Study of Safety and Efficacy of MGCND00EP1 as an Add on Treatment in Children and Adolescents With Resistant Epilepsies

Study Overview
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Brief Summary
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EudraCT: 2018-003887-29 Objective:To evaluate the safety and efficacy of: MGCND00EP1 from MGC PHARMACEUTICALS d.o.o. Study Design: Randomized, double blind, placebo controlled parallel grouped study Sample Size: 103 subjects Study Population: Children from 1 year to 18 years of age Comparator Product :Placebo solution, oral IMP Product : MGCND00EP1 (each ml of solution containing 100 mg of cannabidiol and 5 mg of (-)-trans-Δ9- tetrahydrocannabinol as active substance) from MGC PHARMACEUTICALS D.O.O. According to dosing scheme up to 25 mg/kg BW per day or maximum daily dose 800 mg (whichever smaller) for 6 weeks titration and 6 weeks of treatment, oral administration

Detailed Description
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Subjects on regular therapy with anti-epileptic medications who have evidence from clinical monitoring that current therapy is insufficient, following failure of at least two AEDs for at least during the last 2 months will be enrolled into this study. Upon subjects/parents have consented to participation in the study and after baseline examinations, subjects will continue with current antiepileptic treatment, as clinically needed, for another 28 days at the same dose as before entering the study; drug accountability will be performed for verification of treatment compliance, and diary will be used to record data on epileptic seizures. After that, participating patients will be randomly assigned to MGCND00EP1 or placebo and take it as add on to previous treatment for 6 weeks as titration period and 6 weeks at maintenance dose, and then titrated down during next two weeks. Patients will continue previous anti- epileptic treatment throughout all the periods of the study. Day one - Screening and Enrollment Visit : Total 103 patients: Obtain informed consent from legal guardian. Screen potential subjects by inclusion and exclusion criteria. Visit 1: obtain medical and medication history, vital signs, physical and neurological exam, blood and urine tests, ECG, EEG, concomitant medications, questionnaires. Weeks 1-4 - AED Stabilization Period : Visit 2: vital signs, weight, physical and neurological exam, blood and urine tests, concomitant medications, questionnaires, monitor AEs, PK blood collection (subset of patients), randomize and dispense study drugs Patients will be randomized and will either get placebo or MGCND00EP1 (3:1 active:placebo) Weeks 5-10 - Dose titration period: Dose escalations (2 mg/kg body weight/day increments), as required, up to 25 mg/kg/day or 800 mg/day, the lower of the two, until stable dose is reached. Visit 3: vital signs, weight, physical and neurological exam, blood and urine tests, concomitant medications, questionnaires, collect and issue diaries, dispense study drug, monitor AEs Weeks 11-16 - Maintenance Period : Visit 4: vital signs,weight, physical and neurological exam, blood and urine tests, concomitant medications, questionnaires, PK sample collection (subset of patients), collect and issue diaries, dispense study drug, EEG, monitor AEs Weeks 17-18 - Tapering-off and Follow-up Period: Weekly phone call to determine taper dose at physician's discretion Visit 5: vital signs,weight, physical and neurological exam, blood and urine tests, concomitant medications, questionnaires, monitor AEs, collect diaries and unused drug Weeks 19-20 - Follow-up Period: Weekly phone calls Visits 6: vital signs,weight, physical and neurological exam, concomitant medications, monitor AEs, collect diaries .

Official Title
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Randomized, Double Blind, Placebo Controlled, Parallel Design Phase II b Study of Safety and Efficacy of MGCND00EP1 as an Add on Treatment in Children and Adolescents With Resistant Epilepsies

Conditions
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Resistant Epilepsy, Drug, Adolescent Epilepsy, Children Epilepsy, Children and Adolescents With Resistant Epilepsies

Intervention / Treatment
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* Drug: MGCND00EP1
* Drug: Placebo
* Diagnostic Test: ECG
* Diagnostic Test: EEG
* Diagnostic Test: Blood and urine collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has documented clinically confirmed diagnosis of epilepsy; Patient did not respond to at least 2 AED's therapy given in adequate doses; Patients current therapy is considered inadequate (not completely controlled by AEDs); patients had four or more countable seizures with a motor component per 4 week period; Patient is aged 1 year - 18 years inclusive at screening age; Patient took one or more AEDs treatment at dose which has been stable for at least 4 weeks before enrolment; Females of childbearing potential can only participate in the study if willing to use acceptable, effective methods of contraception during the trial and for three month after end of trial participation as defined in point 7.10 of this protocol; Patient/parent is able to read/understand informed consent. Male patients must either be surgically sterile or he and his female spouse/partner who is of childbearing potential must be willing to use highly effective methods of contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continuing throughout the study. All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation (VNS) were stable for four weeks prior to screening and participants were willing to maintain a stable regimen throughout the study. The ketogenic diet and VNS treatments are not counted as an AED. Exclusion Criteria: Known history or presence of clinically significant unstable medical condition other that epilepsy which, in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of the study results. Known history or presence of serious cardiovascular disease Known or suspected history or family history of: schizophrenia, or other psychotic illness, severe personality disorder or other significant psychiatric disorder. Known or suspected allergy hypersensitivity or idiosyncratic reaction to cannabinoids or any other drug substances with similar activity or to any of the excipients of the IMP. Participant has clinically relevant abnormalities in the 12-lead electrocardiogram measured at screening or randomisation. Patients were currently using or had in the past used recreational or medicinal cannabis or synthetic CBD based medications or preparations within last 3 months or had previous or current treatment with cannabis-based therapy within last 3 months. History of drug or alcohol addiction requiring treatment. History of malabsorption within the last year or presence of clinically significant gastrointestinal disease or surgery that may affect drug bioavailability, including but not limited to cholecystectomy. Presence of hepatic or renal dysfunction. Females who: are pregnant (serum hCG level consistent with pregnancy diagnosis); or are lactating; Participation in a clinical trial that involved administration of an investigational medicinal product within 90 days prior to drug administration, or recent participation in a clinical investigation that, in the opinion of the Investigator, would jeopardize subject safety or the integrity of the study results; Participant has clinically significant abnormal laboratory values (e.g. liver enzymes); Participant has clinically significant findings from a physical examination (fever); In case of ketogenic diet or VNS; the diet need to be stable for at least 4 weeks, and VNS ramping needs to be stable at least 12 weeks before enrolment.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment with current antiepileptic therapy 28 days - Various combinations of anti-epileptic (AE) medications Add on treatment 42 days (6 weeks) - titration period - MGCND00EP1 or placebo in addition to AE medications. Add on treatment 42 days (6 weeks) Maintenance stable treatment period - MGCND00EP1 or placebo in addition to AE medications Add on treatment 14 days (2 weeks)- taper - down titration period - MGCND00EP1 or placebo in addition to AE medications Follow up 28 days - Standard/ previous AE treatment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MGCND00EP1<br>Participants who will assigned to receive add on MGCND00EP1 will receive carrier oil containing THC and CBD in ratio 20:1, (10% of cannabidiol and 0.5 % and (-)-trans-Δ9-tetrahydrocannabinol) . Titration Dose: 1 to 2 mg/kg body weight/day. dose will be increased every week by 2 mg/kg body weight/day up to a maximum 25 mg/kg body weigh/day or maximum daily dose 800 mg (the smaller of those 2 values) (divided into two daily doses). After titration, patients will be receiving a stable maintenance dose of IMP (up to 25 mg/kg BW per day or maximum daily dose 800 mg (whichever smaller)) for 6 weeks period. During forth treatment period participants will commence a 2 weeks down-titration taper period, followed by 4 weeks observational follow up period of previous standard AE treatment without IMP. | Drug: MGCND00EP1<br>* Patients will take cannabis oil during the study<br>* Other names: Cannabis oil;Diagnostic Test: ECG<br>* A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to the investigational site. The ECG has to be performed prior to laboratory samplings at time points indicated in the Schedule of Assessments. The ECG recording will be reviewed by investigator and case of need consultation with cardiologist will be performed. The investigator has the final decision on the clinical significance of the ECG results.<br>Diagnostic Test: EEG<br>* An EEG is an electrophysiological monitoring method that records the electrical activity and measures voltage fluctuations resulting from ionic current within the neurons of the brain. In clinical contexts, EEG refers to the recording of the brain's spontaneous electrical activity over a period of time.<br>Diagnostic Test: Blood and urine collection<br>* safety blood tests - hematology\blood count and biochemistry standard blood tests urinalysis - urine test analysis<br>* Other names: blood tests;|
| Placebo Comparator: PLACEBO<br>Participants who are assigned to receive add on PLACEBO will be administered the carrier oil (without the active ingredients). Titration Dose: 1 to 2 mg/kg body weight/day. dose will be increased every week by 2 mg/kg body weight/day up to a maximum 25 mg/kg body weigh/day or maximum daily dose 800 mg (the smaller of those 2 values) (divided into two daily doses). After titration, patients will be receiving a stable maintenance dose of IMP (up to 25 mg/kg BW per day or maximum daily dose 800 mg (whichever smaller)) for 6 weeks period. During forth treatment period participants will commence a 2 weeks down-titration taper period, followed by 4 weeks observational follow up period of previous standard AE treatment without IMP. | Drug: Placebo<br>* Patient will take carrier oil during the study<br>Diagnostic Test: ECG<br>* A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to the investigational site. The ECG has to be performed prior to laboratory samplings at time points indicated in the Schedule of Assessments. The ECG recording will be reviewed by investigator and case of need consultation with cardiologist will be performed. The investigator has the final decision on the clinical significance of the ECG results.<br>Diagnostic Test: EEG<br>* An EEG is an electrophysiological monitoring method that records the electrical activity and measures voltage fluctuations resulting from ionic current within the neurons of the brain. In clinical contexts, EEG refers to the recording of the brain's spontaneous electrical activity over a period of time.<br>Diagnostic Test: Blood and urine collection<br>* safety blood tests - hematology\blood count and biochemistry standard blood tests urinalysis - urine test analysis<br>* Other names: blood tests;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients showing a >50% reduction in frequency of seizures at week 12 of the study, in the treatment versus placebo groups | study drug overall efficiency as a seizure reducing treatment compared to placebo group | 12 weeks | 
| Change in number of epileptic seizures as documented by patient diaries (Visit 2 level compared to Visit 3 level and Visit 4) in treatment and placebo group. | study drug overall efficiency as a seizure reducing treatment | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of adverse events will be summarized by organ class, severity and duration on weeks 12 and 18 of the study. | Adverse events assessment | 12-18 weeks | 
| Any change in physical examination, vital signs, lab tests results, ect will be collected and analyzed. | Improvement in vital signs, lab test results and physical examination | 18 weeks | 
| Change in duration of epileptic seizures as documented by patient diaries (Visit 2 level compared to Visit 3 level and Visit 4 level compared to Visit 2 level) by treatment group. | seizure frequency assessment | 12-18 weeks | 
| Change in score from Quality of Life in Childhood Epilepsy Questionnaire 55 (QOLCE-55 questionnaire) scoring 0-100 points, higher scoring indicates better condition. scoring will be compared between Visit 2 level and Visit 4 level. | QoL questionnaire assessment | 18 weeks | 
| Change in Clinical Global Impressions Scale (CGI scale) scoring 1-7 points, low scoring indicates better condition. Visit 2 level compared to Visit 4 level by treatment group. | CGI improvement by treatment group | 18 weeks | 
| Percentage of MGCND00EP1-treated patients who will develop a response to MGCND00EP1 (response will be defined as a reduction of seizures frequency by at least 25 % ) as compared between Visit 2 level and Visit 4 level | response to MGCND00EP1 | 18 weeks | 
| Proportion of seizure-free patients between the placebo and treatment group on week 12 of treatment (including titration). | Proportion of seizure-free patients | 12 weeks | 
| Change in form of new seizures and emergency of new forms will be monitored during the trial | New seizure or seizure form emergency | 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epilepsy, resistant epilepsy, adolescents, children