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

Primary Purpose

Tuberous Sclerosis Complex, Aspirin, Epilepsy

Status
Unknown status
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Aspirin
AED
Placebo
Sponsored by
Peking Union Medical College Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberous Sclerosis Complex focused on measuring refractory seizure, cognitive impairment, electroencephalography improvement, seizure reduction, seizure free, aspirin

Eligibility Criteria

6 Years - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Department of Neurology, Peking Union Medical College HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

experimental：asprin & AEDS

control: placebo & AEDS

Arm Description

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

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

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Total days of seizure free
Days of seizure free in a four week observation time
A mild reduction in seizure frequency
At least 25% of median seizure frequency reduction comparing with those in the baseline
Changes of epileptic discharges in electroencephalogram
Epileptic discharge on 2-hour video electroencephalogram in frequency detected at the same lead(s) comparing with baseline
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)
Changes of cognitive condition
Raven standard reasoning test
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

Full Information

First Posted
November 2, 2017
Last Updated
June 5, 2020
Sponsor
Peking Union Medical College Hospital
Collaborators
Shijiazhuang Yiling Pharmaceutical Co. Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT03356769
Brief Title
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

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Unknown status
Study Start Date
November 20, 2017 (Actual)
Primary Completion Date
November 20, 2021 (Anticipated)
Study Completion Date
November 20, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking Union Medical College Hospital
Collaborators
Shijiazhuang Yiling Pharmaceutical Co. Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberous Sclerosis Complex, Aspirin, Epilepsy, Cognitive Decline, Skin Lesions
Keywords
refractory seizure, cognitive impairment, electroencephalography improvement, seizure reduction, seizure free, aspirin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
98 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
experimental：asprin & AEDS
Arm Type
Experimental
Arm Description
Aspirin 5mg/kg，maximum 300mg; once a day plus AEDS
Arm Title
control: placebo & AEDS
Arm Type
Placebo Comparator
Arm Description
placebo 5mg/kg，maximum 300mg; once a day plus AEDS
Intervention Type
Drug
Intervention Name(s)
Aspirin
Other Intervention Name(s)
acetylsalicylic acid, enteric-coated aspirin tablets
Intervention Description
low-dose of aspirin, 5mg/Kg/d, once every day, 25mg per tablets
Intervention Type
Drug
Intervention Name(s)
AED
Other Intervention Name(s)
antiepileptic drugs
Intervention Description
maintain the dosages and the drugs throughout the 3-month observation time
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo tablets
Intervention Description
placebo, 5mg/Kg/d, once every day, 25mg per tablets
Primary Outcome Measure Information:
Title
Percentage of reduction in seizure frequency
Description
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)
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）
Secondary Outcome Measure Information:
Title
Total days of seizure free
Description
Days of seizure free in a four week observation time
Time Frame
Baseline, Week 0-4, Week 4-8, Week 8-12
Title
A mild reduction in seizure frequency
Description
At least 25% of median seizure frequency reduction comparing with those in the baseline
Time Frame
baseline, Week 12
Title
Changes of epileptic discharges in electroencephalogram
Description
Epileptic discharge on 2-hour video electroencephalogram in frequency detected at the same lead(s) comparing with baseline
Time Frame
Baseline, Week 12
Title
Improvement of facial angiofibromas
Description
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)
Time Frame
Baseline, Week 4, Week 8, Week 12
Title
Changes of cognitive condition
Description
Raven standard reasoning test
Time Frame
Baseline, Week 12
Title
Subjective evaluation of treatment-response condition
Description
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
Time Frame
Baseline, Week 12
Other Pre-specified Outcome Measures:
Title
genetic analysis
Description
genotype-phenotype correlation; evaluated by severity of symptoms and treatment effects
Time Frame
Baseline, Week 12
Title
treatment-response annotation
Description
Charts of seizure frequency reduction on different treatment time points would show the fluctuations of treatment effects (eg. the effective time)
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）

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 6-30 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 Exclusion Criteria: 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Qing Liu, MD PhD
Phone
133-6630-5331
Email
drliuqing@126.com
First Name & Middle Initial & Last Name or Official Title & Degree
Hui Xu, MD
Phone
69156874
Email
pumchkyc@126.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qing Liu, MD PhD
Organizational Affiliation
Peking Union Medical College Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neurology, Peking Union Medical College Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100005
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qing Liu, MD, PhD
Phone
86-10-13366305331
Email
drliuqing@126.com

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
16453317
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.
Results Reference
background
PubMed Identifier
21047224
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.
Results Reference
background
PubMed Identifier
22406476
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.
Results Reference
background
PubMed Identifier
22826466
Citation
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.
Results Reference
background
PubMed Identifier
24053982
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.
Results Reference
background
PubMed Identifier
27511181
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.
Results Reference
background
Links:
URL
https://www.ncbi.nlm.nih.gov/pubmed/?term=Franz%2C+D.N.%2C+et+al.%2C+Rapamycin+causes+regression+of+astrocytomas+in+tuberous+sclerosis+complex.+Ann+Neurol%2C+2006.+59(3)%3A+p.+490-8.
Description
Rapamycin in TSC
URL
https://www.ncbi.nlm.nih.gov/pubmed/?term=Krueger%2C+D.A.%2C+et+al.%2C+Everolimus+for+subependymal+giant-cell+astrocytomas+in+tuberous+sclerosis.+N+Engl+J+Med%2C+2010.+363(19)%3A+p.+1801-1
Description
Rapamycin in TSC
URL
https://www.ncbi.nlm.nih.gov/pubmed/?term=Din%2C+F.V.%2C+et+al.%2C+Aspirin+inhibits+mTOR+signaling%2C+activates+AMP-activated+protein+kinase%2C+and+induces+autophagy+in
Description
basic study on aspirin-mTOR
URL
https://www.ncbi.nlm.nih.gov/pubmed/?term=Targeting+the+IKKbeta%2FmTOR%2FVEGF+signaling+pathway+as+a+potential+therapeutic+strategy+for+obesity-related+breast+cancer.+Mol+Cancer+Ther%2C+2012.+11(10)%3A+p.+2212-21
Description
basic study on aspirin-mTOR
URL
https://www.ncbi.nlm.nih.gov/pubmed/?term=International+Tuberous+Sclerosis+Complex+Consensus%2C+Tuberous+sclerosis+complex+diagnostic+criteria+update%3A+recommendations+of+the+2012+Iinternational+Tuberous+Sclerosis+Complex+Consensus+Conference.
Description
TSC
URL
https://www.ncbi.nlm.nih.gov/pubmed/27511181
Description
Rapamycin in TSC

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

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