Clinical Trials Register

Summary
EudraCT Number:	2015-002154-12
Sponsor's Protocol Code Number:	GWEP1521
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-07-15
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2015-002154-12

A.3

Full title of the trial

A double-blind, randomized, placebo-controlled study to investigate the efficacy and safety of cannabidiol (GWP42003-P, CBD) as add-on therapy in patients with tuberous sclerosis complex who experience inadequately-controlled seizures

Estudio aleatorizado doble ciego controlado con placebo para investigar la eficacia y la seguridad del cannabidiol (GWP42003-P, CBD) como terapia complementaria en pacientes con complejo de esclerosis tuberosa que sufren crisis epilépticas inadecuadamente controladas.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study of cannabidiol (GWP42003-P, CBD) in patients with tuberous sclerosis complex who experience seizures.

Estudio de cannabidiol (GWP42003-P, CBD) en pacientes con complejo de esclerosis tuberosa que sufren crisis epilépticas.

A.4.1

Sponsor's protocol code number

GWEP1521

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02544763

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GW Research Ltd.
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GW Research Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GW Research Ltd
B.5.2	Functional name of contact point	GW Research Ltd Switchboard
B.5.3	Address:
B.5.3.1	Street Address	Sovereign House, Vision Park, Chivers Way
B.5.3.2	Town/ city	Histon, Cambridge
B.5.3.3	Post code	CB24 9BZ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	00441223266800
B.5.5	Fax number	00441223235667
B.5.6	E-mail	info@gwpharm.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cannabidiol (CBD)
D.3.2	Product code	GWP42003-P
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	13956-29-1
D.3.9.2	Current sponsor code	GWP42003-P
D.3.9.3	Other descriptive name	CANNABIDIOL
D.3.9.4	EV Substance Code	SUB26600
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	Yes
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	Yes
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Tuberous Sclerosis Complex (TSC)

Complejo de esclerosis tuberosa (CET o TSC, por su sigla en inglés)

E.1.1.1

Medical condition in easily understood language

Genetic disease of benign tumour growth with multiple symptoms including seizures

Enfermedad genética con cremiento tumoral benigno de múltiples síntomas incluidas las crisis epilépticas.

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10045138
E.1.2	Term	Tuberous sclerosis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Blinded Phase:
To evaluate the efficacy of GWP42003-P as add-on therapy in
reducing the frequency of seizures when compared with placebo
in patients with TSC.
Open-label Extension:
To evaluate via the adverse events (AE) profile the long term
safety and tolerability of GWP42003-P as add-on therapy in
children and adults with TSC who experience
inadequately-controlled seizures.

Fase ciega:
Evaluar la eficacia de GWP42003-P como terapia complementaria para reducir la frecuencia de las crisis convulsivas comparado con el placebo en pacientes con TSC.
Fase de extensión abierta:
Evaluar mediante el perfil de acontecimientos adversos (AAs) la seguridad y la tolerabilidad a largo plazo de GWP42003-P como terapia complementaria en niños y adultos con TSC que sufren crisis epilépticas inadecuadamente controladas.

E.2.2

Secondary objectives of the trial

Blinded Phase:
• To evaluate the effect of GWP42003-P compared with
placebo on antiepileptic measures.
• To evaluate the safety and tolerability of GWP42003-P compared with placebo.
• To determine the pharmacokinetics (PK) following single and multiple doses of GWP42003-P.

Open-label Extension:
• To evaluate the long term effects of GWP42003-P, as add-on therapy, on antiepileptic measures.
• To evaluate the long term safety and tolerability of GWP42003.

Fase ciega:
• Evaluar el efecto de GWP42003-P en comparación con el placebo en las medidas antiepilépticas.
• Evaluar la seguridad y tolerabilidad de GWP42003-P en comparación con el placebo.
• Determinar la farmacocinética (PK) tras dosis únicas y múltiples de GWP42003-P.

Estudio abierto de extensión:
• Evaluar los efectos a largo plazo de GWP42003-P, como terapia complementaria, sobre medidas antiepilépticas.
• Evaluar la seguridad y la tolerabilidad a largo plazo de GWP42003-P.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patient is male or female aged between one and 65 years
inclusive.
• Patient and/or parent(s)/legal representative is willing and able
to give informed consent/assent for participation in the study.
• Well-documented history of epilepsy, with compatible
electroencephalogram (EEG) and clinical history.
• Clinical diagnosis of TSC according to criteria agreed by the
2012 International Tuberous Sclerosis Complex Consensus
Conference.
• All medications or interventions for epilepsy (including
ketogenic diet and any neurostimulation devices for epilepsy)
must have been stable for one month prior to screening and the
patient is willing to maintain a stable regimen throughout the
study.
At the end of the baseline period patients must also meet the
following criterion:
• Completed at least 90% of calls to IVRS during the first
28 days of the baseline period (a minimum of 25 completed calls).

• El paciente debe ser hombre o mujer de entre uno a 65 años de edad, inclusive.
• El paciente y/o sus padres/representante legal deben estar dispuestos y ser capaces de dar su consentimiento/asentimiento informado para participar en el estudio.
• El paciente debe tener un historial de epilepsia bien documentado, con electroencefalograma (EEG) e historial clínico compatibles.
• Diagnóstico clínico de TSC según los criterios acordados por la Conferencia Internacional para el Consenso del Complejo de Esclerosis Tuberosa de 2012.
• Todos los medicamentos o las intervenciones para la epilepsia (incluyendo la dieta cetogénica y cualquier dispositivo de neuroestimulación para la epilepsia) deben haber sido estables durante un mes antes de la selección y el paciente está dispuesto a mantener un régimen estable durante todo el estudio.
Al final del periodo basal los pacientes también deben cumplir el siguiente criterio:
• El paciente debe haber cumplimentado como mínimo el 90% de las llamadas al IVRS durante los primeros 28 días del periodo basal (un mínimo de 25 llamadas realizadas).

E.4

Principal exclusion criteria

• Patient has a history of pseudo-seizures.
• Patient has undergone general anesthetic in the four weeks
prior to screening or randomization.
• Patient has undergone surgery for epilepsy in the six months
prior to screening.
• Patient is being considered for epilepsy surgery or any
procedure involving general anesthesia during the blinded
phase of the study.
• Patient is taking felbamate, and they have been taking it for
less than one year prior to screening.
• Patient is taking an oral (mTOR) inhibitor.
• Active suicidal plan/intent in the past six months, or a history
of suicide attempt in the last two years, or more than one
lifetime suicide attempt.
• Patient is currently using or has in the past used recreational or
medicinal cannabis, or cannabinoid-based medications, within
the three months prior to screening and is unwilling to abstain
for the duration for the study.
• Patient has tumor growth which, in the opinion of the
Investigator, could affect the primary endpoint.
• Patient is female and of child bearing potential, or is male
whose partner is of child bearing potential, unless willing to
ensure that they or their partner use a highly effective method
of birth control (e.g., hormonal contraceptives, intrauterine
devices/hormone-releasing systems, bilateral tubal occlusion,
vasectomized partner, sexual abstinence) during the study and
for three months thereafter.
• Female patient who is pregnant (positive pregnancy test),
lactating or planning pregnancy during the course of the study
and for three months thereafter.
• Patient has received an IMP within the 12 weeks prior to the
screening visit.

• El paciente tiene historial de seudocrisis.
• El paciente ha recibido anestesia general en las cuatro semanas antes de la visita de selección o aleatorización.
• El paciente ha sido quirúrgicamente intervenido debido a la epilepsia en los seis meses antes de la visita de selección.
• El paciente está siendo considerado para una intervención quirúrgica asociada con la epilepsia o para cualquier procedimiento en el que se le administre anestesia general durante la fase ciega del estudio.
• Un paciente que esté tomando felbamato y que lo haya estado tomando durante menos de un año antes de la visita de selección.
• Un paciente que esté tomando un inhibidor oral (mTOR).
• El paciente ha tenido algún plan/intención suicida en los últimos seis meses o tiene historial de comportamiento suicida en los últimos dos años o más de un intento suicida durante su vida.
• El paciente utiliza en la actualidad o ha utilizado en el pasado, cannabis recreativo, cannabis medicinal o medicamentos a base de cannabinoides, en los tres meses antes del estudio y no está dispuestos a abstenerse de utilizarlos durante el estudio.
• El paciente tiene crecimiento tumoral que, según la opinión del investigador, podría afectar la variable primaria.
• Una paciente con potencial para procrear o un paciente cuya pareja tenga potencial para procrear, a menos que estén dispuestos a asegurar que tanto él como su pareja utilizarán anticonceptivos altamente eficaces (p. ej., anticonceptivos hormonales, dispositivos intrauterinos, sistemas intrauterinos liberadores de hormonas, oclusión tubárica bilateral, pareja vasectomizada, abstinencia sexual) durante el estudio y tres meses después de finalizar el estudio.
• Una paciente embarazada (prueba de embarazo positiva), que esté dando pecho o planificando un embarazo durante el transcurso del estudio y tres meses después del estudio.
• Pacientes que han recibido un MI en los doce meses anteriores a la visita de selección.

E.5 End points

E.5.1

Primary end point(s)

Blinded Phase:
The primary endpoint is the percentage change from baseline in
number of TSC-associated seizures (average per 28 days) during the treatment period (maintenance and titration) in patients taking GWP42003-P compared with placebo.

Open-label Extension:
The safety of GWP42003-P will be evaluated by assessing the incidence, type and severity of AEs.

Fase ciega:
La variable principal es el porcentaje de cambio respecto al basal en el número de crisis (promedio de 28 días) durante el periodo de tratamiento (mantenimiento y ajuste de dosis) en pacientes que tomen GWP42003-P comparado con el placebo.

Fase de extensión abierta:
Se evaluará la seguridad de GWP42003-P evaluando la incidencia, el tipo y la severidad de los AAs.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline (Visit 2 to Visit 3) and the last 28 days of the evaluable period.

Visita inicial (visita 2 a la visita 3) y los últimos 28 días del período evaluable.

E.5.2

Secondary end point(s)

The following endpoints will be compared between treatment groups over the 16-week, double-blind treatment period (all changes relative to baseline):
-Change in number of total seizures (percentage change from baseline and responder analyses).
-The plasma concentration/time curve of CBD and its major metabolites
Safety and Tolerability:
-Clinical laboratory parameters.
-ECG.
-Physical examination parameters (including height and weight).
-Vital signs.
-C-SSRS (19+ years) or C-SSRS Children’s (6–18 years) score, where applicable.
-Number of inpatient hospitalizations due to epilepsy.
-Abuse liability.
-Effects on menstruation cycles (in females).

Open-label Extension
Will include secondary endpoints as in the core study, with the addition of percentage change in the TSC associated seizures and with removal of PK analysis.

Los siguientes objetivos serán comparados entre los grupos de tratamiento de más de 16 semanas, periodo de tratamiento doble ciego (todos los cambios respecto al valor basal):
-Cambio en el número de crisis epilepticas totales (Variación porcentual respecto al valor basal y análisis de respuesta).
-La Curva de concentración plasmática / tiempo del CDB y sus principales metabolitos.
Seguridad y tolerabilidad:
• Parámetros clínicos de laboratorio.
• ECG
• Parámetros del examen físico (incluyendo la altura y el peso).
• Signos vitales.
• C-SSRS (19 años y más mayores) o C-SSRS, cuando sea aplicable.
• Número de hospitalizaciones debidas a la epilepsia.
• Propensión al abuso del uso del fármaco.
• Efectos sobre los ciclos de menstruación (en las pacientes).

Fase de extensión abierta
Incluirá los mismos objetivos secundarios que en el estudio principal, con la adición de variación porcentual de las crisis epilepticas asociadas a TSC y la eliminación del análisis farmacocinético.

E.5.2.1

Timepoint(s) of evaluation of this end point

Blinded phase (seizures) - Baseline (Visit 2 to Visit 3) and the last 28 days of the evaluable period.
Blinded phase (other efficacy) - Visits 3, 4, 5, 6, 7, 8 , 9 and 10.
Blinded phase (safety) - Visits 3, 4, 5, 6, 7, 8, 9 and 10.
OLE - ALL visit beginning at B1.

Fase ciega (crisis epilepticas) - visita inicial (visita 2 a la visita 3) y los últimos 28 días del período evaluable.
Fase ciega (otro eficacia) - Visitas 3, 4, 5, 6, 7, 8, 9 y 10.
Fase ciega (seguridad) - Visitas 3, 4, 5, 6, 7, 8, 9 y 10.
Fase de extension abierta - TODA visita comienza en B1.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

France

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

108

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Paediatric patients
Patients displaying varying degrees of TAND (TSC Associated Neuropsychiatric Disorders)

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

192

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients who complete the blinded phase of this trial will be given the opportunity to enter into the Open Label Extension (OLE) phase, where they will be guaranteed to receive GWP42003-P. The OLE phase will continue until market authorisation is granted for GWP42003-P in the treatment of Tuberous Sclerosis Complex (TSC).

A aquellos pacientes que completen la fase ciega de este ensayo se les dará la oportunidad de entrar en la fase de extensión abierta (OLE por sus siglas en ingles), donde se les garantiza recibir GWP42003-P. La fase OLE continuará hasta que se conceda la autorización de comercialización para GWP42003-P en el tratamiento del complejo de esclerosis tuberosa (TSC).

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-09-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-11

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