XR-TPM (Trokendi XR)<br> | Drug: IR-TPM (Topamax)<br>* XR-TPM (Trokendi XR)<br>Drug: XR-TPM (Trokendi XR)<br>* XR-TPM (Trokendi XR)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Controlled Oral Word Association Test (COWA)-generative phonemic fluency | The primary outcome measure is the Controlled Oral Word Association (COWA: phonemic generative fluency). COWA was chosen as the primary endpoint since in previous studies of drug-induced cognitive impairment, this measure was sensitive to the effects of topiramate (Meador et al, 2003; Marino et al, 2012; Marino et al, 2015). The primary endpoint is a change in the COWA score from baseline to each post-dose assessment | Baseline (Day 1) through Day 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measures of semantic verbal fluency | Change in scores from individual baseline to each post-dose assessment on measures of semantic verbal fluency (e.g., Animals) | Baseline (Day 1) through Day 52 | 
| Digit Span Backward | Change in scores from individual baseline to each post-dose assessment on measures of working memory (i.e., Digit Span Backward) | Baseline (Day 1) through Day 52 | 
| Digit Symbol Modalities Test (SDMT) | Change in scores from individual baseline to each post-dose assessment on measure of psychomotor speed | Baseline (Day 1) through Day 52 | 
| Trails A & B | Change in scores from individual baseline to each post-dose assessment on measures of executive function | Baseline (Day 1) through Day 52 | 

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