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

NCT03356769 | Unknown Phase 2 DMC

• 1 other identifier: JS-1425
• Study Type: interventional
• Target: 98
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberous Sclerosis Complex; Aspirin; Epilepsy; Cognitive Decline; Skin Lesions

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Total days of seizure free

  Baseline, Week 0-4, Week 4-8, Week 8-12

• A mild reduction in seizure frequency

  baseline, Week 12

• Changes of epileptic discharges in electroencephalogram

  Baseline, Week 12

• Improvement of facial angiofibromas

  Baseline, Week 4, Week 8, Week 12

• Changes of cognitive condition

  Baseline, Week 12

Other Outcomes (2)

• genetic analysis

  Baseline, Week 12

• 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）

Study Arms (2)

experimental：asprin & AEDS

EXPERIMENTAL

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

Drug: Aspirin; Drug: AED

control: placebo & AEDS

PLACEBO COMPARATOR

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

Drug: AED; Drug: Placebo

Interventions

Aspirin DRUG

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

Also known as: acetylsalicylic acid, enteric-coated aspirin tablets

experimental：asprin & AEDS

AED DRUG

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

Also known as: antiepileptic drugs

control: placebo & AEDS; experimental：asprin & AEDS

Placebo DRUG

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

Also known as: Placebo tablets

control: placebo & AEDS

Eligibility Criteria

• Age: 6 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Peking Union Medical College Hospital: lead
• Shijiazhuang Yiling Pharmaceutical Co. Ltd: collaborator

Study Sites (1)

Department of Neurology, Peking Union Medical College Hospital

Beijing, Beijing Municipality, 100005, China

RECRUITING

Related Publications (6)

• 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.

  PMID: 16453317 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.

  PMID: 21047224 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.

  PMID: 22406476 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.

  PMID: 22826466 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.

  PMID: 24053982 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.

  PMID: 27511181 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Tuberous Sclerosis; Epilepsy; Cognitive Dysfunction; Seizures

Interventions

Aspirin; Anticonvulsants

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Brain Diseases; Central Nervous System Diseases; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Central Nervous System Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Qing Liu, MD PhD

  Peking Union Medical College Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Qing Liu, MD PhD

CONTACT

133-6630-5331; drliuqing@126.com

Hui Xu, MD

CONTACT

69156874; pumchkyc@126.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2017
• First Posted: November 29, 2017
• Study Start: November 20, 2017
• Primary Completion: November 20, 2021
• Study Completion: November 20, 2021
• Last Updated: June 9, 2020

Record last verified: 2019-09

Locations

CN (1)