Epilepsy Clinical Trial
Official title:
Long-term, Prospective Study Evaluating Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy - Tuberous Sclerosis Complex
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.
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: sergiusz.jozwiak@gmail.com 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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Diagnostic
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