Aspirin as an add-on Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex

Study Overview
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Brief Summary
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There had been much evidence in aspirin controlling tumorous conditions conducted by basic researches, especially through mammilian target of rapamycin (mTOR) pathway. The investigator observed efficacy of aspirin in the treatment of tuberous sclerosis complex (TSC) in one child who got Kawasaki disease and in the addition four TSC patients with epilepsy. The investigator intend to evaluate whether aspirin would be an effective add-on treatment in TSC patients with refractory seizures.

Detailed Description
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There is no optional treatment for patients with tuberous sclerosis complex (TSC) and refractory epilepsy.The investigator observed efficacy of aspirin in the treatment of in one child who got Kawasaki disease. Subsequent adjunctive aspirin therapy in four patients yielded a reducted frequency of seizure for 51.2-89.7%. The investigator intend to evaluate whether aspirin would be an effective add-on treatment in TSC patients with refractory seizures. Refractory epilepsy was defined as more than 8 times of epileptic events in 4 weeks at baseline, and had been given more than two antiepileptic drugs maintaining for more than 3 months.TSC patients aged 6-30 years' old would be recruited with refractory seizures and randomly assigned to two groups, aspirin and antiepileptic drugs(AEDS) group and placebo-AEDS group after written informed consent be obtained. Patients and their guardians would be instructed to record their own seizure diary on the epileptic events and report monthly.The primary outcome would be reduction of seizure frequency (measured by average seizure frequency and response rate). The secondary outcome would include seizure-free days, seizure-free rates, changes in EEG, changes of facial angiofibromas, and exposure-response relationship analysis.The study is designed as a placebo-controlled, randomized, blinded evaluation trial.

Official Title
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A Placebo-controlled Study of Efficacy & Safety of Aspirin as an add-on Treatment in Patients With Tuberous Sclerosis Complex (TSC) & Refractory Seizures

Conditions
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Tuberous Sclerosis Complex, Aspirin, Epilepsy, Cognitive Decline, Skin Lesions

Intervention / Treatment
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* Drug: Aspirin
* Drug: AED
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 6-30 years old TSC patients (by Gomez criteria) more than 8 seizures occurred in the 4-week baseline time,with no continued seizure-free time of more than 10 days a month more than two antiepileptic drugs (AED) had been administered but fail to control the situation; maintaining with 1 or more than 1 AEDS for over 2 months and intending to continue with the drugs patients who had been treated with rapamycin should have been stopped for more than 3 months vagus nerve stimulation (VNS) is allowed as a previous or current therapy and would maintain until the end of the trial Exclusion Criteria: Subependymal Giant Cell Astrocytoma and requires immediate surgery； a history of intracranial surgery within 6 months; epilepsy caused by improper use of drugs; patients treated with aspirin had severe or intolerant side effects, including gastrointestinal ulcer, bleeding, aspirin allergy, and other conditions; psychogenic seizures; severe renal dysfunction and infection pregnant women and lactating women not regular follow-up other: because when children and adolescents suffering from influenza or chickenpox, using aspirin may cause a rare life-threatening Reye syndrome (characterized with persistent vomiting）, should temporary withdrawal, medication needs to consult a physician before using again.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 30 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental：asprin & AEDS<br>Aspirin 5mg/kg，maximum 300mg; once a day plus AEDS | Drug: Aspirin<br>* low-dose of aspirin, 5mg/Kg/d, once every day, 25mg per tablets<br>* Other names: enteric-coated aspirin tablets;Drug: AED<br>* maintain the dosages and the drugs throughout the 3-month observation time<br>* Other names: antiepileptic drugs;|
| Placebo Comparator: control: placebo & AEDS<br>placebo 5mg/kg，maximum 300mg; once a day plus AEDS | Drug: AED<br>* maintain the dosages and the drugs throughout the 3-month observation time<br>* Other names: antiepileptic drugs;Drug: Placebo<br>* placebo, 5mg/Kg/d, once every day, 25mg per tablets<br>* Other names: Placebo tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of reduction in seizure frequency | Estimated by median percentage of seizure frequency reduction and response rate comparing each group with the baseline; response rate is defined as more than 50% of reduction in seizure frequency. The seizure diary of individual participants would be recorded every day during the trial time by the participants and their guardians. The correct way of recording will be guided by investigator specialized in epileptic disease with discrimination of real or false seizure events. •seizure information was known within the same period of time (baseline or maintenance phase) | Baseline phase (week 0); Observation phase week 1（±1 days）；Observation phase week 2（±2 days）；Observation phase week 4（±3 days）d；Observation phase week 8（±7 days）；Observation phase week 12（±14 days） | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total days of seizure free | Days of seizure free in a four week observation time | Baseline, Week 0-4, Week 4-8, Week 8-12 | 
| A mild reduction in seizure frequency | At least 25% of median seizure frequency reduction comparing with those in the baseline | baseline, Week 12 | 
| Changes of epileptic discharges in electroencephalogram | Epileptic discharge on 2-hour video electroencephalogram in frequency detected at the same lead(s) comparing with baseline | Baseline, Week 12 | 
| Improvement of facial angiofibromas | We observed improvement of facial lesions concurrent with seizure control, in the size, color and number of facial angiofibromas. The improvement will be estimated by Physician's Global Assessement Overall Score (PGA, 7-grade:more than -25%, -25% to 25%, 25-50%, 50-75%, 75%-100%, 100% improvement) | Baseline, Week 4, Week 8, Week 12 | 
| Changes of cognitive condition | Raven standard reasoning test | Baseline, Week 12 | 
| Subjective evaluation of treatment-response condition | evaluated by physician/Caregiver who is familial with the patient with Physician's Global Assessement Overall Score (PGA, 7-grade:more than -25%, -25% to 25%, 25-50%, 50-75%, 75%-100%, 100% improvement ) and a two-page age-specific questionaire | Baseline, Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory seizure, cognitive impairment, electroencephalography improvement, seizure reduction, seizure free, aspirin