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| Name | Class |
|---|---|
| Shijiazhuang Yiling Pharmaceutical Co. Ltd | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| experimental:asprin & AEDS | Experimental | Aspirin 5mg/kg,maximum 300mg; once a day plus AEDS |
|
| control: placebo & AEDS | Placebo Comparator | placebo 5mg/kg,maximum 300mg; once a day plus AEDS |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aspirin | Drug | low-dose of aspirin, 5mg/Kg/d, once every day, 25mg per tablets |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| A mild reduction in seizure frequency | At least 25% of median seizure frequency reduction comparing with those in the baseline |
| Measure | Description | Time Frame |
|---|---|---|
| genetic analysis | genotype-phenotype correlation; evaluated by severity of symptoms and treatment effects | Baseline, Week 12 |
| treatment-response annotation | Charts of seizure frequency reduction on different treatment time points would show the fluctuations of treatment effects (eg. the effective time) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Qing Liu, MD PhD | Contact | 133-6630-5331 | drliuqing@126.com | |
| Hui Xu, MD | Contact | 69156874 | pumchkyc@126.com |
| Name | Affiliation | Role |
|---|---|---|
| Qing Liu, MD PhD | Peking Union Medical College Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Neurology, Peking Union Medical College Hospital | Recruiting | Beijing | Beijing Municipality | 100005 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16453317 | Background | 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. | |
| 21047224 | Background | 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. |
| Label | URL |
|---|---|
| Rapamycin in TSC | View source |
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| ID | Term |
|---|---|
| D014402 | Tuberous Sclerosis |
| D004827 | Epilepsy |
| D060825 | Cognitive Dysfunction |
| D012640 | Seizures |
| ID | Term |
|---|---|
| D006222 | Hamartoma |
| D009369 | Neoplasms |
| D009378 | Neoplasms, Multiple Primary |
| D009386 | Neoplastic Syndromes, Hereditary |
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| ID | Term |
|---|---|
| D001241 | Aspirin |
| D000927 | Anticonvulsants |
| ID | Term |
|---|---|
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
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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.
| AED | Drug | maintain the dosages and the drugs throughout the 3-month observation time |
|
|
| Placebo | Drug | placebo, 5mg/Kg/d, once every day, 25mg per tablets |
|
|
| baseline, Week 12 |
| 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 |
| 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 |
| Changes of cognitive condition | Raven standard reasoning test | Baseline, Week 12 |
| 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 |
| 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) |
| 22406476 | Background | 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. |
| 22826466 | Background | Chen CT, Du Y, Yamaguchi H, Hsu JM, Kuo HP, Hortobagyi GN, Hung MC. Targeting the IKKbeta/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. |
| 24053982 | Background | 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. |
| 27511181 | Background | 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. |
| Rapamycin in TSC | View source |
| basic study on aspirin-mTOR | View source |
| basic study on aspirin-mTOR | View source |
| TSC | View source |
| Rapamycin in TSC | View source |
| D065703 |
| Malformations of Cortical Development, Group I |
| D054220 | Malformations of Cortical Development |
| D009421 | Nervous System Malformations |
| D009422 | Nervous System Diseases |
| D020752 | Neurocutaneous Syndromes |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D002491 | Central Nervous System Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |