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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Estimated 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 :	November 20, 2017
Estimated Primary Completion Date :	November 20, 2019
Estimated Study Completion Date :	November 20, 2020

Arms and Interventions

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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 Name: 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 Name: antiepileptic drugs Drug: Placebo; placebo, 5mg/Kg/d, once every day, 25mg per tablets; Other Name: Placebo tablets

Outcome Measures

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Primary Outcome Measures :

1. Percentage of reduction in seizure frequency [ Time Frame: 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 :

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

1. genetic analysis [ Time Frame: Baseline, Week 12 ]
   genotype-phenotype correlation; evaluated by severity of symptoms and treatment effects
2. treatment-response annotation [ Time Frame: 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

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Ages Eligible for Study:	6 Years to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Qing Liu, MD PhD	133-6630-5331	drliuqing@126.com
Contact: Hui Xu, MD	69156874	pumchkyc@126.com

Locations

China, Beijing
Department of Neurology, Peking Union Medical College Hospital	Recruiting
Beijing, Beijing, China, 100005
Contact: Qing Liu, MD, PhD 86-10-13366305331 drliuqing@126.com

Sponsors and Collaborators

Peking Union Medical College Hospital

Shijiazhuang Pharmaceutical Group Co. Ltd.

Investigators

Principal Investigator:	Qing Liu, MD PhD	Peking Union Medical College Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Rapamycin in TSC 

Rapamycin in TSC 

basic study on aspirin-mTOR 

basic study on aspirin-mTOR 

TSC 

Rapamycin in TSC 

Publications:

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.

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.

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.

Chen CT, Du Y, Yamaguchi H, Hsu JM, Kuo HP, Hortobagyi GN, Hung MC. Targeting the IKKβ/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.

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.

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.

Responsible Party:	Peking Union Medical College Hospital
ClinicalTrials.gov Identifier:	NCT03356769 History of Changes
Other Study ID Numbers:	JS-1425
First Posted:	November 29, 2017
Last Update Posted:	November 29, 2017
Last Verified:	September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Peking Union Medical College Hospital:

refractory seizure; cognitive impairment; electroencephalography improvement	seizure reduction; seizure free; aspirin

Additional relevant MeSH terms:

Sclerosis; Epilepsy; Cognitive Dysfunction; Tuberous Sclerosis; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary

Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Aspirin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs