Sodium-Glucose Cotransporter-2 Inhibitors: A Potential Novel Treatment for Epilepsy

Study Overview
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Brief Summary
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About 30% of persons with epilepsy have seizures that do not respond to drugs. The ketogenic diet is an effective treatment option for them, but this high fat diet is strict and difficult to maintain. The properties of gliflozins, which often are used to treat type 2 diabetes, make them a potential replacement for the ketogenic diet. This pilot study will determine whether gliflozins induce ketosis and could be used to treat adults with epilepsy safely.

Detailed Description
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The 30% of persons with epilepsy who are drug-resistant bear most of the financial and psychosocial costs of this common neurological disorder. An effective, clinically used treatment for these individuals is the ketogenic diet, a high fat, low carbohydrate diet. Newer variants of the ketogenic diet including the modified Atkins diet (MAD) and low glycemic index treatment (LGIT) are more palatable than the older versions but are challenging to maintain because they are strict. The MAD and LGIT lower blood glucose and produce mild ketosis. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) such as empagliflozin have become important additions to the armamentarium for treating type 2 diabetes. SGLT2i decrease blood sugar by causing glucosuria, and they induce mild ketosis. These actions raise the possibility that SGLT2i can replace the MAD and LGIT as epilepsy treatments. This pilot, phase 1 study will determine the feasibility, safety, and tolerability of the SGLT2i empagliflozin in adults with epilepsy.

Official Title
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Sodium-Glucose Cotransporter-2 Inhibitors: A Potential Novel Treatment for Epilepsy

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Empagliflozin 25 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-45 years Focal, generalized, combined generalized and focal, or unknown epilepsy type Drug-responsive or drug-resistant epilepsy Exclusion Criteria: Seizure frequency >2 seizures per day during the 6 months prior to enrollment Status epilepticus during the 2 years prior to enrollment Taking a gliflozin Allergy to gliflozins Taking a carbonic anhydrase inhibitor such as acetazolamide On any ketogenic diet variant Having an absolute contraindication to a ketogenic diet Type 1 or type 2 diabetes Pregnancy Moderate to severe intellectual disability, Significant cardiovascular disease Renal insufficiency Body mass index <18.5 or ≥30 Hemoglobin A1c ≥5.7%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, placebo-controlled, double-blinded, crossover trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin / Placebo<br>Participants randomized to this arm will receive 25 mg of empagliflozin daily for 2 weeks followed placebo daily for 2 weeks | Drug: Empagliflozin 25 mg<br>* Participants will take empagliflozin daily for 2 weeks.<br>* Other names: Jardiance;Drug: Placebo<br>* Participants will take a placebo daily for 2 weeks. The placebo will be identical to empagliflozin in appearance.<br>|
| Experimental: Placebo / Empagliflozin<br>Participants randomized to this arm will receive placebo daily for 2 weeks followed by 25 mg of empagliflozin daily for 2 weeks | Drug: Empagliflozin 25 mg<br>* Participants will take empagliflozin daily for 2 weeks.<br>* Other names: Jardiance;Drug: Placebo<br>* Participants will take a placebo daily for 2 weeks. The placebo will be identical to empagliflozin in appearance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood beta-hydroxybutyrate while on empagliflozin | For each participant, calculate the difference between the blood beta-hydroxybutyrate after two weeks on empagliflozin and after two weeks on placebo. | 2 weeks | 
| Change in blood glucose while on empagliflozin | For each participant, calculate the difference between the blood glucose after two weeks on empagliflozin and after two weeks on placebo. | 2 weeks | 
| Number of participants with adverse effects from empagliflozin | For each participant, calculate the difference in weight, blood pressure, and pulse after two weeks on empagliflozin and after two weeks on placebo. Compare the number of participants having an abnormal complete blood count, comprehensive metabolic panel, hemoglobin A1c, magnesium, phosphorus, and urinalysis after two weeks on empagliflozin and after two weeks on placebo. Compare the number of participants who have increased urination and genital irritation after two weeks on empagliflozin and after two weeks on placebo. Will determine the number of participants with a clinically significant change in any of the listed parameters after two weeks on empagliflozin. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seizure frequency | For each participant, calculate the difference in seizure frequency as determined by seizure diaries during the two weeks on empagliflozin and the two weeks on placebo. | 2 weeks |