The primary objective of this study is to evaluate the efficacy (clinical and MRI) of switching tonatalizumab compared to receiving interferon β1-a or glatiramer acetate.
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the annualized relapse rate in subjects with RRMS.
Secondary outcome
The secondary study objective is to evaluate the effect on quality of life of
switching to
natalizumab compared to receiving interferon β1-a or glatiramer acetate.
The secondary endpoints in this study are:
• Change from baseline to 48 weeks in T2 lesion volume.
• Proportion of subjects free of disease activity. Freedom from disease
activity will be
defined as subjects completing 48 weeks with no clinical relapses, no new Gd+
lesions, no new or newly-enlarging T2 lesions, and no sustained progression on
EDSS.
• Change from baseline to 48 weeks in physical impact score of Multiple
Sclerosis
Impact Scale (MSIS-29).
The additional endpoints in this study are:
• Safety and tolerability
• Change from baseline to 48 weeks in mental impact score of MSIS-29
• Brain MRI measures at 24 and 48 weeks: Number of Gd+ lesions, number of new
and newly-enlarging T2 hyperintense lesions, and number of T1 hypointense
lesions
and MTR (magnetization transfer ratio) [at selected sites].
• Quality of life assessed by the Short Form (SF-12v2) and EuroQol (EQ-5D)
• Neuropsychological changes as assessed by the Symbol Digit Modalities Test
(SDMT)
• Visual testing as measured by the Visual Function Test (VFT)
• Number of relapses requiring IV steroid use
• Number of relapses requiring hospitalization
• Disability progression as measured by 1 point increase from baseline EDSS
>=1.0 or
1.5 point increase from baseline EDSS = 0
* Sustained for >=12 weeks
* Sustained for >=24 weeks
• Disability improvement as measured by 1 point decrease from baseline EDSS >=1.0
* Sustained for >=12 weeks
* Sustained for >=24 weeks
• Nine-hole Peg Test (9HPT) score
• Timed 25-Foot Walk
• Cognitive changes as assessed by the 3 Second Paced Auditory Serial Addition
Test
(PASAT 3)
• Health resource utilization data and Work Status and Absenteeism data
• Biomarker analyses
Background summary
The current disease modifying treatments (DMTs) of multiple sclerosis (MS),
including interferon β and glatiramer acetate, are only partly effective, which
is demonstrated by the large number of patients who continue to suffer clinical
disease activity demonstrated by magnetic resonance imaging (MRI). These
patients and physicians are faced with the difficult decision of what to do in
case disease activity still occurs. It is generally accepted that stopping
earlier with a less effective treatment gives a new treatment better chances of
success. In addition, recent literature indicates that it is probably possible
to identify patients with a higher probability of worse results, based on
clinical and MRI activity in the first 6 months to one year of the treatment.
However, in practice patients often continue to follow a treatment until
repeated clinical relapses occur which each have an immediate effect on the
quality of life and an increased risk of long-term problems. Despite the
growing evidence that these risks occur, there is no clear consensus yet about
the moment when the current treatment with interferon or glatiramer acetate has
to be abandoned to proceed with another treatment, for example natalizumab.
Up to present the only available data about switching DMTs come from small
observation studies which present an inherent risk of being biased as a result
of the lack of randomisation. Even though these are not large, well-controlled
studies, the observations made are consistent with the idea that the decision
to change to a different treatment has to be taken in an early stage of the
treatment. Patients whose disease stays active during the current treatment are
ideal candidates for a treatment with natalizumab because enough down
modulation of the inflammation reaction has to be achieved in order to treat
RRMS as effectively as possible and avoid an increase of the disease burden. In
this study three different algorithms for the treatment of patients with a
continuing disease activity despite treatment will be strictly assessed in a
well-controlled way.
Study objective
The primary objective of this study is to evaluate the efficacy (clinical and
MRI) of switching to
natalizumab compared to receiving interferon β1-a or glatiramer acetate.
Study design
A multicenter, randomized, rater-blind, active-controlled study in parallel
groups
Patients who will be included are already treated by interferon β-1a (900
patients) or glatiramer acetate (900 patients). All patients will change
medication after randomisation. About 900 patients will receive natalizumab 300
mg IV every 4 weeks, about 450 patients will receive interferon β-1a 44 mcg SC
three times a week and about 450 patients will receive glatiramer acetate 20 mg
SC once a day.
Efficacy assessment: Relapse assessment, EDSS, MSIS-29, SF-12v2, EQ-5D, VFT,
SDMT, MRI scan of the brain, the 9HPT, recorded 10 metre walking test, PASAT 3.
The administration of the study medicine will be open-label. However, the
assessing neurologist and the technician will remain blinded with regard to the
administered treatment in order to assess the efficacy of the medicine.
Intervention
At the start of the study patients will be prescribed new medication for RRMS.
About 900 patients will receive natalizumab 300 mg IV every 4 weeks, about 450
patients will receive interferon β-1a 44 mcg SC three times a week and about
450 patients will receive glatiramer acetate 20 mg SC once a day.
Study burden and risks
Patients will be screened at the start of the study.
Patients will take part in the study for at least 48 weeks (13 visits) and not
longer than 96 weeks (26 visits), depending on the moment when the patient
starts on the study. If the patient does not continue the treatment upon
termination of the study, a follow-up telephone call will take place 12 weeks
after the last dose of study medication was administered. The patient will come
to the hospital every 4 weeks. If the MS gets worse, extra visits will be
scheduled for further investigation.
During the study the patients will be subjected to the procedures as described
under question E4.
A detailed description of the patient load is included in appendix 2 of the
informed consent.
Besides the study actions there are known risks related to taking the
registered medicines used in this study. These risks are described in the
patient leaflets of the medicines in question. An overview of the risks is also
described in appendix 3 of the informed consent.
Innovation House, 70 Norden Road
SL6 4AY Maidenhead, Berkshire
United Kingdom
Innovation House, 70 Norden Road
SL6 4AY Maidenhead, Berkshire
United Kingdom
Listed location countries
Age
Inclusion criteria
1. Have signed written informed consent (in person or through guardian) to participate in the study and provided written authorization to use protected health information in accordance with local laws.
2. Have a diagnosis of relapsing remitting multiple sclerosis as defined by the revised McDonald Committee criteria (Polman 2005).
3. Must have been treated with a stable regimen of either glatiramer acetate (20 mg per day SC) or interferon β-1a (44 mcg 3 times per week) as their principal first therapy for MS for 6 to 25 months prior to screening. (Note: prior treatment with another MS therapy of <=30 days total duration is not exclusionary [e.g. titration to 44 mcg is allowed]).
4. Have shown evidence of disease activity within 12 months prior to screening while on therapy. Disease activity must be observed after a minimum of 6 months on treatment but before 25 months of treatment. . Disease activity is defined as:
• One or more clinical relapses
(Relapses must occur after 6 months of treatment, but before 25 months of
treatment)
AND/OR
• Two or more new MRI lesions (Gd+ and/or T2 hyperintense) observed on an MRI
scan. Qualifying lesions must be observed on scans performed after 6 months of
treatment, but before 25 months of treatment.
For inclusion purposes: (a) a relapse is defined as neurologic signs and/or symptoms documented in the medical record by a neurologist and of sufficient duration to be determined by the Investigator or the Treating Physician as consistent with an MS relapse or (b) MRI activity must be verified by the central reader center.
5. Be naïve to natalizumab.
6. Be between the ages of 18 and 60, inclusive at the time of informed consent.
7. Have a documented EDSS score between 0.0 and 5.5, inclusive.
Exclusion criteria
1. Have a diagnosis of 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. Patients with these conditions may also have superimposed relapses, but are distinguished from relapsing-remitting patients by the lack of clinically stable periods or clinical improvement.
2. Have known intolerance, contraindication to, or history of non-compliance with, the use of glatiramer acetate or interferon β-1a.
3. Have had an MS exacerbation (relapse) within 30 days prior to randomization AND/OR the patient has not stabilized from a previous relapse, in the opinion of the Investigator, prior to randomization.
4. The patient is considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or due to prior immunosuppressive or immunomodulating treatment.
5. Subjects for whom MRI is contraindicated, i.e., have pacemakers or other contraindicated implanted metal devices, have suffered or are at risk for side effects from gadolinium (Gd), or have claustrophobia that cannot be medically managed.
6. History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or other major disease that would preclude participation in a clinical trial.
7. History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
8. Known history of Human Immunodeficiency Virus (HIV).
9. Positive test result for Hepatitis C virus (test for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (test for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).
10. History of transplantation or any anti-rejection therapy.
11. History of severe allergic or anaphylactic reactions or known drug hypersensitivity.
12. A clinically significant infectious illness (e.g. cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.
13. History of PML.
14. Prior treatment with total lymphoid irradiation, cladribine, mitoxantrone, fingolimod, T cell or T-cell receptor vaccination, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, or any therapeutic monoclonal antibody, including natalizumab or rituximab.
15. Prior treatment with intravenous immunoglobulin (IVIg), plasmapheresis or cytapheresis within 6-months prior to randomization.
16. Treatment with IV or oral corticosteroids
17. Treatment with 4-aminopyridine for subjects in countries where marketing
authorization has not been obtained. Treatment with compounded formulations
of 4-aminopyridine is prohibited for all subjects.
18. Treatment with an approved formulation of 4-aminopyridine (i.e.,
fampridine-SR, dalfampridine, or Ampyra) for <=90 days prior to randomization
in countries where marketing authorization has been obtained.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-015556-15-NL |
| ClinicalTrials.gov | NCT01058005 |
| CCMO | NL31545.094.10 |