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

Epilepsy Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03356769
• Other study ID #: JS-1425
• Status: Recruiting
• Phase: Phase 2
• Start date: November 20, 2017
• Est. completion date: November 20, 2021

Study information

• Verified date: September 2019
• Source: Peking Union Medical College Hospital
• Contact: Qing Liu, MD PhD
• Phone: 133-6630-5331
• Email: drliuqing[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 98
• Est. completion date: November 20, 2021
• Est. primary completion date: November 20, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 30 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aspirin
• Cognitive Decline
• Cognitive Dysfunction
• Epilepsy
• Sclerosis
• Skin Lesions
• Tuberous Sclerosis
• Tuberous Sclerosis Complex

Intervention

Drug:
• Aspirin
low-dose of aspirin, 5mg/Kg/d, once every day, 25mg per tablets
• AED
maintain the dosages and the drugs throughout the 3-month observation time
• Placebo
placebo, 5mg/Kg/d, once every day, 25mg per tablets

Locations

Country	Name	City	State
China	Department of Neurology, Peking Union Medical College Hospital	Beijing	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital	Shijiazhuang Yiling Pharmaceutical Co. Ltd

Country where clinical trial is conducted

China, 

References & Publications (6)

Chen CT, Du Y, Yamaguchi H, Hsu JM, Kuo HP, Hortobagyi GN, Hung MC. Targeting the IKKß/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer. Mol Cancer Ther. 2012 Oct;11(10):2212-21. doi: 10.1158/1535-7163.MCT-12-0180. Epub 2012 Jul 23. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	genetic analysis	genotype-phenotype correlation; evaluated by severity of symptoms and treatment effects	Baseline, Week 12
Other	treatment-response annotation	Charts of seizure frequency reduction on different treatment time points would show the fluctuations of treatment effects (eg. the effective time)	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)
Primary	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	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
Secondary	A mild reduction in seizure frequency	At least 25% of median seizure frequency reduction comparing with those in the baseline	baseline, Week 12
Secondary	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
Secondary	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
Secondary	Changes of cognitive condition	Raven standard reasoning test	Baseline, Week 12
Secondary	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

External Links

•   basic study on aspirin-mTOR
•   basic study on aspirin-mTOR
•   Rapamycin in TSC
•   Rapamycin in TSC
•   Rapamycin in TSC
•   TSC