Clinical Trials Register

Summary
EudraCT Number:	2013-001895-40
Sponsor's Protocol Code Number:	109MS406
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-03-06
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

Ireland - HPRA

A.2

EudraCT number

2013-001895-40

A.3

Full title of the trial

A Phase 4, Randomized, Double-Blind Study with a Safety Extension Period to Evaluate the Effect of Aspirin on Flushing Events in Subjects with Relapsing-Remitting Multiple Sclerosis Treated with Tecfidera™ (dimethyl fumarate) delayed-release capsules (ASSURE)

A.3.1

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

A study to evaluate the effect of aspirin on flushing in patients with RRMS treated with Tecfidera

A.3.2

Name or abbreviated title of the trial where available

ASSURE

A.4.1

Sponsor's protocol code number

109MS406

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	Clinical Trials - Neurology
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	neurologyclinicalstudies@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	Yes
D.2.1.1.1	Trade name	Tecfidera
D.2.1.1.2	Name of the Marketing Authorisation holder	Biogen Idec Limited
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	Tecfidera
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	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	Yes
D.2.1.1.1	Trade name	Tecfidera
D.2.1.1.2	Name of the Marketing Authorisation holder	Biogen Idec Limited
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	Tecfidera
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	240
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	Yes
D.2.1.1.1	Trade name	Micropirin
D.2.1.1.2	Name of the Marketing Authorisation holder	Dexcel-Pharma Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Capsule
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	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.3	Other descriptive name	ASA
D.3.9.4	EV Substance Code	SUB12730MIG
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	75
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
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

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	16.1
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	16.1
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 primary objective of the study is to evaluate whether 150 mg enteric-coated ASA taken BID with DMF administration or 75 mg enteric-coated ASA taken once daily in the morning (QAM) with DMF administration reduces the incidence and/or severity of flushing events in subjects with RRMS compared with ASA-placebo administered with DMF in the clinical practice setting.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study in this study population are:

1. To evaluate the safety and tolerability of DMF administered with and without enteric-coated ASA in the clinical practice setting.

2. To evaluate the impact of DMF administration on quality of life as measured by the Short Form 36 (SF-36®) and European Quality of Life – 5 Dimensions – 5 Levels (EQ-5D-5L) questionnaires.

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 Screening/Baseline Visit or at the time point specified in the individual eligibility criterion listed:

1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent in accordance with national and local subject privacy regulations.
2. Age ≥18 years at the time of informed consent.
3. Naïve to fumaric acid esters (e.g., DMF, Fumaderm®, compounded fumarates).
4. Diagnosed with RRMS and satisfies the approved therapeutic indication for DMF.
5. Subjects of childbearing potential must practice effective contraception and be willing and able to continue contraception during the study through at least the Week 12 Visit. For further details of contraceptive requirements for this study.
6. Ability to complete the tolerability scales accurately using the eDiary and ability to complete the paper Flushing Diaries.

E.4

Principal exclusion criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the Screening/Baseline Visit or at the time point specified in the individual criterion listed:

1. Inability or unwillingness to comply with study requirements or, at the discretion of the Investigator, is deemed unsuitable for study participation.
2. One or more major comorbidities that, in the opinion of the Investigator, may affect the outcome of the study or otherwise makes the subject an unsuitable candidate for study participation. The prevailing product labels for both DMF and ASA should be used as guides.
3. Known active malignancies (subjects with cutaneous basal cell carcinoma that has been completely excised prior to study entry remain eligible).
4. Chronic use (≥7 consecutive days) of ASA- or NSAID-containing products within the month prior to enrolment in the study.
5. A known intolerance to ASA.
6. Active peptic ulceration or a history of peptic ulceration, hemophilia or other clotting disorders, or gout.
7. Known hypersensitivity reactions (e.g., bronchospasm, rhinitis, urticaria) in response to ASA or NSAID administration.
8. Impaired hepatic or renal function, in the opinion of the Investigator.
9. Female subject is pregnant, lactating, or will be attempting to become pregnant during the Double-Blind Period of the study.
10. Currently participating in another interventional clinical trial.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoints are as follows:

1. The incidence of subject-reported flushing events based on the Modified Global Flushing Severity Scale (MGFSS) and Modified Flushing Severity Scale (MFSS) data recorded on the hand-held subject reporting device (eDiary) during the first 4 weeks of the study

2. The severity of subject-reported flushing events based on the MGFSS and MFSS data recorded on the eDiary during the first 4 weeks of the study

E.5.1.1

Timepoint(s) of evaluation of this end point

The first 4 weeks of the study

E.5.2

Secondary end point(s)

The secondary endpoints are as follows:
1. Overall incidence of subject-reported flushing events during Weeks 5 through 8 and Weeks 9 through 12 of the study using MGFSS and MFSS data recorded on the eDiary
2. Severity of subject-reported flushing events during Week 5 through 8 and Weeks 9 through 12 of the study using MGFSS and MFSS data recorded on the eDiary
3. Duration of subject-reported flushing events during Weeks 1 through 4, Weeks 5 through 8, and Weeks 9 through 12 of the study based on the MGFSS and MFSS data recorded on the eDiary
4. Overall incidence of subject-reported flushing events using data obtained from the paper Flushing Diaries during Weeks 13 through 48 of the study
5. Incidence of treatment discontinuation and study withdrawal due to any AE
6. Incidence of treatment discontinuation and study withdrawal due to flushing events
7. Incidence of treatment-emergent AEs (excluding nonserious flushing events or flushing events that lead to treatment discontinuation or study withdrawal)
8. Incidence of SAEs
9. Change from Baseline to Week 24 and Week 48 in SF-36 and EQ-5D-5L assessments (quality-of-life measurements)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. During Weeks 5 through 8 and Weeks 9 through 12 of the study
2. During Week 5 through 8 and Weeks 9 through 12 of the study
3. During Weeks 1 through 4, Weeks 5 through 8, and Weeks 9 through 12 of the study
4. During Weeks 13 through 48 of the study
5. When the subject withdraws from treatment/the study, or at week 48
6. When the subject withdraws from treatment/the study, or at week 48
7. When the subject withdraws from treatment/the study, or at week 48
8. At week 48
9. Week 24 and then Week 48

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 study is last subject, last visit (the Week 48 Visit for subjects who complete 48 weeks of DMF dosing; the Safety Follow-Up Interview for subjects who discontinue DMF prior to the Week 48 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 months

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:

220

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

240

F.4.2.2

In the whole clinical trial

240

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)

After a patient has completed/terminated their study participation, long term care for the participant will remain the responsibility of their hospital consultant .

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

2014-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-09

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