Long-term, Prospective Study Evaluating Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy – Tuberous Sclerosis Complex

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Brief Title

Long-term, Prospective Study Evaluating Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy - Tuberous Sclerosis Complex

Official Title

Long-term, Prospective Study Evaluating Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy - Tuberous Sclerosis Complex

Brief Summary

      The primary objective of clinical part of EPISTOP project is to identify the clinical and
      molecular biomarkers of epileptogenesis in a prospective clinical study of patients with TSC.

      Secondary objective of the clinical part of EPISTOP is to compare the effects of standard
      antiepileptic treatment in patients diagnosed as having epilepsy after clinical seizures vs
      after electroencephalographic epileptiform discharges, in a randomized trial in TSC patients.
    

Detailed Description

      Overview of study design This is a prospective study of epileptogenesis in TSC infants. In
      control subjects only one blood sampling will be performed and those infants will not be
      observed prospectively.

      The study consists of two phases: (1) prospective tracking of epileptogenesis by means of
      serial vEEG recordings; (2) treatment of epilepsy diagnosed after clinical or after
      electroencephalographic epileptiform discharges.

      All patients enrolled in the study will participate in the first phase. The second phase will
      concern only the children with epilepsy with electroencephalographic epileptiform discharges
      and/or clinical seizures, whose parents/caregivers will give consent for the randomized part
      of the project.

      At baseline, all patients will undergo neuroimaging examination by means of MRI, a battery of
      neuropsychological tests, blood biomarker sampling, and the review of medical history of the
      patient and the family.

      Epileptogenesis in TSC infants will be tracked by means of serial vEEG recordings. In
      children with diagnosed epilepsy, standard therapy with recommended first line antiepileptic
      drug will be given. Children with clinical seizures, either noticed by a caregiver, or a
      treating neurologist or recorded on video during vEEG will be immediately diagnosed as having
      epilepsy. Infants that have epileptiform discharges on vEEG and no clinical seizures, if
      their parents/caregivers give consent, will enter the randomized part of the study. Those
      children will be randomized into two groups: group A will be diagnosed as having epilepsy
      after subclinical (electroencephalographic) epileptiform discharges, and the patients in
      group B will be diagnosed as epileptic after clinical seizures appear. All infants diagnosed
      with epilepsy will receive standard therapy with recommended first line antiepileptic drug
      starting from the day of diagnosis.

      Children whose parents/caregivers will not give consent for the randomized part of the
      project, will be followed with serial vEEG and epilepsy will be diagnosed after clinical
      seizures.

      Children without seizures and no epileptiform discharges on vEEG will be followed without
      treatment.

      Blood samples for biomarker studies will be collected at study entry, at the onset of
      epileptiform discharges on vEEG or at the age of 6 months, whichever is applicable, at the
      onset of clinical seizures, and at the end of follow-up (age 2 years) in all patients
      participating in the project.

      At the age of 24 months, all TSC infants participating in the study will undergo neuroimaging
      examination by means of MRI, a battery of neuropsychological tests, and epilepsy analysis.

      Statistical considerations Full analysis set comprises all patients participating in the
      study, including the control group. This set will be divided into subsets: control group, TSC
      patients with epilepsy, and TSC patients with no epilepsy. Among TSC patients with epilepsy,
      patients with well-controlled seizures and patients with drug-resistant epilepsy will be
      identified. In full analysis set the blood biomarkers will be analysed. Clinical analysis set
      will comprise of all TSC infants enrolled in the study and the clinical biomarkers of
      epileptogenesis (neuroimaging, vEEG, data from medical history) will be analysed in this set.
      Treatment analysis set will comprise of infants participating in the randomized part of the
      study and the efficacy of antiepileptic treatment in respect to the point of epilepsy
      diagnosis (electroencephalographic epileptiform discharges onset in group A and clinical
      seizures onset in group B) will be assessed in this set.

      The interim analyses will be performed when 70% of the patients will complete the whole
      study. Final analyses will be performed when the last patient will complete the study (at the
      age of 24 months).

      Rationale for the study design This study is composed of two phases: (1) prospective tracking
      of epileptogenesis by means of serial vEEG recordings; (2) treatment of epilepsy diagnosed
      after clinical or after electroencephalographic epileptiform discharges. All TSC infants
      enrolled in the study as well as control children will participate in phase 1, whereas only
      children diagnosed with epilepsy will participate in phase 2. The time point of epilepsy
      diagnosis (at the onset of electroencephalographic epileptiform discharges or clinical
      seizures) will be randomly assigned to participating children by central randomizer and will
      be blinded to the patients' caregivers and treating neurologists.

      The identification of the biomarkers of ongoing epileptogenesis, as well as delineation of
      the point of no return, at which the occurrence of clinical seizures is inevitable, requires
      the prospective study, starting before the onset of clinical seizures. To achieve the
      clinical usefulness of potential biomarkers, they should be based on the analysis of standard
      clinical tests: neuroimaging by means of MRI, EEG, blood samples.

      Our study will use the standard clinical tests to identify the biomarkers of epileptogenesis
      on neuroimaging studies, EEG, and in the blood samples in TSC infants before and after the
      onset of seizures, to track the changes in measured parameters during ongoing
      epileptogenesis. Investigators will compare the results obtained in individual patients
      before the onset of EEG abnormalities, after the onset of electroencephalographic
      epileptiform discharges, after clinical seizures and at the age of 24 months. In order to
      identify the risk of epilepsy among TSC patients, Investigators will compare the results
      obtained in patients who develop epilepsy and those who remain epilepsy free. We will also
      compare the results obtained in TSC children with age-matched non-epileptic infants.

      The aim of the study is to establish the earliest possible point to diagnose epilepsy in TSC
      infants. It is now widely accepted that the clinical seizures are preceded by the progressing
      deterioration of EEG. Such deterioration is not seen in TSC infants who do not develop
      clinical seizures. EEG is a standard, non-invasive procedure in epileptic children.
      Therefore, EEG will be used to track epileptogenesis and to set the points for biomarkers
      sampling. Patients with epileptiform discharges on EEG recordings will enter the blinded,
      randomized part of the study, aimed to compare the effects of preclinical diagnosis and
      treatment of epilepsy vs diagnosis and treatment after clinical seizures appearance.

      To ascertain blinding of the study, the reports of vEEG recordings will not be sent to
      treating neurologist, but only to central randomizer. He will provide the treating
      neurologist with the diagnosis of epilepsy or no epilepsy, without giving the details of EEG.
      If the diagnosis of epilepsy is provided, it can mean either of the following: the patient
      had clinical seizures recorded on videoEEG, or had electroencephalographic epileptiform
      discharges and was randomized to group diagnosed with epilepsy at that point. Similarly, if
      the treating neurologist receives a diagnosis of no epilepsy in a patient, it is not known
      whether EEG was normal, or the patient had epileptiform EEG, but was randomized to group
      diagnosed as epileptic at the onset of clinical seizures.

      Taken together, the treating neurologist and the patient's parents/caregivers will be blinded
      to the diagnostic approach in a patient, but at the same time, an adequate treatment can be
      implemented.

      Epileptiform discharges on EEG not only precede clinical seizures, but also reflect changes
      in the brain that may per se cause neurodevelopmental delay and autism in children. In animal
      models it was shown that epileptogenesis could be interfered by antiepileptic treatment
      implemented before the onset of clinical seizures. A recent study showed that initiation of
      antiepileptic treatment before the onset of clinical seizures but after the onset of
      epileptiform discharges on EEG reduced the risk of mental retardation and drug-resistant
      epilepsy. Amelioration of epilepsy by implementation of antiepileptic drugs before the
      clinical seizures onset was also shown in neonates with severe hypoxic-ischemic
      encephalopathy. Current guidelines for epilepsy management in TSC patients recommend
      treatment of subclinical seizures equally to standard treatment after clinical seizures
      onset.

      Patients' numbering Each patient will be identified in the study by code, that will be
      assigned during baseline visit. This code will be the primary identifier of the patient
      throughout the study. The code will consist of site identifier and sequential patient number
      (for example: 01-001). Once assigned, the patient's code cannot be re-used or changed.

      Randomization procedures Patients with epileptiform discharges on vEEG noted prior to
      clinical seizures will enter the randomized part of the study. The time point of
      randomization will not be known to the treating neurologist to keep the study blinded.
      Central randomizer will provide the diagnosis of the patient to the treating neurologist
      after each EEG recording.

      Randomization will be performed as block randomization stratified for centre. Patients will
      be randomized in ratio 1:1.

      Adverse events An Adverse Event (AE) is any adverse change from the patient's baseline
      condition that occurs during the course of the study, irrespective to the relation to the
      epilepsy approach. However, it is important that this study does not test any investigational
      product, so only the undesirable effects of epilepsy diagnosis before or after the onset of
      clinical seizures should be considered as study-related (and not drug-related, as there is no
      investigational drug).

      Adverse events do not include:

        -  epileptic seizures, unless worsened due to late epilepsy diagnosis;

        -  planned medical or surgical procedures, ie. vaccinations, hospitalizations related to
           control examinations, like cardiologic follow-ups etc.

        -  pre-existing disease or medical condition that does not worsen, However, these events
           should be mentioned in eCRF (in Others or Comments section in the respective visit
           record). Seizures must be reported on dedicated eCRF sections. Parents of patients
           experiencing seizures should be asked to report the number and type of seizures daily
           and these data should be transferred to eCRF.

      For each AE, the relation to the study should be assessed by the investigator and reported in
      eCRF. If the causal relationship between the AE and the project is possible or certain, the
      relevant comment including the justification must be recorded on eCRF.

      Serious Adverse Events (SAE) is any AE fulfilling any of the following criteria:

        -  fatal

        -  life-threatening

        -  requiring hospitalization or prolongation of existing hospitalization, with the
           exception of planned hospitalizations

        -  resulting in persistent or significant disability

        -  medically significant or requiring intervention to prevent any of the outcomes listed
           above All SAE regardless their relation to the study must be recorded in eCRF and
           reported to the Project Coordinator (Sergiusz Jóźwiak, at IPCZD) within 48 hours by fax:
           +48 22 815 74 02 or e-mail: [email protected] The coordinator will contact
           appropriate health authorities as well as Scientific Advisory Board and Ethics
           Committee. All SAEs must be followed until resolution or stabilization. Follow up report
           must be recorded within 30 days after the onset of SAE or earlier, if possible, and
           reported to the Study Coordinator by fax or e-mail.

      Data collection and management Clinical data will be captured using electronic Case Report
      Form (eCRF). Data will be documented in various source documents and then manually entered
      into the eCRF by study site personnel. eCRF will be provided to each site by IPCZD.

      All information about study subjects will be confidential and managed according to local
      regulations and laws. Specifically, a signed authorization of the patient's caregivers
      informing of the following is required:

        -  what protected health information will be collected from the patients in this study

        -  who will have access to that information and why

        -  who will use or disclose that information

        -  the rights of the study subject caregivers to revoke their authorization for use of
           their protected health information.

      The patient's caregivers will be told that representatives of the Consortium, ethics
      committees, and regulatory authorities may inspect their medical records to verify the
      information collected. They will also be told that all personal data available for the
      inspection will be handled in strictest confidence and in accordance with local data
      protection laws.

      In case that a patient's caregivers revoke their authorization to use or to collect protected
      health information, only information collected prior to the revocation of the authorization
      can be used.

      Following the study completion, all documents related to the project, including patients'
      source data, should be stored on site according to local legal regulations.

      Monitoring plan Monitoring will be performed by monitor (CRA) chosen by IPCZD, coordinating
      site. In each participating centre one monitoring visit will be conducted annually.

      Verification of source data

        -  100% check of presence and correctness of Informed Consent Forms

        -  100% check of inclusion and exclusion criteria

        -  50% check of source documents of the following study data:

             -  Age

             -  Sex

             -  Diagnosis TSC

             -  Diagnosis allocation

             -  Date of inclusion

             -  Result of MRI, EEG and neuropsychological tests

             -  Seizures diary

        -  100% check of SAE's and SUSAR's as well as verification of the appropriate reporting
           procedures General control

        -  For each visit of each centre the rate of inclusion and the dropout rate will be
           reported.

        -  For each centre the presence and completeness of the Investigator Site File will be
           checked and for the sponsor the Trial Master File will be checked as well.

        -  For each centre study procedures will be checked as well as the ability of the study
           personnel to comply with these procedures.

      Reporting The monitor will provide a written report to the sponsor after each visit to a
      study location. This report will be stored by the sponsor and will be directly available for
      an audit. A study location will receive a written summary of the control procedures that have
      been performed and the associated findings.

      The 'monitor visit report' will include:

        -  A summary of control procedures performed by the monitor

        -  A general description of quality at the study site

        -  A summary stating the most important findings / facts, deviations and shortcomings

        -  An overview of proposed measures and recommendations to ensure compliance with the
           protocol

        -  The general conclusion The sponsor will receive the originals of initiation visit report
           and the close-out visit report and principal investigator of each site will receive
           copies of these documents. If applicable, other relevant contacts considering the trial
           will be enclosed as a written report.

      Data quality assurance The eCRFs and other essential documents will be reviewed by a clinical
      monitor designed by IPCZD.

      Essential documents include:

        -  signed informed consent documents for all subjects

        -  the decision of ethics committee together with the composition of ethics committee

        -  records of all communications between the investigator and the ethics committee

        -  all source documents (patient records, hospital records, laboratory records, seizure
           diaries, etc)

        -  any other documents required by local laws or GCP guidelines. Data on CRFs will be
           source-verified during site visits for accuracy and completeness according to the
           monitoring plan. The visits will take place annually as the minimum. The first visit
           will be scheduled 12 months after the first visit of the first patient enrolled by the
           site. The investigator will allocate adequate time for such monitoring activities. The
           investigator will also ensure that the monitor is given access to all above noted study
           documents and has adequate space to conduct the monitoring visit.

      The safety of patients in the study will be monitored by Independent Ethics Board supported
      by a biostatistician designated by IPCZD. The Independent Ethics Board will perform the
      review of the safety and efficacy after 70% of all planned randomized patients complete the
      study and their seizures outcome data are available.

      Early stopping rules The randomized part of the study can be stopped early if the external
      Scientific Advisory Board together with Steering Committee decides so, based on the analysis
      of study safety and/or efficacy. Particularly, the study can be stopped for unacceptable
      safety. In this case, all participating and new patients will enter the observational part of
      the project only.

      Second, the study may be stopped if any of the compared epilepsy approaches (early diagnosis
      versus diagnosis after clinical seizures) shows clear benefit in terms of seizure outcome,
      evidenced by the interim statistical analysis. Seizure outcome includes the number of
      seizure-free patients, the number of patients with normalized EEG, and the number of patients
      with drug-resistant epilepsy. The interim analysis will be performed when 70% of all planned
      randomized patients complete the study and their seizures outcome data are available. The
      statistical significance of P-value of 0.001 at interim analysis as evidence to stop early
      for benefit is required. In this case, all new patients and patients already participating in
      the study but not having abnormal EEG yet, will be offered the approach that was proved to be
      significantly more efficient. Other patients already participating in the study will continue
      their treatment.

      Withdrawal of individual subjects Subjects can leave the study at any time for any reason if
      they wish to do so without any consequences. The investigator/ treating physician can decide
      to withdraw a subject from the study whenever he/she considers that continuation in the trial
      would adversely affect the subjects' health. Participants that are under follow-up and
      treatment of the collaborating centres will continue to be so.

      Statistical analyses Full analysis set comprises all patients participating in the study,
      including the control group. This set will be divided into subsets: control group, TSC
      patients with epilepsy, and TSC patients with no epilepsy. Among TSC patients with epilepsy,
      patients with well-controlled seizures and patients with drug-resistant epilepsy will be
      identified. In full analysis set the blood biomarkers will be analysed. Clinical analysis set
      will comprise of all TSC infants enrolled in the study and the clinical biomarkers of
      epileptogenesis (neuroimaging, vEEG, data from medical history) will be analysed in this set.
      Treatment analysis set will comprise of infants participating in the randomized part of the
      study and the efficacy of antiepileptic treatment in respect to the point of epilepsy
      diagnosis (electroencephalographic epileptiform discharges onset in group A and clinical
      seizures onset in group B) will be assessed in this set.

      The interim analyses will be performed when 70% of the patients will complete the whole
      study. Final analyses will be performed when the last patient will complete the study (at the
      age of 24 months).

      Regarding clinical outcome measures and the study endpoints, the sample size was determined
      based on our previous study, in which similar parameters were assessed. The statistical
      analysis will include two types of tests:

        -  qualitative variables (frequencies of occurrence) will be analysed using chi-square
           tests

        -  quantitative variables using non-parametric equivalencies of ANOVA tests. The power of
           these tests was calculated for the p-level (alpha error) set at 0.5, and assuming the
           balanced distribution of patients in the groups. As described, we expect that 60-70% of
           subjects will have subclinical seizures prior to onset of clinical epilepsy, and thus be
           randomized to either A or B group. We predict that early diagnosis and treatment will be
           50-60% effective in preventing clinical seizure development in the patients that are
           randomized to group A. Given a set of 60 patients, with 30 going to group A and 30 to
           group B, our power to detect this difference in clinical seizure development is higher
           than 80%. All calculations were done using G*Power v 3.1.3 freeware, Kiel University,
           Germany.

      Ethical considerations

      EPISTOP project was designed and shall be implemented and reported in accordance with ICH
      Harmonized Tripartite Guidelines for Good Clinical Practice and the following EU
      legislations:

        -  The Charter of Fundamental Rights 2000 of the EU;

        -  European Directives 95/46/EC, 2002/58/EC, and 2001/20/EC.

      All participants in EPISTOP will respect the ethical principles laid down by national
      regulations and the following international conventions and declarations:

        -  Helsinki Declaration;

        -  Oviedo Convention of the CE on Human Rights and Biomedicine;

        -  UN Convention on the Rights of Child;

        -  Universal Declaration on the human genome and human rights adopted by UNESCO. This
           clinical study was designed, shall be implemented and reported in accordance with Good
           Clinical Practice, the regulations given in EU Directive No 20/2001 and other relevant
           regulations to ensure patients' safety. All Investigators will use a unified electronic
           Case Report Form to ensure the quality of data entered into the database, and an
           external data monitor (Clinical Research Associate; CRA) to monitor the progress of the
           study. Ethics issues will be supervised also by the external Scientific Advisory Board
           and Ethical Committee.

      EPISTOP has been already accepted by the local Ethics Boards at the Children's Memorial
      Health Institute (IPCZD), at Universita Degli Studi Di Roma Tor Vergata (TVG) and at Fakultni
      Nemocnice V Motole (UHM).

      Personal data protection EPISTOP will follow the principles for the protection of personal
      data laid down by European legal regulations. The study coordinator will ensure that consent
      for data storage is obtained from all participants and the data will be used only if there is
      consent for its use. Study subjects genetic, epigenetic, biochemical, proteomic,
      electroencephalographic, neuroimaging, and other medical data will be stored and analyzed in
      a coded/anonymous form. Data management and data safety reports will be regularly presented
      to the Advisory Board.

      Electronic case report form will be used for web-based data entry. The data entered into this
      database will be de-identified and only the responsible researchers will have the access to
      identifying details.

      The collaborative nature of EPISTOP requires the exchange of information and biological
      material between European and US partners. For purposes of WP3, WP5, WP7, biological samples
      obtained from patients and the relevant medical data will be transferred between sites. Only
      de-identified and coded samples as well as necessary medical data will be sent. The special
      safety provisions concerning biological material transportation will be considered and has
      been taken into account when calculating the costs of the project.

      The participants of EPISTOP and/or their legal representatives will be informed that they
      have the right to cancel their consent at any time by giving written notice to investigator.
      If the consent is cancelled, then the investigators will no longer use or disclose any
      medical information of the participant. However, canceling this consent will not affect
      previous uses and disclosures and the already existing participant's medical information
      would not be removed from the study records.

      The data produced in this study will be stored in a locked, secure location. Only members of
      the research team will have access to this location. Following completion of the research
      study the data will be kept as long as required by law and then destroyed as required by the
      hospital, laboratory or institute policy.

      EPISTOP assures that the key design elements of the project will be posted in its publicly
      accessible website. The results of the project will be submitted to publication in medical
      journals with the respect of participants' personal data protection.
    


Study Type

Interventional


Primary Outcome

number of patients with epilepsy


Condition

TSC

Intervention

epilepsy early diagnosis protocol

Study Arms / Comparison Groups

 epilepsy early diagnosis
Description:  Infants that have epileptiform discharges on vEEG and no clinical seizures, if their parents/caregivers give consent, will enter the randomized part of the study. Those children will be randomized into two groups: group A will be diagnosed as having epilepsy after subclinical (electroencephalographic) epileptiform discharges, and the patients in group B will be diagnosed as epileptic after clinical seizures appear. All infants diagnosed with epilepsy will receive standard therapy with recommended first line antiepileptic drug starting from the day of diagnosis.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

100

Start Date

November 2013

Completion Date

October 2018

Primary Completion Date

October 2018

Eligibility Criteria

        Inclusion criteria

        Inclusion criteria for TSC patients:

          -  male or female infants with a definite diagnosis of TSC (Roach criteria; Roach 1998 or
             DNA confirmed),

          -  age up to 4 months at the moment of enrolment,

          -  no clinical seizures seen by caregivers or on baseline videoEEG recording,

          -  written informed consent of caregivers. It is possible to give consent for the
             observational part of the study only. In this case, the child will not enter the
             randomized part of the study.

        Inclusion criteria for the control group:

          -  male or female infants who have undergone routine MRI for reasons other than epilepsy
             and brain tumor or cortical defects,

          -  age up to 24 months at the moment of study entry,

          -  written informed consent of caregivers. Exclusion criteria

        Exclusion criteria for TSC patients:

          -  any type of seizures observed till baseline visit,

          -  antiepileptic treatment at or prior to study entry,

          -  contraindications to MRI,

          -  any severe and/or uncontrolled medical condition that is considered by the
             investigator as possibly affecting the EPISTOP analyses or procedures.

        Exclusion criteria for the control group:

          -  any sign or symptom suggesting TSC diagnosis,

          -  any type of seizures observed at study entry,

          -  antiepileptic treatment at study entry,

          -  history of seizures, with the exception of febrile seizures,

          -  any severe and/or uncontrolled medical condition that is considered by the
             investigator as possibly affecting the EPISTOP analyses or procedures.
      

Gender

All

Ages

N/A - 4 Months

Accepts Healthy Volunteers

No

Contacts

Seriusz Jozwiak, Md, PhD, 0048228157404, [email protected]

Location Countries

Austria

Location Countries

Austria

Administrative Informations


NCT ID

NCT02098759

Organization ID

EPISTOP

Secondary IDs

602391

Responsible Party

Sponsor-Investigator

Study Sponsor

Sergiusz Jozwiak

Collaborators

 University of Rome Tor Vergata

Study Sponsor

Seriusz Jozwiak, Md, PhD, Principal Investigator, Children's Memorial Health Institute


Verification Date

April 2014