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

Phase 2

• Conditions: Aspirin; Epilepsy; Tuberous Sclerosis Complex; Cognitive Decline; Skin Lesions
• Interventions: Drug: Aspirin; Drug: AED; Drug: Placebo

• Registration Number: NCT03356769
• Lead Sponsor: Peking Union Medical College Hospital

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2017-11-02
• Study Start: 2017-11-20
• Study First Submitted QC: 2017-11-23
• Study First Posted: 2017-11-29
• Status Verified: 2019-09
• Last Update Submitted: 2020-06-05
• Last Update Posted: 2020-06-09
• Primary Completion: 2021-11-20
• Study Completion: 2021-11-20

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 98

Inclusion Criteria

1. 6-30 years old TSC patients (by Gomez criteria)
2. more than 8 seizures occurred in the 4-week baseline time,with no continued seizure-free time of more than 10 days a month
3. 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
4. patients who had been treated with rapamycin should have been stopped for more than 3 months
5. vagus nerve stimulation (VNS) is allowed as a previous or current therapy and would maintain until the end of the trial

Exclusion Criteria

1. Subependymal Giant Cell Astrocytoma and requires immediate surgery；
2. a history of intracranial surgery within 6 months;
3. epilepsy caused by improper use of drugs;
4. patients treated with aspirin had severe or intolerant side effects, including gastrointestinal ulcer, bleeding, aspirin allergy, and other conditions;
5. psychogenic seizures;
6. severe renal dysfunction and infection
7. pregnant women and lactating women
8. not regular follow-up
9. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
experimental：asprin & AEDS	Aspirin	Aspirin 5mg/kg，maximum 300mg; once a day plus AEDS
experimental：asprin & AEDS	AED	Aspirin 5mg/kg，maximum 300mg; once a day plus AEDS
control: placebo & AEDS	Placebo	placebo 5mg/kg，maximum 300mg; once a day plus AEDS
control: placebo & AEDS	AED	placebo 5mg/kg，maximum 300mg; once a day plus AEDS

Primary Outcome Measures

Name	Time	Method
Percentage of reduction in seizure frequency	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）	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)

Secondary Outcome Measures

Name	Time	Method
Total days of seizure free	Baseline, Week 0-4, Week 4-8, Week 8-12	Days of seizure free in a four week observation time
Improvement of facial angiofibromas	Baseline, Week 4, Week 8, Week 12	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)
Subjective evaluation of treatment-response condition	Baseline, Week 12	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
A mild reduction in seizure frequency	baseline, Week 12	At least 25% of median seizure frequency reduction comparing with those in the baseline
Changes of epileptic discharges in electroencephalogram	Baseline, Week 12	Epileptic discharge on 2-hour video electroencephalogram in frequency detected at the same lead(s) comparing with baseline
Changes of cognitive condition	Baseline, Week 12	Raven standard reasoning test

Trial Locations

Locations (1)

Department of Neurology, Peking Union Medical College Hospital; 🇨🇳 Beijing, Beijing, China