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

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ClinicalTrials.gov Identifier: NCT03356769
Recruitment Status : Recruiting
First Posted : November 29, 2017
Last Update Posted : November 29, 2017
Sponsor:
Collaborator:
Shijiazhuang Yiling Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Peking Union Medical College Hospital

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

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

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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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03356769


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 Yiling Pharmaceutical Co. Ltd
Investigators
Principal Investigator: Qing Liu, MD PhD Peking Union Medical College Hospital
More Information
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Additional Information:
Rapamycin in TSC  This link exits the ClinicalTrials.gov site
Rapamycin in TSC  This link exits the ClinicalTrials.gov site
basic study on aspirin-mTOR  This link exits the ClinicalTrials.gov site
basic study on aspirin-mTOR  This link exits the ClinicalTrials.gov site
TSC  This link exits the ClinicalTrials.gov site
Rapamycin in TSC  This link exits the ClinicalTrials.gov site

Publications:

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    Key Record Dates
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