Clinical Trials Register

Summary
EudraCT Number:	2014-004562-22
Sponsor's Protocol Code Number:	109MS416
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-05-06
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-004562-22

A.3

Full title of the trial

A Multicenter, Treatment-Blind Phase 3b Study to Evaluate Whether 6-Week Up-Titration in Tecfidera® Dose is Effective in Reducing the Incidence of Gastrointestinal Adverse Events in Patients with Multiple Sclerosis

Studio multicentrico di Fase 3b, con trattamento in cieco, per valutare se la titolazione a crescere della dose di Tecfidera®, della durata di 6 settimane, sia efficace nel ridurre l’incidenza degli eventi avversi gastrointestinali in pazienti affetti da sclerosi multipla

A.3.1

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

Study to Evaluate Whether 6-Week Up-Titration in Tecfidera® Dose is
Effective in Reducing the Incidence of Gastrointestinal Adverse Events in
Patients with Multiple Sclerosis

Studio per valutare se la titolazione a crescere della dose di Tecfidera®, della durata di 6 settimane, sia efficace nel ridurre l’incidenza degli eventi avversi gastrointestinali in pazienti affetti da sclerosi multipla

A.4.1

Sponsor's protocol code number

109MS416

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	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	n/a
B.5.3	Address:
B.5.3.1	Street Address	Innovation House, 70 Norden Road
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 4AY
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	cta.submissions@biogenidec.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.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	Capsule, hard
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

Multiple Sclerosis

Sclerosi Multipla

E.1.1.1

Medical condition in easily understood language

Multiple Sclerosis

Sclerosi Multipla

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	18.0
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	18.0
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 primary objective of the study is to assess whether a 6-week titration (compared with a 1-week titration) is effective in reducing the incidence of BG00012-related GI AEs in subjects with MS.

L’obiettivo primario dello studio è valutare se una titolazione di 6 settimane (rispetto a una titolazione di 1 settimana) sia efficace nel ridurre l’incidenza degli EA gastrointenstinali correlati a BG00012 nei soggetti affetti da SM.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is to assess whether a 6-week titration (compared with a 1-week titration) is effective in reducing the average severity and duration of GI symptoms over 12 weeks of BG00012 treatment in this study population.

L’obiettivo secondario di questo studio è valutare se una titolazione di 6 settimane (rispetto a una titolazione di 1 settimana) sia efficace nel ridurre la gravità media e la durata dei sintomi gastrointestinali nel corso di 12 settimane di trattamento con BG00012 in questa popolazione di studio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible to participate in this study, candidates must meet the following eligibility criteria at the baseline visit:
1. Ability 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
2. Aged 18 to 65 years old, inclusive, at the time of informed consent
3. Diagnosis of MS consistent with locally labeled indication for BG00012
4. No prior treatment with BG00012
5. Female subjects of childbearing potential who are not surgically sterile must practice effective contraception (see Section 15.5.3) during their participation in the study
6. Have had a recent (i.e., at screening or within the previous 6 months) complete blood count (CBC), including lymphocyte count, that does not preclude the subject’s participation in the study, in the judgment of the Investigator

Per essere ammessi a partecipare a questo studio, i candidati devono soddisfare i seguenti criteri di eleggibilità alla visita basale:
1. Capacità di comprendere lo scopo e rischi dello studio e fornireun consenso informato firmato e datato e l'autorizzazione ad utilizzare le informazioni sanitarie protette (PHI) in conformità con le normative sulla privacy della persona nazionali e locali
2. Età compresa fra 18 e 65 anni inclusi, al momento del consenso informato
3. Diagnosi di SM coerente con la locale indicazione in etichetta er BG00012
4. Nessun precedente trattamento con BG00012
5. I soggetti di sesso femminile in età fertile che non sono chirurgicamente
sterili devono praticare una contraccezione efficace (si veda la Sezione 15.5.3) durante la loro partecipazione allo studio
6. Hanno avuto un recente (cioè, allo screening o entro 6 mesi precedenti)
emocromo (CBC), includso la conta dei linfociti, che non fa
precludere la partecipazione del soggetto nello studio a giudizio dello Sperimentatore

E.4

Principal exclusion criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the baseline visit, unless specified otherwise:
1. Are unwilling or unable to comply with study requirements, or are deemed unsuitable for study participation as determined by the Investigator
2. Have a recent history or ongoing GI illness (e.g., peptic ulcer, irritable bowl syndrome) or any other current condition with GI signs and symptoms (e.g., nausea, vomiting, abdominal pain, or diarrhea) that may interfere with assessment of study endpoints, as determined by the Investigator
3. Have other major comorbid conditions that preclude participation in the study, as determined by the Investigator
4. Subject is pregnant, breastfeeding, or planning a pregnancy during the study period
5. Are receiving concomitant disease-modifying therapies for MS including, but not limited to, natalizumab, IFN-β, glatiramer acetate, fingolimod, alemtuzumab, teriflunomide, or laquinimod at screening
6. History of severe allergic or anaphylactic reactions or known drug hypersensitivity
7. Current enrollment in any clinical study or Biogen Idec-sponsored study or other studies that may conflict with this study (e.g., health economics studies or local registries)

I candidati saranno esclusi dall’entrata nello studio se una qualsiasi delle seguenti criteri di esclusione esisteranno alla visita basale, se non diversamente specificato:
1. Riluttanza o l'incapacità di rispettare i requisiti di studio, tra cui la presenza di qualsiasi condizione (fisica, mentale o sociale) che è probabile che influenzi la capacità del soggetto di rispettare il protocollo di studio.
2. Hanno una storia recente o in ocrso di malattia GI (ad esempio, ulcera peptica, sindrome del colon irritabile) o qualsiasi altra condizione corrente con segni e
sintomi GI (ad esempio, nausea, vomito, dolore addominale o diarrea) che
potrebbe interferire che può interferire con la valutazione degli endpoint dello studio, come stabilito dallo Sperimentatore
3. Hanno altre importanti comorbidità che precludono la partecipazione allo
studio, come determinato dallo Sperimentatore
4. Il soggetto è in stato di gravidanza, sta allattando al seno, o programmando una gravidanza durante il periodo di studio
5. Stanno ricevendo allo screening terapie modificanti la malattia concomitanti per la SM compresi, ma non limitatamente a, natalizumab, IFN-β, glatiramer acetato, fingolimod, alemtuzumab, teriflunomide, o laquinimod
6. Storia di reazioni allergiche o anafilattiche gravi o di ipersensibilità nota al farmaco
7. Arruolamento attuale in qualsiasi studio clinico o in studio sponsorizzato da Biogen Idec o in altri studi che possono entrare in conflitto con questo studio (ad esempio, la studi di economia della salute o registri locali)

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the proportion of subjects with a worsening in severity of GI AEs, defined as a positive average change from baseline to the end of BG00012 treatment in the Gastrointestinal Symptom Rating Scale (GSRS).

L’endpoint primario è la proporzione di soggetti con peggioramento della gravità degli EA gastrointestinali, definita come una variazione positiva media dal basale alla fine del trattamento con BG00012 nella scala di valutazione dei sintomi gastrointestinali (Gastrointestinal Symptom Rating Scale, GSRS).

E.5.1.1

Timepoint(s) of evaluation of this end point

Subjects will be required to record their GI symptoms in the eDiary every day from the baseline visit until the end of the 12-week BG00012 treatment period (Week 14). Timepoint for evaluation of the change in GSRS score from baseline will be Week 14.

I soggetti saranno tenuti a registrare i loro sintomi gastrointestinali in un diario elettronico
ogni giorno dalla visita basale fino alla fine del periodo di trattamento di 12 settimane con BG00012 (Settimana 14). Il Tempo per la valutazione della variazione
del punteggio GSRS rispetto al basale sarà la settimana 14.

E.5.2

Secondary end point(s)

The secondary endpoints are as follows:
1. Average change from baseline in GSRS scores over the 12 weeks of BG00012 treatment as measured by the total change in GSRS scores from baseline divided by the total number of days with GSRS scores recorded
2. Time to first worsening in GSRS score from baseline
3. Time to recovery to baseline score from the last occurrence of worst GSRS score
4. Average change from baseline in GSRS scores to the end of Weeks 4, 6, 8, 10, 12, and 14

Gli endpoint secondari dello studio sono i seguenti:
1. Variazione media dal basale nei punteggi GSRS nelle 12 settimane di trattamento con BG00012, come misurato in base alle variazioni totali dei punteggi GSRS dal basale diviso il numero totale di giorni con punteggi GSRS registrati;
2. Tempo trascorso fino al primo peggioramento del punteggio GSRS dal basale;
3. Tempo trascorso fino al recupero del punteggio basale dall’ultima comparsa di punteggio GSRS peggiore;
Variazione media dal basale dei punteggi GSRS fino alla fine delle Settimane 4, 6, 8, 10, 12 e 14.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoint for evaluation of:
1. Timepoint for evaluation of the change in GSRS score from baseline will be Week 14.
2 and 3. will be evaluated as they occur.
4. Timepoint for evaluation will be Weeks 4, 6, 8, 10, 12, and 14

Timepoint per la valutazione di:
1. timepoint per la valutazione della variazione del punteggio GSRS dal basale
sarà la Settimana 14.
2 e 3. saranno valutati quando si verificano.
4. timepoint per la valutazione saranno le Settimane 4, 6, 8, 10, 12 e 14

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3.1

Comparator description

titolazione della dose più lenta rispetto alla titolazione standard

slower dose titration vs. the standard dose titration

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

Belgium

Canada

Czech Republic

France

Germany

Hungary

Italy

Spain

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

The end of the study is the last subject, last safety follow-up telephone interview for final collection of data.

La conclusione dello studio è l'ultima intervista telefonica di follow-up per la sicurezza per la raccolta definitiva dei dati, dell’ultimo paziente

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

285

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

192

F.4.2.2

In the whole clinical trial

300

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)

Continuing treatment with BG00012 following completion of the study will be left to the discretion of the subject and prescribing physician.

Sarà lasciato a discrezione del soggetto e del medico prescrittore continuare il trattamento con BG00012 dopo il completamento dello studio.

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

2015-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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