Clinical trial NCT03356769: Aspirin as an add-on Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Tuberous Sclerosis Complex
Aspirin
Epilepsy
Cognitive Decline
Skin Lesions
Keywords: refractory seizure
cognitive impairment
electroencephalography improvement
seizure reduction
seizure free
aspirin
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: Shijiazhuang Yiling Pharmaceutical Co. Ltd
First posted: 2017-11-29
Enrollment: 98
Sex: ALL
Minimum age (years): 6
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of reduction in seizure frequency
timeFrame: 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 outcomes:
measure: Total days of seizure free
timeFrame: Baseline, Week 0-4, Week 4-8, Week 8-12
measure: A mild reduction in seizure frequency
timeFrame: baseline, Week 12
measure: Changes of epileptic discharges in electroencephalogram
timeFrame: Baseline, Week 12
measure: Improvement of facial angiofibromas
timeFrame: Baseline, Week 4, Week 8, Week 12
measure: Changes of cognitive condition
timeFrame: Baseline, Week 12
measure: Subjective evaluation of treatment-response condition
timeFrame: Baseline, Week 12
Other outcomes:
measure: genetic analysis
timeFrame: Baseline, Week 12
measure: treatment-response annotation
timeFrame: 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）
Locations:
city: Beijing
country: China
facility: Department of Neurology, Peking Union Medical College Hospital
state: Beijing
Study officials:
affiliation: Peking Union Medical College Hospital
name: Qing Liu, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, Dinopoulos A, Thomas G, Crone KR. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006 Mar;59(3):490-8. doi: 10.1002/ana.20784.
citation: Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010 Nov 4;363(19):1801-11. doi: 10.1056/NEJMoa1001671.
citation: Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012 Jun;142(7):1504-15.e3. doi: 10.1053/j.gastro.2012.02.050. Epub 2012 Mar 6.
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citation: Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct;49(4):243-54. doi: 10.1016/j.pediatrneurol.2013.08.001.
citation: Overwater IE, Rietman AB, Bindels-de Heus K, Looman CW, Rizopoulos D, Sibindi TM, Cherian PJ, Jansen FE, Moll HA, Elgersma Y, de Wit MC. Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. Neurology. 2016 Sep 6;87(10):1011-8. doi: 10.1212/WNL.0000000000003077. Epub 2016 Aug 10.