Epilepsy Trial Summary

Sackler Faculty of Medicine, ,‫מסונף לפקולטה לרפואה ע"ש סאקלר‬
Tel-Aviv University ‫אוניברסיטת תל אביב‬
Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

Prof Uri Kramer, MD ‫פרופ' אורי קרמר‬
Director - Pediatric Epilepsy Service
"Dana" Children's Hospital

‫המרכז הרפואי תל אביב ע"ש סוראסקי‬
Tel Aviv- Sourasky Medical Center
EPILEPSY
Trial Summary
Prof. Uri Kramer

December 2016
* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬
* To make an appointment: +972-3-697400: ‫* זימון תורים‬


1. Purpose
A two year (11/2013 - 10/2015) retrospective study intended to describe the

experience of four Israeli pediatric epilepsy clinics treating children and adolescents
diagnosed as having intractable epilepsy with a regimen of known and well-controlled
composition of whole plant Cannbidiol (CBD) - enriched medical cannabis oil extract
(CECO). The participating clinics are all tertiary referral centers for pediatric epilepsy
in Israel, and each treats thousands of patients with epilepsy, including many with
intractable disease¹.
The study was approved by the Israeli Ministry of Health (MoH) and the IRB
committee of the four participating centers.
2. Subject¹
 Recruitment: 130 patients all diagnosed with intractable epilepsy.

 Age: 83% < 15 years old.
 Prior Rx: 5-10 AEDs: 40%, > 10 AEDs: 60%, VNS &/or KTG; 43%.
 88% of the patients were cognitively impaired as follows: (1) mild - 22%, (2)
moderate – 19%, (3) severe - 46%, (4) normal cognition - 13%.
 CECO: the selected formula contained CBD and THC at a ratio of 20:1 dissolved in
organic olive oil administrated sublingually.
 Seizure frequency was assessed by parental report during clinical visits.
 Patients were divided into six groups based on seizure etiology: (1) Acquired, (2)
Early epileptic encephalopathy with a known genetic etiology, (3) Epileptic
encephalopathy without a known genetic etiology, (4) Congenital brain
malformations, (5) Hypoxic ischemic encephalopathy, (6) Other (etiology not
defined).

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬


3. Study Medication ⁽¹⁾ ⁽²⁾
 CECO was supplied by two licensed Israeli growers (Cann Pharmaceutical and
Tikun Olam), and the preparation of the oil was made by two methods.
 Most of the participants were treated with Cann Pharmaceutical’s EP1, a CBD-
enriched whole plant cannabis oil extract holding a 20:1 ratio of CBD to THC.
 Preparation of Cann Pharmaceutical’s CECO was made by extraction in PhEur

absolute ethanol, followed by evaporation and decarboxylation before being
diluted in PhEur organic olive oil.
 Dosage ranged from 1 to 27 mg/kg/d, divided into two groups, 1–10 mg/kg/d and
10–27 mg/kg/d. Final dose used for each patient was defined according to seizure
response and Adverse Reactions (ARs). In some cases, the patient’s other
medications were reduced if there was decrease in seizure frequency and
adjusted according to ARs, in addition to drug level adjustments while on CECO.
 Seizure reduction was rated according to four levels: (1) 0%, <25%, (2) 25– 50%,
(3) 50–75%, and (4) 75–100%, as reported by parents and older patients. Parents
were asked to report the number of seizures per period. ARs were also reviewed.
 Quality Assurance: QA tests were conducted during the different stages of the
preparation process using high performance liquid chromatography (HPLC) in two
independent laboratories approved by the MoH.

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬


4. Final Results ⁽²⁾
 7 / 130 pts (5%) - 100% seizure reduction.

 20 / 130 pts (15%) - more than 75% reduction of seizures.
 30/ 130 pts (23%) - 50%-75% reduction of seizures.
 34 / 130 pts (26%) - reduction of up to 50% of seizures.
 39 out of 130 (30%) - no reduction of seizures.
In addition to the oral treatment, a group of 24 patients with the most severe
symptoms were approved the medical vaporizer treatment using Cann
Pharmaceutical’s dried herb of the source strain ("Ph.D"). Results were presented by
Prof. Linder during the Annual Epilepsy Conference held by the Israeli “League against
Epilepsy” in January 2016:
 2/24 (8%) patients experienced immediate seizure relief within seconds.

 8/24 (34%) patients experienced less severe (mild) seizure.
 6/24 (25%) patients experienced shorter clusters.
 2/24 (8%) patients showed low compliance.
 6/24 (25%) patients did not experience any effect.
5. Additional Positive Reactions ⁽¹⁾
The initial patients group experienced additional positive response not related to
seizure frequency which were reported by 44/74 patients and included:
 25/44 (57%) - Improved behavior and alertness.

 11/44 (25%) - Improved language, communication & motor skills.
 8/44 (18%) - Improved sleep.

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬


6. Adverse Reactions (ARs) ⁽¹⁾
ARs were reported by 34/74 patient (see Table below) which led to the withdrawal
of medical cannabis in five patients.
ARs No. of Cases

Seizure aggravation 13 (18%)
Somnolence/fatigue 16 (22%)
Gastrointestinal problems and irritability 5 (7%)
Side effects of substance use were inevitable, but their rate and severity were not
different from most known AEDs. Seizure aggravation reported in 7% of the patients
can be partly related to the disease’s natural history. Most of our study patients were
cognitively impaired, thus preventing the option to assess the effect of CECO on
cognition.
All ARs were reversible.

Severe ARs disappeared within 24 hours of cessation of cannabis treatment.
In general, oral administration of CBD is well tolerated and safe in humans even at
chronic high doses of up to 1500mg/day, although when administrated in conjunction
with pharmaceutical drugs interactive relation should be monitored ⁽³¯⁶⁾.
According to the National Institute of Health ⁽⁷⁾, cannabinoid receptors, unlike opioid
receptors, are not located in the brainstem areas controlling respiration hence lethal
overdoses from Cannabis and cannabinoids do not occur.
GW’s Epidiolex AR ⁽⁸¯¹⁰⁾

AR were recorded in 79% of all patients and included: Somnolence, Fatigue, Diarrhea,
Appetite Increase/Decrease. Serious adverse events were reported in 48 patients
(30%), including one death, regarded as unrelated to CBD. Serious adverse events
which were deemed possibly related to CBD occurred in 20 patients ⁽¹⁰⁾.

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬


Reference
1. Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S . CBD-enriched

medical cannabis for intractable pediatric epilepsy: The current Israeli experience.
Seizure, 01/2016
2. U Kramer, Cannabidiol (CBD) in Refractory Epilepsy Presentation, 2016
3. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL,
Lander N, Mechoulam R., Chronic administration of cannabidiol to healthy volunteers
and epileptic patients, 1980
4. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA, Safety and Side Effects of
Cannabidiol, a Cannabis sativa Constituent, 2011
5. Franjo Grotenhermen, Even high doses of oral cannabidiol do not cause THC-like
effects in humans, 2016
6. Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, Allen

P, Seal M, Langohr K, Farré M, Zuardi AW, McGuire PK, Acute effects of a single, oral
dose of THC and CBD administration in healthy volunteers, 2012
7. NIH, National Cancer Institute, Adverse Effects Cannabis & Cannabinoids
8. Devinsky O, Marsh E, Friedman D, et al. Epidiolex (Cannabidiol) in Treatment Resistant

Epilepsy 12/2015
9. GW Press Release: The Lancet Neurology Publishes Data from the Epidiolex Expanded
Access Program in Children and Young Adults with Treatment-Resistant Epilepsy,
4/12/2015
10. GW Press Release: The Lancet Neurology Publishes Data from the Epidiolex®
Expanded Access Program in Children and Young Adults with Treatment-Resistant
Epilepsy The Lancet Neurology Publishes Data from the Epidiolex® Expanded Access
Program in Children and Young Adults with TRE, 24/12/15

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬


APPENDIX A: Additional Reading Material
1. Williamson EM, Evans FJ, Cannabinoids in clinical practice, 2000
2. Guzmán M, Cannabinoids: potential anticancer agents, 2003
3. Sutton IR, Daeninck P, Cannabinoids in the management of intractable chemotherapy-

induced nausea & vomiting & cancer-related pain, 2006
4. Grotenhermen F, Russo E, eds., Cannabis and Cannabinoids: Pharmacology,

Toxicology, and Therapeutic Potential, 2002
5. Adams IB, Martin BR, Cannabis: pharmacology and toxicology in animals and humans,
1996
6. Staff News & Analysis, In the Race to 'Medicalize' Cannabis, Big Pharma Stumbles,
09/01/15
7. Kristina Fiore, Still Only Open-Label Evidence for Cannabis Drug - Data from
randomized controlled trials expected in February, 08/12/15
Uri Kramer M.D.

Director – Pediatric Epilepsy Service
Tel Aviv, Sourasky, Medical Center
Full Professor of Pediatrics
Urikramer100@gmail.com
+972-3-5408386

* Tel: +972-3-6974517 :'‫ * טל‬Fax: +972-3-6973281: ‫* פקס‬

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Sackler Faculty of Medicine, ,‫מסונף לפקולטה לרפואה ע"ש סאקלר‬

Tel-Aviv University ‫אוניברסיטת תל אביב‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

Prof. Uri Kramer

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

A two year (11/2013 - 10/2015) retrospective study intended to describe the

 Recruitment: 130 patients all diagnosed with intractable epilepsy.

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

3. Study Medication ⁽¹⁾ ⁽²⁾

 Preparation of Cann Pharmaceutical’s CECO was made by extraction in PhEur

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

4. Final Results ⁽²⁾

 7 / 130 pts (5%) - 100% seizure reduction.

 2/24 (8%) patients experienced immediate seizure relief within seconds.

5. Additional Positive Reactions ⁽¹⁾

 25/44 (57%) - Improved behavior and alertness.

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

6. Adverse Reactions (ARs) ⁽¹⁾

ARs No. of Cases

All ARs were reversible.

GW’s Epidiolex AR ⁽⁸¯¹⁰⁾

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

1. Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S . CBD-enriched

2. U Kramer, Cannabidiol (CBD) in Refractory Epilepsy Presentation, 2016

6. Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, Allen

7. NIH, National Cancer Institute, Adverse Effects Cannabis & Cannabinoids

8. Devinsky O, Marsh E, Friedman D, et al. Epidiolex (Cannabidiol) in Treatment Resistant

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

Pediatric Neurology Unit ‫היחידה לנוירולוגית ילדים‬

"Dana" Children's Hospital

APPENDIX A: Additional Reading Material

1. Williamson EM, Evans FJ, Cannabinoids in clinical practice, 2000

2. Guzmán M, Cannabinoids: potential anticancer agents, 2003

3. Sutton IR, Daeninck P, Cannabinoids in the management of intractable chemotherapy-

4. Grotenhermen F, Russo E, eds., Cannabis and Cannabinoids: Pharmacology,

Uri Kramer M.D.

* 6, Weizman St, Tel-Aviv 64239, Israel * 64239 ‫ תל אביב‬,6 ‫* רח' ויצמן‬

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