Clinical Trials Register

Summary
EudraCT Number:	2010-021978-11
Sponsor's Protocol Code Number:	101MS326
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-08-15
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

Finland - Fimea

A.2

EudraCT number

2010-021978-11

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive 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

A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMS

A.4.1

Sponsor's protocol code number

101MS326

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 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 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 Limited
B.5.2	Functional name of contact point	Not available
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@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	Tysabri
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.3.2	Product code	AN100226, BG00002
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NATALIZUMAB
D.3.9.1	CAS number	189261-10-7
D.3.9.3	Other descriptive name	SUB22282
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	300
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Secondary Progressive 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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10063400
E.1.2	Term	Secondary progressive 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

Part 1: The primary objective of the study is to investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in subjects with SPMS.

Part 2: The primary objective of Part 2 of the study is to evaluate the safety profile of natalizumab in subjects with SPMS.

E.2.2

Secondary objectives of the trial

The secondary objectives of Part 1 of this study are to determine:
• the proportion of subjects with consistent improvement in Timed 25-foot Walk
• the change in subject-reported ambulatory status as measured by the 12-item MS Walking Scale
• the change in manual ability based on the ABILHAND Questionnaire
• the impact of natalizumab on subject-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical
• the change in whole brain brain volume between the end of study and Week 24 using magnetic resonance imaging (MRI)
• the proportion of subjects experiencing progression of disability as measured by individual physical Expanded Disability Status Scale (EDSS) system scores;
The secondary objectives of Part 2 of the study are as follows:
• To investigate long-term disability (based on clinical or patient-reported assessments) in subjects with SPMS receiving natalizumab treatment for approximately 4 years
• To assess change in brain volume and T2 lesion volume

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Substudies are detailed in main protocol , version 2 Final dated 29 June 2011, section 13.5.
The substudies to be performed in any of the involved countries are as follows:
- CSF Concentrations of Natalizumab and Inflammatory Markers: US, Canada, UK, Sweden, Denmark, Poland and Germany
- Cognition: Australia, Canada, Italy, Spain, UK, US
- Genetic Analysis: in all the countries after patient consent.

E.3

Principal inclusion criteria

To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of randomization (Day 0), or at the timepoint 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 and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
2. Be between the ages of 18 and 58, inclusive, at the time of informed consent.
3. Onset of SPMS at least 2 years prior to enrollment. SPMS is defined as relapsing-remitting disease followed by progression of disability independent of or not explained by MS relapses (Lublin, Reingold, 1996) for at least 2 years.
4. Have EDSS score of 3.0 to 6.5, inclusive.
5. Have an MS Severity Score (MSSS) of 4 or higher.
6. Have documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.
7. Subjects must have completed those baseline assessments associated with components of the primary endpoint (EDSS, T25FW, 9HPT) prior to randomization (Day 0)
8. Subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 3 months after their last infusion.
Part 2: To be eligible to participate in the Part 2 Extension Phase of this study, candidates must meet the following eligibility criteria at the time of consent into Part 2, or at the timepoint specified in the individual eligibility listed:
1. Ability to understand the purpose and risks of the study and provide signed and datedinformed consent and authorization to use PHI in accordance with national and local subject privacy regulations.
2. Subjects must have participated in Part 1, have documented Week 108 assessment attempts for EDSS, T25FW, and 9HPT prior to first open-label dosing at Week 108 and not have missed 2 or more consecutive infusions in Part 1 of the study.
3. Subjects of childbearing potential must practice effective contraception during the study and be able to continue contraception for 3 months after their last infusion.

E.4

Principal exclusion criteria

Part 1:Candidates will be excluded from study entry if any of following exist at time of randomization (Day 0) or at timepoint specified in individual criterion listed
1.Have a diagnosis of RRMS or PPMS as defined by revised McDonald Committee criteria
2.Had recent clinical relapse (within 3 mos) prior to randomization
3.Have T25FW test of >30 secs during screening period
4.Any value below lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils
5.Considered by Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines or due to prior immunosuppressive or immunomodulating treatment
6.Subjects for whom MRI is contraindicated (ie have pacemakers or other contraindicated implanted metal devices or have claustrophobia that cannot be medically managed)
7.History of any clinically significant (as determined by Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal or other major disease that would preclude participation in a clinical study
8.History of malignant disease, including solid tumors and hematologic malignancies (with exception of basal cell and squamous cell carcinomas of skin that have been completely excised and are considered cured)
9.Known history of or positive test result for HIV
10.Positive test result for HCV or HBV (test for hepatitis B surface antigen and/or hepatitis B core antibody)
11.History of transplantation or any antirejection therapy
12.Presence of any infectious disease (eg cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening
13.History of PML or other opportunistic infections including active tuberculosis
14.Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab or bone marrow ablation
15.Any prior treatment with natalizumab
16.Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 mos prior to randomization
17.Treatment with IV or oral corticosteroids, IvIg, or plasmapheresis for treatment of MS within 3 mos prior to randomization
18.Treatment with glatiramer acetate or any interferon beta preparations within 4 wks prior to randomization
19.Treatment with 4-aminopyridine within 30 days prior to randomization unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study
20.Female subjects considering becoming pregnant while in the study
21.Female subjects of childbearing potential who have positive pregnancy test at either Screening Visit or Wk 0
22.Female subjects who are pregnant or currently breastfeeding
23.History of drug or alcohol abuse in opinion of Investigator within 2 years prior to entry
24.Unwillingness or inability to comply with the requirements of protocol including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with protocol
25.Participation in any other investigational treatment study within 3 mos prior to screening or concurrent with this study
26.Any prescheduled elective procedure during study period that in opinion of Investigator would interfere with study parameters
27.Any other condition, clinical finding or reason that in opinion of Investigator is determined to be unsuitable for enrollment into study
28.Previous participation in this study
Part 2:Candidates will be excluded from Part 2 Extension Phase if any of following exist at time of consent into Part 2 of study:
1.Subjects with any significant change in clinical status including laboratory tests that in opinion of Investigator would make them unsuitable to participate in extension study. Investigator must rereview the subject’s medical fitness for participation and consider any diseases that would preclude treatment
2.Subjects who discontinued study treatment in Part 1 OR had fewer than 20 infusions in Part 1 OR missed 2 or more consecutive infusions in Part 1
3.Considered by Investigator to be immunocompromised based on medical history, physical examination, laboratory testing or any other testing required by local guidelines
4.Part 1 exclusion criteria no 6
5.Part 1 exclusion criteria no 7
6.New onset of drug or alcohol abuse during Part 1 of study
7.Part 1 exclusion criteria no 8.
8.Signs or symptoms of PML
9.Part 1 exclusion criteria no 20
10.Female subjects of childbearing potential who have positive pregnancy test at either Wk 96 (serum) or Wk 108 (serum and urine)
11.Part 1 exclusion criteria no 22
12.Part 1 exclusion criteria no 24
13.Part 1 exclusion criteria no 26
14.Part 1 exclusion criteria no 27.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is a binary outcome of confirmed progressors or non-progressors of disability, where progressors are defined as subjects who meet at least one of the
following criteria:

∙ Confirmed progression in EDSS: EDSS score increased from baseline by
at least 1 point if baseline EDSS ≤5.5 or by at least 0.5 points if baseline EDSS ≥
6, confirmed at a second visit at least 6 months later and at Week 96 (or at
the last available study visit for subjects who withdraw from the study
early)
∙ Confirmed progression in T25FW: Time taken for T25FW increased by
at least 20% of the baseline walk, confirmed at a second visit at least 6 months
later and at Week 96 (or at the last available study visit for subjects who
withdraw from the study early)
∙ Confirmed progression in 9HPT: Time taken for 9HPT increased by at
least 20% of the time taken at baseline, confirmed at a second visit at least 6
months later and at Week 96 (or at the last available study visit for
subjects who withdraw from the study early). The progression in 9HPT
can occur on either hand, but will have to be confirmed on the same
hand.
Part 2: The primary endpoint in Part 2 of the study is the incidence of AEs and SAEs

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1: at 6 month intervals
Part 2: as necessary

E.5.2

Secondary end point(s)

The secondary endpoints for this study are as follows:
• Percentage of T25FW responders (defined as any improvement from best pre-dose T25FW in at least 75% of the scheduled on-treatment visits through Week 96).
• Change from baseline in MSWS-12 score to Week 96.
• Change from baseline in ABILHAND Questionnaire scores to Week 96.
• Change from baseline in MSIS-29-Physical score to Week 96.
• Percentage change from Week 24 in whole brain volume at Week 96.
• Percentage of subjects experiencing confirmed worsening in the individual EDSS Physical Functional System Scores where confirmed is defined as 2 examinations at least 6 months apart
Part 2: The secondary endpoints in Part 2 of the study are as follows:
•Percentage of subjects with disability worsening at each scheduled efficacy visit in Part 2, defined as one or more of the following: ≥20% worsening from Part 1 baseline in T25FW, ≥20% worsening from Part 1 baseline in 9HPT, or worsening from Part 1 baseline in EDSS (≥1 point increase if Part 1 baseline EDSS ≤5.5 or ≥0.5 point increase if Part 1 baseline EDSS >5.5).
•Absolute and percentage change in T25FW, 9HPT, and EDSS, from Part 1 baseline to each scheduled efficacy visit in Part 2, in all subjects and in subjects with and without disability worsening as defined above.
•Absolute and percentage change in the 6MWT, MSIS-29 Physical, and SDMT, from Part 1 baseline to each scheduled efficacy visit in Part 2.
•Absolute and percentage change in the WPAI-MS Questionnaire over the Extension Phase, from Part 2 baseline to each scheduled efficacy visit in Part 2.
•Percentage change in whole brain volume from Week 24 (Part 1) to each scheduled efficacy visit in Part 2.
•Percentage change in gray matter brain volume from Part 1 baseline to each scheduled efficacy visit in Part 2.
•Absolute and percentage change in number of new/enlarging T2 lesions from Part 1 baseline to each scheduled efficacy visit in Part 2.

E.5.2.1

Timepoint(s) of evaluation of this end point

Part 1: • % T25FW responders (every 3 months) • Change from baseline in MSWS-12 score to Week 96 (every 3 months) • Change from baseline in ABILHAND Questionnaire scores to Week 96 (every 3 months) • Change from baseline in MSIS-29-Physical score to Week 96 (every 6 months) • % change from Week 24 in whole brain volume at Week 96 (every 6 months) • % of subjects experiencing confirmed worsening in the individual EDSS Physical Functional System Scores where confirmed is defined as 2 examinations at least 6 months apart (6 month intervals) Part 2: T25FW, 9HPT, EDSS, 6MWT, MSIS-29 Physical, WPAI-MS, and brain MRI assessments will be taken annually (every 48 weeks) and SDMT will be taken every 4 weeks

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

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Optional Open-Label Extension

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

126

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

Belgium

Canada

Czech Republic

Denmark

Finland

France

Germany

Ireland

Israel

Italy

Netherlands

Poland

Russian Federation

Spain

Sweden

United Kingdom

United States

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

The end of study is last subject, last visit for final collection of data.

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