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

Sponsor

Peking Union Medical College Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT03356769

Collaborator

Shijiazhuang Yiling Pharmaceutical Co. Ltd (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberous Sclerosis Complex Aspirin Epilepsy Cognitive Decline Skin Lesions	Drug: Aspirin Drug: AED Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

98 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation, but allocation was not concealed from personnel in charge of drug supply, and implementation of the randomisation list. The Data Safety Monitoring Board (DSMB) independent statistician and programmer were semi-blind to treatment allocation at the time of DSMB meetings.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 20, 2017

Anticipated Primary Completion Date :

Nov 20, 2021

Anticipated Study Completion Date :

Nov 20, 2021

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: experimental：asprin & AEDS

Aspirin 5mg/kg，maximum 300mg; once a day plus AEDS

Drug: Aspirin

low-dose of aspirin, 5mg/Kg/d, once every day, 25mg per tablets

Other Names:

acetylsalicylic acid

enteric-coated aspirin tablets

Drug: AED

maintain the dosages and the drugs throughout the 3-month observation time

Other Names:

antiepileptic drugs

Placebo Comparator: control: placebo & AEDS

placebo 5mg/kg，maximum 300mg; once a day plus AEDS

Drug: AED

maintain the dosages and the drugs throughout the 3-month observation time

Other Names:

antiepileptic drugs

Drug: Placebo

placebo, 5mg/Kg/d, once every day, 25mg per tablets

Other Names:

Placebo tablets

Outcome Measures

Primary Outcome Measures

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

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
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
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)
Changes of cognitive condition [Baseline, Week 12]
Raven standard reasoning test
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

Other Outcome Measures

genetic analysis [Baseline, Week 12]
genotype-phenotype correlation; evaluated by severity of symptoms and treatment effects
treatment-response annotation [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）]
Charts of seizure frequency reduction on different treatment time points would show the fluctuations of treatment effects (eg. the effective time)

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.