Clinical Trials Register

Summary
EudraCT Number:	2018-002485-39
Sponsor's Protocol Code Number:	TAK-935-18-001
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-05-07
Trial 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

Poland - Office for Medicinal Products

A.2

EudraCT number

2018-002485-39

A.3

Full title of the trial

A Phase 2, Prospective, Interventional, Open-Label, Multisite, Extension Study To Assess the Long-Term Safety and Tolerability of Soticlestat (TAK-935) as Adjunctive Therapy in Subjects With Developmental Epileptic Encephalopathies Including Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome (ENDYMION 1).

A.3.1

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

A.4.1

Sponsor's protocol code number

TAK-935-18-001

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/491/2021

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Takeda Development Center Americas, Inc.
B.1.3.4	Country	United States
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	Takeda Development Center Americas, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Development Center Americas, Inc.
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	35/F, New Bund Center, No. 688 Jiyang Road,Pudong district,
B.5.3.2	Town/ city	Shanghai
B.5.3.3	Post code	200124
B.5.3.4	Country	China
B.5.4	Telephone number	+86 18513725073
B.5.6	E-mail	yuan.yao@takeda.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000066312
D.3 Description of the IMP
D.3.1	Product name	Soticlestat
D.3.2	Product code	TAK-935
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Soticlestat
D.3.9.1	CAS number	1429505-03-2
D.3.9.2	Current sponsor code	TAK-935
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000066312
D.3 Description of the IMP
D.3.1	Product name	Soticlestat
D.3.2	Product code	TAK-935
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Soticlestat
D.3.9.1	CAS number	1429505-03-2
D.3.9.2	Current sponsor code	TAK-935
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Epileptic Encephalopathies: Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome.

E.1.1.1

Medical condition in easily understood language

Epileptic Encephalopathies: Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10073682
E.1.2	Term	Dravet syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10048816
E.1.2	Term	Lennox-Gastaut syndrome
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	PT
E.1.2	Classification code	10083005
E.1.2	Term	CDKL5 deficiency disorder
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10083952
E.1.2	Term	Dup15q syndrome
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

Assess the long-term safety and tolerability of soticlestat when administered as adjunctive therapy to at least one anti-seizure therapy (ie, antiepileptic drugs [AEDs], vagal nerve stimulator, ketogenic diet or modified Atkins diet) in subjects with rare epilepsies.

E.2.2

Secondary objectives of the trial

The secondary objectives, in subjects receiving soticlestat as adjunctive therapy to at least one anti-seizure therapy, are the following:
- To assess the effect of soticlestat on seizure frequency.
- To assess the effect of soticlestat on the Clinical Global Impression of
Severity (CGI-S) provided by the investigator.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subjects must have participated in a previous TAK-935 study and meet one of the following conditions:
• Successfully completed a TAK-935 clinical study.
• Received at least 10 weeks of treatment (combined Dose Optimization and Maintenance Period) with the study drug in a TAK-935 clinical study and the subjects did not have a serious or severe AE that, in the investigator's or Sponsor's opinion, was related to the study drug and would make it unsafe for the patient to continue receiving the study drug.
2) In the opinion of the investigator, the subject has the potential to benefit from the administration of TAK935.
3) The subject provides written informed consent, or the subject's legal representative (parent or legal guardian) provides written informed consent and the subject provides assent, before any study procedures are performed.
4)The subject and subject's legal representative (ie, parent or guardian [as applicable]) are willing to comply with all study requirements.
5) From signing of informed consent, throughout the duration of the study, and for 30 days after last dose of study drug, female patients of childbearing potential* who are sexually active with a nonsterilized male partner** must agree to use a highly effective method of contraception (from the list below). In addition, they must not donate ova during this period.
* Females NOT of childbearing potential are defined as those who are prior to first menarche or who have been surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal (eg, defined as ≥1 year since last regular menses with a follicle stimulating hormone level >40 IU/L or ≥5 years since last regular menses, confirmed before any study drug is administered).
**Sterilized males should be ≥1 year postvasectomy and have confirmed that they have obtained documentation of the absence of sperm in the ejaculate.
A highly effective method of contraception is defined as one that has no higher than a 1% failure rate per year when used consistently and correctly. In this study, the only acceptable methods of contraception are as follows:
a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• Oral
• Intravaginal
• Transdermal
b. Progestogen-only hormonal contraception associated with inhibition of ovulation:
Oral
• Injectable
• Implantable
c. Double-barrier methods (each time the patient has intercourse):
• Sponge (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream or jelly.
• Cap (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream or jelly.
• Diaphragm (plus spermicidal cream or jelly) PLUS male condom with or without spermicidal cream or jelly.
d. Intrauterine device (Copper T PLUS condom)
e. Intrauterine hormone-releasing system
f. Sterilization:
• Bilateral tubal occlusion
• Vasectomized partner (provided that the partner is the sole sexual partner of the patient and the absence of sperm in the ejaculate has been confirmed)
g. Sexual abstinence, if it is the preferred and usual lifestyle of the patient, will be considered an acceptable method of contraception on a case-by-case basis upon prior approval by the medical monitor. Patients practicing abstinence as a method of contraception must refrain from heterosexual intercourse throughout the duration of the study and for 30 days after last dose of study drug.
From signing of informed consent, throughout the duration of the study, and for 30 days after last dose of study drug, male patients (post pubertal unless permanently sterilized**) who are sexually active with a female partner of childbearing potential* must agree to use barrier contraception (eg, condom with or without spermicidal cream or jelly).In addition, they must not donate sperm during this period.

E.4

Principal exclusion criteria

1. Clinically significant disease, that, in the investigator’s opinion, precludes study participation
2. Enrollment in any other clinical trial involving an investigational drug, device, or treatment in the past 90 days (with the exception of an antecedent study involving TAK-935)
3. Subject is currently pregnant or breastfeeding or is planning to become pregnant during the study or
within 30 days of the last study drug administration
4. Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the Columbia- Suicide Severity Rating Scale [C-SSRS] at Screening) or appearing suicidal per investigator judgment

E.5 End points

E.5.1

Primary end point(s)

•Incidence of AEs
•Change from Baseline in behavioral and adaptive functional measures using the Vineland Adaptive
Behavior Scale (VABS)
•Change from Baseline in behavior measures using total scores and subscale scores of the Aberrant
Behavior Checklist-Community Edition (ABC-C) for subjects ≥6 years of age
•Change from Baseline in the Columbia-Suicide Severity Rating Scale (CSSRS) categorization based onColumbia Classification Algorithm of Suicide Assessment categories 1,2,3,4, and 5 for subjects ≥6 years of age
≥6 years of age.
•Absolute values and change from Baseline in clinical laboratory assessments, vital sign measurements,
body weight, and ECG parameters
•Incidence of potentially clinically significant clinical safety laboratory test values, vital signs, weight,
height/length, and ECG evaluations

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary end points will be assessed throughout the study.

E.5.2

Secondary end point(s)

•Percent change from Baseline in all seizure 28-day frequency
• Percent change from Baseline in drop seizure 28-day frequency (LGS subjects)
• Percent change from Baseline in convulsive seizure 28-day frequency (DS subjects)
• Percent change from Baseline in motor seizure 28-day frequency
• Change from Baseline in CGI-S

E.5.2.1

Timepoint(s) of evaluation of this end point

At Weeks 12, 24, 36, 48, 64, 80, 104, and 108

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

Canada

China

Israel

United States

Poland

Spain

Portugal

E.8.7

Trial has a data monitoring committee

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

It has been defined as the last subject last visit

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

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:

165

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)

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:

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

pediatric population (≥2 years ≤17 years)

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

176

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)

Will be provided to subjects for the duration of the study and not afterwards.

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

2019-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-15

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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