Clinical Trials Register

Summary
EudraCT Number:	2012-000827-42
Sponsor's Protocol Code Number:	N01372
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-05-02
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

UK - MHRA

A.2

EudraCT number

2012-000827-42

A.3

Full title of the trial

AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO EVALUATE THE LONG-TERM SAFETY AND EFFICACY OF BRIVARACETAM USED AS ADJUNCTIVE TREATMENT IN SUBJECTS AGED 16 YEARS OR OLDER WITH EPILEPSY

A.3.1

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

An Open-Label Trial to look at the long-term safety and effectiveness of Brivaracetam used in addition to the subjects main treatment in subjects aged 16 years or older with epilepsy

A.4.1

Sponsor's protocol code number

N01372

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	UCB Pharma SA
B.1.3.4	Country	Belgium
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	UCB Pharma SA
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UCB BIOSCIENCES GmbH
B.5.2	Functional name of contact point	Clin Trial Reg & Results Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Alfred-Nobel-Strasse 10
B.5.3.2	Town/ city	Monheim
B.5.3.3	Post code	40789
B.5.3.4	Country	Germany
B.5.4	Telephone number	492173481515
B.5.5	Fax number	492173481573
B.5.6	E-mail	clinicaltrials@ucb.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	Brivaracetam
D.3.4	Pharmaceutical form	Film-coated tablet
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	BRIVARACETAM
D.3.9.1	CAS number	357336-20-0
D.3.9.2	Current sponsor code	ucb34714
D.3.9.3	Other descriptive name	(2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide
D.3.9.4	EV Substance Code	SUB25397
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	10
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Brivaracetam
D.3.4	Pharmaceutical form	Film-coated tablet
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	BRIVARACETAM
D.3.9.1	CAS number	357336-20-0
D.3.9.2	Current sponsor code	ucb34714
D.3.9.3	Other descriptive name	(2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide
D.3.9.4	EV Substance Code	SUB25397
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	25
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: 3
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	Brivaracetam
D.3.4	Pharmaceutical form	Film-coated tablet
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	BRIVARACETAM
D.3.9.1	CAS number	357336-20-0
D.3.9.2	Current sponsor code	ucb34714
D.3.9.3	Other descriptive name	(2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide
D.3.9.4	EV Substance Code	SUB25397
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	50
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

Nonpyschotic Behavioural Side Effects in Subjects With Epilepsy

E.1.1.1

Medical condition in easily understood language

Epilepsy

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10015037
E.1.2	Term	Epilepsy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the long-term safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day as adjunctive treatment in adult subjects with epilepsy

E.2.2

Secondary objectives of the trial

To evaluate the maintenance of efficacy of BRV over time.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. An Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved written Informed Consent form is signed and dated by the subject or by the parent(s) or legal representative. The Informed Consent form or a specific Assent form, where required, will be signed and dated by minors.
2. Subject is male or female and 16 years or older. Subjects under 18 years of age may be included only where legally permitted and ethically accepted.
3. Subjects having completed the Treatment Period of N01394, N01395, or other planned BRV Phase 3b studies in epilepsy, and have access to the present study.
4. Subject for whom the Investigator believes a reasonable benefit from the long-term administration of BRV may be expected.
5. Female subject without childbearing potential (postmenopausal for at least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with childbearing potential are eligible if they use a medically accepted contraceptive method. Oral or depot contraceptive treatment with at least ethinylestradiol 30μg per intake (or ethinylestradiol 50μg per intake if associated with any strong enzyme inducer [eg, carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. John’s Wort, rifampicin]), monogamous relationship with vasectomized partner, or double-barrier contraception are acceptable methods. The subject must understand the consequences and potential risks of inadequately protected sexual activity, be educated about and understand the proper use of contraceptive methods, and undertake to inform the Investigator of any potential change in status. Abstinence will be considered as an acceptable method of contraception if the Investigator can document that the subject agrees to be compliant. True abstinence when this is in line with the preferred and usual lifestyle of the subject will be
considered as an acceptable method of contraception if the Investigator can document that the subject agrees to be compliant (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
6. Subject/legal representative is considered reliable and capable of adhering to the protocol (eg, able to understand and complete diaries and questionnaires), visit schedule, or medication intake according to the judgment of the Investigator.

E.4

Principal exclusion criteria

1. Subject has developed hypersensitivity to any components of the investigational medicinal product (IMP) or comparative drugs as stated in this protocol during the course of the prior study.
2. Severe medical, neurological, or psychiatric disorders, or laboratory values that may have an impact on the safety of the subject.
3. Poor compliance with the visit schedule or medication intake in the previous BRV study.
4. Planned participation in any other clinical study of another investigational drug or device during this study.
5. Pregnant or lactating woman.
6. Any medical condition which, in the Investigator’s opinion, warrants exclusion.
7. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at the last visit of the previous study or at the EV of N01372 if not completed at the last visit of the previous study.
8. Subject has impaired hepatic function: ALT/SGPT (alanine aminotransferase/serum glutamic pyruvate transaminase), AST/SGOT (aspartate aminotransferase/serum glutamic
oxaloacetic transaminase), or alkaline phosphatase of more than 2 times the upper limit of the reference range.
9. Subject has gamma-glutamyltransferase (GGT) values of more than 3 times the upper limit of the reference range. A result of GGT exceeding 3 times the upper limit can be
accepted only if attributable to hepatic enzyme induction caused by concomitant antiepileptic treatment and other hepatic enzymes are below 2 times the upper limit of the reference range.
10. Subject has clinically significant deviations from reference range values for laboratory parameters: creatinine clearance (CrCl) calculated <30mL/min, platelets <100,000/μL, or neutrophil cells <1,800/μL.

E.5 End points

E.5.1

Primary end point(s)

The primary objective is to evaluate the long-term safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day as adjunctive treatment in adult subjects with epilepsy.

E.5.1.1

Timepoint(s) of evaluation of this end point

'Occurrence of a TEAE', ‘Withdrawal due to an AE’ and ‘Occurrence of an SAE’ ongoing on a daily basis. Laboratory tests (hematology, blood chemistry, urinalysis), and Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) every 3 months; and body weight, ECG, and Physical and neurological examinations every 6 months.

E.5.2

Secondary end point(s)

Evaluate the maintenance of efficacy of BRV over time by means of seizure count information recorded on the Daily Record Card. Secondary efficacy variables for subjects with focal-onset epilepsy are the partial-onset seizure (POS) (Type I) frequency per 28 days during the Evaluation Period, the percent reduction in POS (Type I) frequency per 28 days from Baseline of the previous study to the Evaluation Period, and the responder rate in POS (Type I) frequency over the Evaluation Period. A responder is defined as a subject with a ≥50% reduction in seizure frequency from the Baseline Period of the previous study. No secondary efficacy variables are defined for subjects with generalized epilepsy.
Other efficacy variables for subjects with focal-onset epilepsy include the percentage of subjects continuously seizure free for all seizure types (I+II+III) for at least 6 months and at least 12 months during the Evaluation Period.
Other efficacy variables for subjects with generalized epilepsy include the number of generalized (Type II) seizure days per 28 days during the Evaluation Period, the percent reduction in generalized (Type II) seizure days per 28 days from Baseline of the previous study to the Evaluation Period, the responder rate for generalized (Type II) seizure days over the Evaluation Period, and the percentage of subjects continuously seizure free for all seizure types (I+II+III) for at least 6 months and at least 12 months during the Evaluation Period.

E.5.2.1

Timepoint(s) of evaluation of this end point

Ongoing on a daily basis

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

Yes

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

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

E.8.1.1

Randomised

E.8.1.2

Open

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

120

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

France

Germany

Italy

Spain

United Kingdom

United States

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

Last visit of last subject (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)

F.1.1.5

Children (2-11years)

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:

624

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

650

F.4.2.2

In the whole clinical trial

650

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)

Please see protocol.

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

2012-06-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-08-09

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