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

• Register: EUCTR
• Last refreshed on: 3 July 2017
• Main ID: EUCTR2010-021978-11-IE
• Date of registration: 14/05/2012
• Prospective Registration: Yes
• Primary sponsor: Biogen Idec Limited
• Public title: A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMS
• Scientific title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis
• Date of first enrolment: 06/07/2012
• Target sample size: 856
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-021978-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Optional Open-Label Extension If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, Poland, Russian Federation, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Not available
• Affiliation: Biogen Idec Limited

• Name: Not available
• Affiliation: Biogen Idec Limited

Key inclusion & exclusion criteria

Inclusion criteria:
Part 1:
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 criterion listed:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use PHI in accordance with national and local subject privacy regulations.
2. Subjects must have participated in and completed Part 1 per protocol, and have documented Week 108 assessment attempts for EDSS, T25FW, and 9HPT prior to first open-label dosing at Week 108.
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.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 856
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

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, are allergic to gadolinium, 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 months 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
op

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Secondary Progressive Multiple Sclerosis
MedDRA version: 16.0 Level: PT Classification code 10063400 Term: Secondary progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Trade Name: Tysabri
Product Code: AN100226, BG00002
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: NATALIZUMAB
CAS Number: 189261-10-7
Other descriptive name: SUB22282
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Primary end point(s): Part 1: 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

Secondary Objective: 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.

Timepoint(s) of evaluation of this end point: Part 1: at 6 month intervals

Part 2: as necessary

Main Objective: 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.

Secondary Outcome(s)

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

Secondary end point(s): The secondary endpoints for Part 1 of 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.

Secondary ID(s)

101MS326

2010-021978-11-SE

Source(s) of Monetary Support

Biogen Idec Limited