<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04406948</url>
  </required_header>
  <id_info>
    <org_study_id>MGC-002</org_study_id>
    <nct_id>NCT04406948</nct_id>
  </id_info>
  <brief_title>Study of Safety and Efficacy of MGCND00EP1 as an Add on Treatment in Children and Adolescents With Resistant Epilepsies</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MGC Pharmaceuticals d.o.o</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>MGC Pharmaceuticals d.o.o</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      EudraCT: 2018-003887-29&#xD;
&#xD;
      Objective:To evaluate the safety and efficacy of: MGCND00EP1 from MGC PHARMACEUTICALS d.o.o.&#xD;
&#xD;
      Study Design: Randomized, double blind, placebo controlled parallel grouped study Sample&#xD;
      Size: 103 subjects Study Population: Children from 1 year to 18 years of age Comparator&#xD;
      Product :Placebo solution, oral IMP Product : MGCND00EP1 (each ml of solution containing 100&#xD;
      mg of cannabidiol and 5 mg of (-)-trans-Δ9- tetrahydrocannabinol as active substance) from&#xD;
      MGC PHARMACEUTICALS D.O.O.&#xD;
&#xD;
      According to dosing scheme up to 25 mg/kg BW per day or maximum daily dose 800 mg (whichever&#xD;
      smaller) for 6 weeks titration and 6 weeks of treatment, oral administration&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects on regular therapy with anti-epileptic medications who have evidence from clinical&#xD;
      monitoring that current therapy is insufficient, following failure of at least two AEDs for&#xD;
      at least during the last 2 months will be enrolled into this study. Upon subjects/parents&#xD;
      have consented to participation in the study and after baseline examinations, subjects will&#xD;
      continue with current antiepileptic treatment, as clinically needed, for another 28 days at&#xD;
      the same dose as before entering the study; drug accountability will be performed for&#xD;
      verification of treatment compliance, and diary will be used to record data on epileptic&#xD;
      seizures. After that, participating patients will be randomly assigned to MGCND00EP1 or&#xD;
      placebo and take it as add on to previous treatment for 6 weeks as titration period and 6&#xD;
      weeks at maintenance dose, and then titrated down during next two weeks. Patients will&#xD;
      continue previous anti- epileptic treatment throughout all the periods of the study.&#xD;
&#xD;
      Day one - Screening and Enrollment Visit :&#xD;
&#xD;
      Total 103 patients: Obtain informed consent from legal guardian. Screen potential subjects by&#xD;
      inclusion and exclusion criteria. Visit 1: obtain medical and medication history, vital&#xD;
      signs, physical and neurological exam, blood and urine tests, ECG, EEG, concomitant&#xD;
      medications, questionnaires.&#xD;
&#xD;
      Weeks 1-4 - AED Stabilization Period :&#xD;
&#xD;
      Visit 2: vital signs, weight, physical and neurological exam, blood and urine tests,&#xD;
      concomitant medications, questionnaires, monitor AEs, PK blood collection (subset of&#xD;
      patients), randomize and dispense study drugs&#xD;
&#xD;
      Patients will be randomized and will either get placebo or MGCND00EP1 (3:1 active:placebo)&#xD;
&#xD;
      Weeks 5-10 - Dose titration period:&#xD;
&#xD;
      Dose escalations (2 mg/kg body weight/day increments), as required, up to 25 mg/kg/day or 800&#xD;
      mg/day, the lower of the two, until stable dose is reached.&#xD;
&#xD;
      Visit 3: vital signs, weight, physical and neurological exam, blood and urine tests,&#xD;
      concomitant medications, questionnaires, collect and issue diaries, dispense study drug,&#xD;
      monitor AEs&#xD;
&#xD;
      Weeks 11-16 - Maintenance Period :&#xD;
&#xD;
      Visit 4: vital signs,weight, physical and neurological exam, blood and urine tests,&#xD;
      concomitant medications, questionnaires, PK sample collection (subset of patients), collect&#xD;
      and issue diaries, dispense study drug, EEG, monitor AEs&#xD;
&#xD;
      Weeks 17-18 - Tapering-off and Follow-up Period:&#xD;
&#xD;
      Weekly phone call to determine taper dose at physician's discretion&#xD;
&#xD;
      Visit 5: vital signs,weight, physical and neurological exam, blood and urine tests,&#xD;
      concomitant medications, questionnaires, monitor AEs, collect diaries and unused drug&#xD;
&#xD;
      Weeks 19-20 - Follow-up Period:&#xD;
&#xD;
      Weekly phone calls&#xD;
&#xD;
      Visits 6: vital signs,weight, physical and neurological exam, concomitant medications,&#xD;
      monitor AEs, collect diaries .&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">August 2023</start_date>
  <completion_date type="Anticipated">September 2024</completion_date>
  <primary_completion_date type="Anticipated">August 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Treatment with current antiepileptic therapy 28 days - Various combinations of anti-epileptic (AE) medications&#xD;
Add on treatment 42 days (6 weeks) - titration period - MGCND00EP1 or placebo in addition to AE medications.&#xD;
Add on treatment 42 days (6 weeks) Maintenance stable treatment period - MGCND00EP1 or placebo in addition to AE medications&#xD;
Add on treatment 14 days (2 weeks)- taper - down titration period - MGCND00EP1 or placebo in addition to AE medications&#xD;
Follow up 28 days - Standard/ previous AE treatment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The proportion of patients showing a &gt;50% reduction in frequency of seizures at week 12 of the study, in the treatment versus placebo groups</measure>
    <time_frame>12 weeks</time_frame>
    <description>study drug overall efficiency as a seizure reducing treatment compared to placebo group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>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.</measure>
    <time_frame>16 weeks</time_frame>
    <description>study drug overall efficiency as a seizure reducing treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The incidence of adverse events will be summarized by organ class, severity and duration on weeks 12 and 18 of the study.</measure>
    <time_frame>12-18 weeks</time_frame>
    <description>Adverse events assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Any change in physical examination, vital signs, lab tests results, ect will be collected and analyzed.</measure>
    <time_frame>18 weeks</time_frame>
    <description>Improvement in vital signs, lab test results and physical examination</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>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.</measure>
    <time_frame>12-18 weeks</time_frame>
    <description>seizure frequency assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>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.</measure>
    <time_frame>18 weeks</time_frame>
    <description>QoL questionnaire assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>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.</measure>
    <time_frame>18 weeks</time_frame>
    <description>CGI improvement by treatment group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>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</measure>
    <time_frame>18 weeks</time_frame>
    <description>response to MGCND00EP1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of seizure-free patients between the placebo and treatment group on week 12 of treatment (including titration).</measure>
    <time_frame>12 weeks</time_frame>
    <description>Proportion of seizure-free patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in form of new seizures and emergency of new forms will be monitored during the trial</measure>
    <time_frame>18 weeks</time_frame>
    <description>New seizure or seizure form emergency</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">103</enrollment>
  <condition>Resistant Epilepsy, Drug</condition>
  <condition>Adolescent Epilepsy</condition>
  <condition>Children Epilepsy</condition>
  <condition>Children and Adolescents With Resistant Epilepsies</condition>
  <arm_group>
    <arm_group_label>MGCND00EP1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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) .&#xD;
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).&#xD;
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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PLACEBO</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants who are assigned to receive add on PLACEBO will be administered the carrier oil (without the active ingredients).&#xD;
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).&#xD;
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.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MGCND00EP1</intervention_name>
    <description>Patients will take cannabis oil during the study</description>
    <arm_group_label>MGCND00EP1</arm_group_label>
    <other_name>Cannabis oil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patient will take carrier oil during the study</description>
    <arm_group_label>PLACEBO</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>ECG</intervention_name>
    <description>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.&#xD;
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.</description>
    <arm_group_label>MGCND00EP1</arm_group_label>
    <arm_group_label>PLACEBO</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>EEG</intervention_name>
    <description>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.</description>
    <arm_group_label>MGCND00EP1</arm_group_label>
    <arm_group_label>PLACEBO</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Blood and urine collection</intervention_name>
    <description>safety blood tests - hematology\blood count and biochemistry standard blood tests urinalysis - urine test analysis</description>
    <arm_group_label>MGCND00EP1</arm_group_label>
    <arm_group_label>PLACEBO</arm_group_label>
    <other_name>blood tests</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient has documented clinically confirmed diagnosis of epilepsy;&#xD;
&#xD;
          -  Patient did not respond to at least 2 AED's therapy given in adequate doses;&#xD;
&#xD;
          -  Patients current therapy is considered inadequate (not completely controlled by AEDs);&#xD;
             patients had four or more countable seizures with a motor component per 4 week period;&#xD;
&#xD;
          -  Patient is aged 1 year - 18 years inclusive at screening age;&#xD;
&#xD;
          -  Patient took one or more AEDs treatment at dose which has been stable for at least 4&#xD;
             weeks before enrolment;&#xD;
&#xD;
          -  Females of childbearing potential can only participate in the study if willing to use&#xD;
             acceptable, effective methods of contraception during the trial and for three month&#xD;
             after end of trial participation as defined in point 7.10 of this protocol;&#xD;
&#xD;
          -  Patient/parent is able to read/understand informed consent.&#xD;
&#xD;
          -  Male patients must either be surgically sterile or he and his female spouse/partner&#xD;
             who is of childbearing potential must be willing to use highly effective methods of&#xD;
             contraception consisting of 2 forms of birth control (1 of which must be a barrier&#xD;
             method) starting at screening and continuing throughout the study.&#xD;
&#xD;
          -  All medications or interventions for epilepsy (including ketogenic diet and vagus&#xD;
             nerve stimulation (VNS) were stable for four weeks prior to screening and participants&#xD;
             were willing to maintain a stable regimen throughout the study. The ketogenic diet and&#xD;
             VNS treatments are not counted as an AED.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known history or presence of clinically significant unstable medical condition other&#xD;
             that epilepsy which, in the opinion of the Investigator, would jeopardize the safety&#xD;
             of the subject or impact the validity of the study results.&#xD;
&#xD;
          -  Known history or presence of serious cardiovascular disease&#xD;
&#xD;
          -  Known or suspected history or family history of: schizophrenia, or other psychotic&#xD;
             illness, severe personality disorder or other significant psychiatric disorder.&#xD;
&#xD;
          -  Known or suspected allergy hypersensitivity or idiosyncratic reaction to cannabinoids&#xD;
             or any other drug substances with similar activity or to any of the excipients of the&#xD;
             IMP.&#xD;
&#xD;
          -  Participant has clinically relevant abnormalities in the 12-lead electrocardiogram&#xD;
             measured at screening or randomisation.&#xD;
&#xD;
          -  Patients were currently using or had in the past used recreational or medicinal&#xD;
             cannabis or synthetic CBD based medications or preparations within last 3 months or&#xD;
             had previous or current treatment with cannabis-based therapy within last 3 months.&#xD;
&#xD;
          -  History of drug or alcohol addiction requiring treatment.&#xD;
&#xD;
          -  History of malabsorption within the last year or presence of clinically significant&#xD;
             gastrointestinal disease or surgery that may affect drug bioavailability, including&#xD;
             but not limited to cholecystectomy.&#xD;
&#xD;
          -  Presence of hepatic or renal dysfunction.&#xD;
&#xD;
          -  Females who: are pregnant (serum hCG level consistent with pregnancy diagnosis); or&#xD;
             are lactating;&#xD;
&#xD;
          -  Participation in a clinical trial that involved administration of an investigational&#xD;
             medicinal product within 90 days prior to drug administration, or recent participation&#xD;
             in a clinical investigation that, in the opinion of the Investigator, would jeopardize&#xD;
             subject safety or the integrity of the study results;&#xD;
&#xD;
          -  Participant has clinically significant abnormal laboratory values (e.g. liver&#xD;
             enzymes);&#xD;
&#xD;
          -  Participant has clinically significant findings from a physical examination (fever);&#xD;
&#xD;
          -  In case of ketogenic diet or VNS; the diet need to be stable for at least 4 weeks, and&#xD;
             VNS ramping needs to be stable at least 12 weeks before enrolment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rubi Zomer</last_name>
    <role>Study Director</role>
    <affiliation>MGC Pharmacuticals</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Nadia Lisovoder</last_name>
    <phone>+972529573063</phone>
    <email>nadyal@galilee-cbr.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Schneider Children's Medical Center of Israel</name>
      <address>
        <city>Petach Tikvah</city>
        <state>Central District</state>
        <zip>4920235</zip>
        <country>Israel</country>
      </address>
    </facility>
    <contact>
      <last_name>Dror Kraus</last_name>
      <phone>+972523302002</phone>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Children's Hospital Ljubljana University Medical Centre Ljubljana</name>
      <address>
        <city>Ljubljana</city>
        <zip>1000</zip>
        <country>Slovenia</country>
      </address>
    </facility>
    <contact>
      <last_name>David Neubauer, MD, PhD</last_name>
      <phone>+386 1 522 9231</phone>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
    <country>Slovenia</country>
  </location_countries>
  <link>
    <url>https://www.nice.org.uk/guidance/cg137/chapter/1-Guidance</url>
    <description>nice.org-( dne: 14.februarja 2016)</description>
  </link>
  <reference>
    <citation>Berg AT, Zelko FA, Levy SR, Testa FM. Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study. Neurology. 2012 Sep 25;79(13):1384-91. doi: 10.1212/WNL.0b013e31826c1b55. Epub 2012 Sep 12.</citation>
    <PMID>22972641</PMID>
  </reference>
  <reference>
    <citation>Devinsky O, Vickrey BG, Cramer J, Perrine K, Hermann B, Meador K, Hays RD. Development of the quality of life in epilepsy inventory. Epilepsia. 1995 Nov;36(11):1089-104. doi: 10.1111/j.1528-1157.1995.tb00467.x.</citation>
    <PMID>7588453</PMID>
  </reference>
  <reference>
    <citation>Donner EJ. Opportunity gained, opportunity lost: treating pharmacoresistant epilepsy in children. Epilepsia. 2013 May;54 Suppl 2:16-8. doi: 10.1111/epi.12178.</citation>
    <PMID>23646965</PMID>
  </reference>
  <reference>
    <citation>Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia. 2014 Jun;55(6):787-90. doi: 10.1111/epi.12635. Epub 2014 May 22.</citation>
    <PMID>24854434</PMID>
  </reference>
  <reference>
    <citation>Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014 Jun;55(6):783-6. doi: 10.1111/epi.12610. Epub 2014 May 22.</citation>
    <PMID>24854149</PMID>
  </reference>
  <reference>
    <citation>Sharp GB, Samanta D, Willis E. Options for pharmacoresistant epilepsy in children: when medications don't work. Pediatr Ann. 2015 Feb;44(2):e43-8. doi: 10.3928/00904481-20150203-11.</citation>
    <PMID>25658218</PMID>
  </reference>
  <reference>
    <citation>Bent S. Herbal medicine in the United States: review of efficacy, safety, and regulation: grand rounds at University of California, San Francisco Medical Center. J Gen Intern Med. 2008 Jun;23(6):854-9. doi: 10.1007/s11606-008-0632-y. Epub 2008 Apr 16.</citation>
    <PMID>18415652</PMID>
  </reference>
  <reference>
    <citation>Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007 Aug;4(8):1614-48. doi: 10.1002/cbdv.200790144.</citation>
    <PMID>17712811</PMID>
  </reference>
  <reference>
    <citation>Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006 Apr;39(4):421-9. doi: 10.1590/s0100-879x2006000400001. Epub 2006 Apr 3.</citation>
    <PMID>16612464</PMID>
  </reference>
  <reference>
    <citation>Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. Erratum In: Lancet Neurol. 2016 Apr;15(4):352.</citation>
    <PMID>26724101</PMID>
  </reference>
  <reference>
    <citation>Cortesi M, Fusar-Poli P. Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy. Med Hypotheses. 2007;68(4):920-1. doi: 10.1016/j.mehy.2006.09.030. Epub 2006 Nov 16. No abstract available.</citation>
    <PMID>17112679</PMID>
  </reference>
  <reference>
    <citation>Dan B. Cannabinoids in paediatric neurology. Dev Med Child Neurol. 2015 Nov;57(11):984. doi: 10.1111/dmcn.12926. No abstract available.</citation>
    <PMID>26443475</PMID>
  </reference>
  <reference>
    <citation>Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. 2015 Apr;45:49-52. doi: 10.1016/j.yebeh.2015.02.043. Epub 2015 Apr 3.</citation>
    <PMID>25845492</PMID>
  </reference>
  <reference>
    <citation>Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014 Jun;55(6):791-802. doi: 10.1111/epi.12631. Epub 2014 May 22.</citation>
    <PMID>24854329</PMID>
  </reference>
  <reference>
    <citation>Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011 Sep 1;6(4):237-49. doi: 10.2174/157488611798280924.</citation>
    <PMID>22129319</PMID>
  </reference>
  <reference>
    <citation>Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63. doi: 10.1212/WNL.0000000000000363.</citation>
    <PMID>24778283</PMID>
  </reference>
  <reference>
    <citation>Izquierdo I, Tannhauser M. Letter: The effect of cannabidiol on maximal electroshock seizures in rats. J Pharm Pharmacol. 1973 Nov;25(11):916-7. doi: 10.1111/j.2042-7158.1973.tb09976.x. No abstract available.</citation>
    <PMID>4149660</PMID>
  </reference>
  <reference>
    <citation>Chesher GB, Jackson DM, Malor RM. Interaction of delta9-tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J Pharm Pharmacol. 1975 Aug;27(8):608-9. doi: 10.1111/j.2042-7158.1975.tb09515.x. No abstract available.</citation>
    <PMID>239178</PMID>
  </reference>
  <reference>
    <citation>Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569-77. doi: 10.1124/jpet.109.159145. Epub 2009 Nov 11.</citation>
    <PMID>19906779</PMID>
  </reference>
  <reference>
    <citation>Mula M. Investigational new drugs for focal epilepsy. Expert Opin Investig Drugs. 2016;25(1):1-5. doi: 10.1517/13543784.2016.1110144. Epub 2015 Nov 4.</citation>
    <PMID>26535466</PMID>
  </reference>
  <reference>
    <citation>Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, Paolini JL, Thiele EA. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016 Oct;57(10):1617-1624. doi: 10.1111/epi.13499. Epub 2016 Oct 3.</citation>
    <PMID>27696387</PMID>
  </reference>
  <reference>
    <citation>Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6.</citation>
    <PMID>26800377</PMID>
  </reference>
  <reference>
    <citation>Goldstein B. Cannabis in the treatment of pediatric epilepsy. O'Shaugnessy's 2016:7-9.</citation>
  </reference>
  <reference>
    <citation>Reddy DS, Golub VM. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016 Apr;357(1):45-55. doi: 10.1124/jpet.115.230151. Epub 2016 Jan 19.</citation>
    <PMID>26787773</PMID>
  </reference>
  <reference>
    <citation>Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015 Aug;56(8):1246-51. doi: 10.1111/epi.13060. Epub 2015 Jun 26.</citation>
    <PMID>26114620</PMID>
  </reference>
  <reference>
    <citation>O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017 May;70(Pt B):341-348. doi: 10.1016/j.yebeh.2016.11.012. Epub 2017 Feb 8.</citation>
    <PMID>28188044</PMID>
  </reference>
  <reference>
    <citation>Goodwin SW, Lambrinos AI, Ferro MA, Sabaz M, Speechley KN. Development and assessment of a shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Epilepsia. 2015 Jun;56(6):864-72. doi: 10.1111/epi.13000. Epub 2015 Apr 25.</citation>
    <PMID>25912151</PMID>
  </reference>
  <reference>
    <citation>Conway L, Widjaja E, Smith ML, Speechley KN, Ferro MA. Validating the shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in a sample of children with drug-resistant epilepsy. Epilepsia. 2017 Apr;58(4):646-656. doi: 10.1111/epi.13697. Epub 2017 Feb 15.</citation>
    <PMID>28199002</PMID>
  </reference>
  <reference>
    <citation>Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37.</citation>
    <PMID>20526405</PMID>
  </reference>
  <reference>
    <citation>Bornheim LM, Everhart ET, Li J, Correia MA. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochem Pharmacol. 1994 Jul 5;48(1):161-71. doi: 10.1016/0006-2952(94)90236-4.</citation>
    <PMID>8043019</PMID>
  </reference>
  <reference>
    <citation>Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704.</citation>
    <PMID>22193671</PMID>
  </reference>
  <reference>
    <citation>Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Rev Neurol Dis. 2007 Spring;4(2):103-6.</citation>
    <PMID>17609644</PMID>
  </reference>
  <reference>
    <citation>Volkow ND, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014 Aug 28;371(9):879. doi: 10.1056/NEJMc1407928. No abstract available.</citation>
    <PMID>25162899</PMID>
  </reference>
  <reference>
    <citation>Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013 Dec;29(3):574-7. doi: 10.1016/j.yebeh.2013.08.037.</citation>
    <PMID>24237632</PMID>
  </reference>
  <reference>
    <citation>Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD009270. doi: 10.1002/14651858.CD009270.pub2.</citation>
    <PMID>22696383</PMID>
  </reference>
  <reference>
    <citation>Zaccara G, Giovannelli F, Schmidt D. Placebo and nocebo responses in drug trials of epilepsy. Epilepsy Behav. 2015 Feb;43:128-34. doi: 10.1016/j.yebeh.2014.12.004. Epub 2015 Feb 19.</citation>
    <PMID>25703333</PMID>
  </reference>
  <reference>
    <citation>Sativex smpc , 20.09.2018</citation>
  </reference>
  <reference>
    <citation>Wall ME, Sadler BM, Brine D, Taylor H, Perez-Reyes M. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther. 1983 Sep;34(3):352-63. doi: 10.1038/clpt.1983.179.</citation>
    <PMID>6309462</PMID>
  </reference>
  <reference>
    <citation>Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980 Sep;28(3):409-16. doi: 10.1038/clpt.1980.181.</citation>
    <PMID>6250760</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>May 17, 2020</study_first_submitted>
  <study_first_submitted_qc>May 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>March 14, 2023</last_update_submitted>
  <last_update_submitted_qc>March 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>epilepsy</keyword>
  <keyword>resistant epilepsy</keyword>
  <keyword>adolescents</keyword>
  <keyword>children</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epilepsy</mesh_term>
    <mesh_term>Drug Resistant Epilepsy</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04406948
org study id: MGC-002
nct id: NCT04406948
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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 .
allocation: Randomized
intervention model: Parallel Assignment
intervention 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
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: The proportion of patients showing a >50% reduction in frequency of seizures at week 12 of the study, in the treatment versus placebo groups
time frame: 12 weeks
description: study drug overall efficiency as a seizure reducing treatment compared to placebo group
measure: 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.
time frame: 16 weeks
description: study drug overall efficiency as a seizure reducing treatment
measure: The incidence of adverse events will be summarized by organ class, severity and duration on weeks 12 and 18 of the study.
time frame: 12-18 weeks
description: Adverse events assessment
measure: Any change in physical examination, vital signs, lab tests results, ect will be collected and analyzed.
time frame: 18 weeks
description: Improvement in vital signs, lab test results and physical examination
measure: 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.
time frame: 12-18 weeks
description: seizure frequency assessment
measure: 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.
time frame: 18 weeks
description: QoL questionnaire assessment
measure: 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.
time frame: 18 weeks
description: CGI improvement by treatment group
measure: 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
time frame: 18 weeks
description: response to MGCND00EP1
measure: Proportion of seizure-free patients between the placebo and treatment group on week 12 of treatment (including titration).
time frame: 12 weeks
description: Proportion of seizure-free patients
measure: Change in form of new seizures and emergency of new forms will be monitored during the trial
time frame: 18 weeks
description: New seizure or seizure form emergency
arm group label: MGCND00EP1
arm group type: Experimental
description: 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.
arm group label: PLACEBO
arm group type: Placebo Comparator
description: 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.
intervention type: Drug
intervention name: MGCND00EP1
description: Patients will take cannabis oil during the study
arm group label: MGCND00EP1
other name: Cannabis oil
intervention type: Drug
intervention name: Placebo
description: Patient will take carrier oil during the study
arm group label: PLACEBO
intervention type: Diagnostic Test
intervention name: ECG
description: 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.
arm group label: MGCND00EP1
arm group label: PLACEBO
intervention type: Diagnostic Test
intervention name: EEG
description: 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.
arm group label: MGCND00EP1
arm group label: PLACEBO
intervention type: Diagnostic Test
intervention name: Blood and urine collection
description: safety blood tests - hematology\blood count and biochemistry standard blood tests urinalysis - urine test analysis
arm group label: MGCND00EP1
arm group label: PLACEBO
other name: blood tests
criteria: 
gender: All
minimum age: 1 Year
maximum age: 18 Years
healthy volunteers: No
last name: Rubi Zomer
role: Study Director
affiliation: MGC Pharmacuticals
last name: Nadia Lisovoder
phone: +972529573063
email: nadyal@galilee-cbr.com
facility: 
contact: 
facility: 
contact: 
country: Israel
country: Slovenia
url: https://www.nice.org.uk/guidance/cg137/chapter/1-Guidance
description: nice.org-( dne: 14.februarja 2016)
citation: Berg AT, Zelko FA, Levy SR, Testa FM. Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study. Neurology. 2012 Sep 25;79(13):1384-91. doi: 10.1212/WNL.0b013e31826c1b55. Epub 2012 Sep 12.
PMID: 22972641
citation: Devinsky O, Vickrey BG, Cramer J, Perrine K, Hermann B, Meador K, Hays RD. Development of the quality of life in epilepsy inventory. Epilepsia. 1995 Nov;36(11):1089-104. doi: 10.1111/j.1528-1157.1995.tb00467.x.
PMID: 7588453
citation: Donner EJ. Opportunity gained, opportunity lost: treating pharmacoresistant epilepsy in children. Epilepsia. 2013 May;54 Suppl 2:16-8. doi: 10.1111/epi.12178.
PMID: 23646965
citation: Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia. 2014 Jun;55(6):787-90. doi: 10.1111/epi.12635. Epub 2014 May 22.
PMID: 24854434
citation: Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014 Jun;55(6):783-6. doi: 10.1111/epi.12610. Epub 2014 May 22.
PMID: 24854149
citation: Sharp GB, Samanta D, Willis E. Options for pharmacoresistant epilepsy in children: when medications don't work. Pediatr Ann. 2015 Feb;44(2):e43-8. doi: 10.3928/00904481-20150203-11.
PMID: 25658218
citation: Bent S. Herbal medicine in the United States: review of efficacy, safety, and regulation: grand rounds at University of California, San Francisco Medical Center. J Gen Intern Med. 2008 Jun;23(6):854-9. doi: 10.1007/s11606-008-0632-y. Epub 2008 Apr 16.
PMID: 18415652
citation: Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007 Aug;4(8):1614-48. doi: 10.1002/cbdv.200790144.
PMID: 17712811
citation: Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006 Apr;39(4):421-9. doi: 10.1590/s0100-879x2006000400001. Epub 2006 Apr 3.
PMID: 16612464
citation: Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. Erratum In: Lancet Neurol. 2016 Apr;15(4):352.
PMID: 26724101
citation: Cortesi M, Fusar-Poli P. Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy. Med Hypotheses. 2007;68(4):920-1. doi: 10.1016/j.mehy.2006.09.030. Epub 2006 Nov 16. No abstract available.
PMID: 17112679
citation: Dan B. Cannabinoids in paediatric neurology. Dev Med Child Neurol. 2015 Nov;57(11):984. doi: 10.1111/dmcn.12926. No abstract available.
PMID: 26443475
citation: Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. 2015 Apr;45:49-52. doi: 10.1016/j.yebeh.2015.02.043. Epub 2015 Apr 3.
PMID: 25845492
citation: Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014 Jun;55(6):791-802. doi: 10.1111/epi.12631. Epub 2014 May 22.
PMID: 24854329
citation: Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011 Sep 1;6(4):237-49. doi: 10.2174/157488611798280924.
PMID: 22129319
citation: Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63. doi: 10.1212/WNL.0000000000000363.
PMID: 24778283
citation: Izquierdo I, Tannhauser M. Letter: The effect of cannabidiol on maximal electroshock seizures in rats. J Pharm Pharmacol. 1973 Nov;25(11):916-7. doi: 10.1111/j.2042-7158.1973.tb09976.x. No abstract available.
PMID: 4149660
citation: Chesher GB, Jackson DM, Malor RM. Interaction of delta9-tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J Pharm Pharmacol. 1975 Aug;27(8):608-9. doi: 10.1111/j.2042-7158.1975.tb09515.x. No abstract available.
PMID: 239178
citation: Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569-77. doi: 10.1124/jpet.109.159145. Epub 2009 Nov 11.
PMID: 19906779
citation: Mula M. Investigational new drugs for focal epilepsy. Expert Opin Investig Drugs. 2016;25(1):1-5. doi: 10.1517/13543784.2016.1110144. Epub 2015 Nov 4.
PMID: 26535466
citation: Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, Paolini JL, Thiele EA. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016 Oct;57(10):1617-1624. doi: 10.1111/epi.13499. Epub 2016 Oct 3.
PMID: 27696387
citation: Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6.
PMID: 26800377
citation: Goldstein B. Cannabis in the treatment of pediatric epilepsy. O'Shaugnessy's 2016:7-9.
citation: Reddy DS, Golub VM. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016 Apr;357(1):45-55. doi: 10.1124/jpet.115.230151. Epub 2016 Jan 19.
PMID: 26787773
citation: Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015 Aug;56(8):1246-51. doi: 10.1111/epi.13060. Epub 2015 Jun 26.
PMID: 26114620
citation: O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017 May;70(Pt B):341-348. doi: 10.1016/j.yebeh.2016.11.012. Epub 2017 Feb 8.
PMID: 28188044
citation: Goodwin SW, Lambrinos AI, Ferro MA, Sabaz M, Speechley KN. Development and assessment of a shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Epilepsia. 2015 Jun;56(6):864-72. doi: 10.1111/epi.13000. Epub 2015 Apr 25.
PMID: 25912151
citation: Conway L, Widjaja E, Smith ML, Speechley KN, Ferro MA. Validating the shortened Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in a sample of children with drug-resistant epilepsy. Epilepsia. 2017 Apr;58(4):646-656. doi: 10.1111/epi.13697. Epub 2017 Feb 15.
PMID: 28199002
citation: Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37.
PMID: 20526405
citation: Bornheim LM, Everhart ET, Li J, Correia MA. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochem Pharmacol. 1994 Jul 5;48(1):161-71. doi: 10.1016/0006-2952(94)90236-4.
PMID: 8043019
citation: Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704.
PMID: 22193671
citation: Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Rev Neurol Dis. 2007 Spring;4(2):103-6.
PMID: 17609644
citation: Volkow ND, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014 Aug 28;371(9):879. doi: 10.1056/NEJMc1407928. No abstract available.
PMID: 25162899
citation: Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013 Dec;29(3):574-7. doi: 10.1016/j.yebeh.2013.08.037.
PMID: 24237632
citation: Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD009270. doi: 10.1002/14651858.CD009270.pub2.
PMID: 22696383
citation: Zaccara G, Giovannelli F, Schmidt D. Placebo and nocebo responses in drug trials of epilepsy. Epilepsy Behav. 2015 Feb;43:128-34. doi: 10.1016/j.yebeh.2014.12.004. Epub 2015 Feb 19.
PMID: 25703333
citation: Sativex smpc , 20.09.2018
citation: Wall ME, Sadler BM, Brine D, Taylor H, Perez-Reyes M. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther. 1983 Sep;34(3):352-63. doi: 10.1038/clpt.1983.179.
PMID: 6309462
citation: Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980 Sep;28(3):409-16. doi: 10.1038/clpt.1980.181.
PMID: 6250760
responsible party type: Sponsor
mesh term: Epilepsy
mesh term: Drug Resistant Epilepsy
sharing ipd: No