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

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

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

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 .

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.