Clinical Trials Register

Summary
EudraCT Number:	2013-002318-11
Sponsor's Protocol Code Number:	109MS306
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-05-03
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

Bulgarian Drug Agency

A.2

EudraCT number

2013-002318-11

A.3

Full title of the trial

Open-Label, Randomized, Multicenter, Multiple-Dose, Active Controlled, Parallel-Group, Efficacy and Safety Study of BG00012 in Children From 10 to Less Than 18 Years of Age With Relapsing-Remitting Multiple Sclerosis, With Optional Open-Label Extension

A.3.1

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

Phase 3 Efficacy and Safety Study of BG00012 in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMs).

A.3.2

Name or abbreviated title of the trial where available

CONNECT

A.4.1

Sponsor's protocol code number

109MS306

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/027/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biogen Idec Research Limited
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	Biogen Idec Research Limited
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	Biogen Idec Research Limited
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	Innovation House, 70 Norden Road
B.5.3.2	Town/ city	Maidenhead
B.5.3.3	Post code	SL6 4AY
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	clinicaltrials@biogen.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	BG00012
D.3.2	Product code	BG00012
D.3.4	Pharmaceutical form	Gastro-resistant capsule, hard
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	DIMETHYL FUMARATE
D.3.9.1	CAS number	624-49-7
D.3.9.2	Current sponsor code	BG00012
D.3.9.3	Other descriptive name	DIMETHYL FUMARATE
D.3.9.4	EV Substance Code	SUB13608MIG
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	120
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	Comparator
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	Yes
D.2.1.1.1	Trade name	AVONEX
D.2.1.1.2	Name of the Marketing Authorisation holder	Biogen Idec Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Avonex
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Interferon beta-1a
D.3.9.1	CAS number	220581-49-7
D.3.9.3	Other descriptive name	INTERFERON BETA-1A
D.3.9.4	EV Substance Code	SUB12440MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	7.5 to 30
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	No
D.3.11.9	Recombinant medicinal product	Yes
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

Relapsing-Remitting Multiple Sclerosis

E.1.1.1

Medical condition in easily understood language

Multiple Sclerosis

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	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
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

The main objectives of Part 1 are as follows:
• To evaluate the safety, tolerability, and efficacy on the disease course of BG00012 (dimethyl fumarate) in pediatric subjects with RRMS, as compared with a disease modifying treatment.
• To assess health outcomes and evolution of disability

The primary objective of Part 2 is to evaluate the long-term safety of BG00012 in subjects who completed week 96 in Part 1 of Study 109MS306.

E.2.2

Secondary objectives of the trial

Not Applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key Inclusion Criteria:
1.Ability of parents , legal guardians, and/or subjects to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. Subjects will provide assent in addition to the parental or guardian consent, as appropriate, as per local regulations.
2.Males and females aged from 10 to less than 18 years old at the time of informed consent or assent.
3.Must have a body weight of ≥30 kg.
4.Must have a diagnosis of RRMS according to the International Pediatric Multiple Sclerosis Study Group criteria for pediatric MS (2013) [Krupp 2013] (consensus definition for pediatric RRMS).
5.Must be ambulatory with a baseline EDSS score between 0 and 5.5, inclusive.
6.Must have experienced at least 1 relapse within the last 12 months prior to Day 1 or at least 2 relapses within the last 24 months prior to Day 1, with a prior brain MRI demonstrating lesions consistent with MSb), or evidence of Gd enhancing lesions of the brain on an MRI performed within the 6 weeks prior to Day 1.
7.Must be neurologically stable, with no evidence of relapse within 50 days prior to Day 1 and no evidence of corticosteroid treatment within 30 days prior to Day 1.
8.Subjects of childbearing potential who are sexually active must be willing to practice effective contraception during the study and be willing and able to continue contraception for at least 30 days after their final dose of study treatment.

-Part 2;
- Subjects who have completed Week96 in Part 1

NOTE: Other protocol defined inclusion criteria may apply

E.4

Principal exclusion criteria

Key Exclusion Criteria:
1.Primary progressive, secondary progressive, or progressive relapsing MS (as defined by [Lublin and Reingold 1996]). These conditions require the presence of continuous clinical disease worsening over a period of at least 3 months. Subjects with these conditions may also have superimposed relapses but are distinguished from relapsing remitting subjects by the lack of clinically stable periods or clinical improvement.
2.Disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren disease, lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.
3.History of premalignant or malignant disease. Subjects with basal cell carcinoma that has been completely excised prior to screening will remain eligible.
4.History of severe allergic or anaphylactic reactions, or known drug hypersensitivity to DMF, fumaric acid esters, or interferon β-1a (IFN β-1a).
5.History of abnormal laboratory results indicative of any significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, renal, and/or any other major disease that would preclude participation in a clinical study.
6.History of clinically significant cardiovascular, pulmonary, GI, dermatologic, growth, developmental, psychiatric (including depression), neurologic (other than MS), and/or other major disease that would preclude participation in a clinical study.
7.History of human immunodeficiency virus.
8.History of drug or alcohol abuse (as defined by the Investigator) within the 2 years prior to Day 1.
9.An MS relapse that has occurred within 50 days prior to Day 1 AND/OR the subject has not stabilized from a previous relapse prior to Day 1.
10.History or positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb]). Subjects with immunity to hepatitis B from either active vaccination (defined as negative HBsAg, positive hepatitis B surface antibody [HBsAb] and negative HBcAb) or from previous natural infection (defined as negative HBsAg, positive HBsAb IgG, and positive HBcAb) are eligible to participate in the study (definitions are based on the Centers for Disease Control and Prevention [CDC]’s interpretation of the hepatitis B serology panel [CDC 2007]; Appendix 4, Section 25]).
11.Any of the following abnormal blood test results at Screening:
-ALT, AST, or gamma glutamyl transferase (GGT) ≥2 × ULN
-leukocytes <3500/mm3
-eosinophils >0.7 × 103/μL or >0.7 GI/L
-absolute lymphocyte count <LLN
12.Proteinuria (1+ or greater) at Screening confirmed by a spot protein/creatinine ratio (with morning void) >0.2 mg/mg approximately 2 weeks later. Note: Documented benign proteinuria is not exclusionary.
OR
Any of the following additional abnormal urine tests at Screening confirmed by a second urinalysis approximately 2 weeks later: hematuria, without known etiology,glycosuria, without known etiology
Note: If a subject has a positive test at Screening and the etiology is known (e.g., due to menses or urinary tract infection in the case of hematuria or due to recent steroid use or elevated serum glucose in the case of glycosuria), a repeat test is not required.
13.Any previous treatment with Fumaderm® or BG00012.
14.Prior treatment with any of the following:total lymphoid irradiation,cladribine,T-cell or T-cell receptor vaccination,-any therapeutic monoclonal antibody, with the exception of rituximab (see Exclusion Criterion 15) or natalizumab (see Exclusion Criterion 16)
15.Prior treatment with any of the following medications within the 12 months prior to Day 1:mitoxantrone,-cyclophosphamide,-rituximab
16.Prior treatment with any of the following medications or procedures within 6 months prior to Day:fingolimod,teriflunomide,natalizumab,cyclosporine,
azathioprine,methotrexate,mycophenolate mofetil,laquinimod,IV immunoglobulin,plasmapheresis or cytapheresis
17.Treatment with any of the following medications within 30 days prior to Day 1:
-steroids (IV or oral corticosteroid treatment, including agents that may act through the corticosteroid pathway [e.g., low dose naltrexone])
-4-aminopyridine or related products (except subjects on a stable dose of controlled-release fampridine for 3 months)

For remaining text Please refer to protocol pages 59.

Part 2;
- Any significant changes in medical history occurring after enrollment in Part 1
- Subjects who could not tolerate BG00012 in Part 1

NOTE: Other protocol defined exclusion criteria may apply

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of Part 1 is the proportion of subjects free of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Week 96.

The primary endpoint of Part 2 is the incidence of AEs, SAEs, and discontinuations of BG00012 due to an AE.

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1 - Day 1 (baseline visit), weeks 24, 48, 72, 96

Part 2 - up to week 244

E.5.2

Secondary end point(s)

The secondary endpoints of Part 1 are as follows:
-Number of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Weeks 24 and 96
-Proportion of subjects free of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Weeks 24 and 48
-Proportion of subjects free of new MRI activity (i.e., free of Gd-enhancing and free of new ornewly enlarging T2 MRI lesions on brain MRI scans) at Weeks 24, 48, and 96
-Time to first relapse
- Proportion of subjects free of relapse up to Week 96
- Annualized relapse rate (ARR) at Weeks 48 and 96
- Incidence of adverse events (AEs) and serious adverse events (SAEs), including prospective follow-up of flushing, nausea, abdominal pain,
and diarrhea
- Vital signs, electrocardiograms (ECGs), and changes in clinical laboratory data, including monitoring of liver function, renal function, hematologic, and coagulation parameters
- Fatigue as measured by the Pediatric Quality of Life Inventory (PedsQL™) Multidimensional Fatigue Scale scores
- Quality of life as measured by the PedsQL
-Change from baseline to Week 96 in the
Expanded Disability Status Scale (EDSS) score

E.5.2.1

Timepoint(s) of evaluation of this end point

Part 1 - The various secondary endpoints will be measured throughout the study as defined by the Schedule of Events. Specifically there are visits at Screening (within 6 weeks of Baseline); Baseline (Day 1); and weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 . At Week 2, subjects will receive a follow-up safety telephone call.

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Part 2 is open label with all subjects receiving BG00012

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

Kuwait

Serbia

Turkey

Belgium

Bulgaria

Canada

Czechia

Denmark

Germany

Hungary

Israel

Italy

Poland

Spain

Sweden

United Kingdom

United States

France

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: The end of study is last subject, last visit for final collection of data for the primary outcome

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:

132

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:

122

F.1.2

Adults (18-64 years)

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

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

127

F.4.2.2

In the whole clinical trial

132

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)

Subjects who choose not to enroll in the extension study will have a Safety Follow-Up Visit 4 weeks after taking the final dose. Subjects who withdraw from the study prematurely will complete the Early Withdrawal Visit and the Safety Follow-Up Visit 4 weeks after taking their final dose.

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

2017-06-20

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed

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