Natalizumab De-escalation With Interferon Beta-1b
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Purpose
Multiple Sclerosis (MS) is the most common neurological disorder causing disability in young adults. The management of MS-patients requires treatment with disease-modifying agents, monoclonal antibodies such as natalizumab or immunosuppressants. Natalizumab showed good efficacy and is approved for treatment of relapsing MS with a number of restrictions due to safety issues. Cognitive data related to natalizumab treatment are still scarce. Interferon-beta-1b is approved for high-frequency, subcutaneous (sc) administration in the treatment of multiple sclerosis. It reduces the relapse rate, severity, hospitalisation and the disease activity as seen on MRI.
This is a pilot study to explore the concept of de-escalating natalizumab treatment to interferon-beta-1b e.o.d compared to continuous treatment with natalizumab in patients with relapsing-remitting multiple sclerosis previously treated with natalizumab for 12 months. The study is designed as prospective, controlled, randomized, rater-blinded, parallel-group, two arm, mono-centric including patients of the Ticino Cohort. One arm will be treated with Interferon-beta 1b 250mcg given subcutaneously every other day, the other with Natalizumab 300 mg given intravenously (i.v.), every four weeks. The treatment duration is 12 months, the follow-up period 12 months. The time to first on-study relapse will be compared between the to treatment arms (primary outcome). Other efficacy parameter include clinical and radiological parameters, patient reported outcome on quality of life and fatigue. Safety is assessed by reports of adverse events.
| Condition | Intervention | Phase |
|---|---|---|
|
Relapsing-remitting Multiple Sclerosis |
Drug: interferon beta-1b Drug: Natalizumab |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | De-escalation After Natalizumab Treatment With Interferon-beta-1b in Patients With Relapsing-remitting Multiple Sclerosis |
- Time to first on-study relapse [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
- Clinical parameters [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]Number of relapses, number of relapse-free patients, severity of relapses by functional system score, 3-month confirmed EDSS progression (of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5. Assessments every 3 months.
- Multiple sclerosis functional composite score [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT). Assessments every 3 months.
- Cognitive functioning [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]MUSIC (Multiple Sclerosis Inventory of Cognition.This short screening instrument consists of 5 subtests aimed at evaluating the mental status on the basis of the most relevant cognitive domains (working memory, learning, interference). Assessments at month 12, month 24.
- MRI parameters [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]Number of new T2-hyperintense lesions, Number of Gd-enhancing lesions on T1-weighted images. Assessments at month 3, 6, 9, 12, 18, 24.
- Quality of life [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]EQ-5D: self administered 15 items questionnaires representing 5 different domains of health conditions. Assessments at month 6, 12, 24.
- Fatigue [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]FSMC (Fatigue Scale for Motor and Cognitive functions. This is a validated scale allowing a differentiation between cognitive as well as motor-related aspects of fatigue. Assessments at month 6, 12, 24.
- Vital signs [ Time Frame: up to 24 months ] [ Designated as safety issue: Yes ]For Interferon Beta-1b treated patients. Body temperature, heart rate (for 1 min, after being seated for 3 min.), systolic and diastolic blood pressure (after being seated for 3 min.). Assessmetns at month 3, 6, 9, 12, 15, 18, 21, 24.
- Vital signs [ Time Frame: up to 24 months ] [ Designated as safety issue: Yes ]For Natalizumab treated patients. Body temperature, heart rate (for 1 min, after being seated for 3 min.), systolic and diastolic blood pressure (after being seated for 3 min.). Monthly assessments.
- Functional assessment multiple sclerosis (FAMS) [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]Self administered questionnaire to reflect patients' perceptions of mobility and quality of life. Six sub-scales (mobility, symptoms, emotional well being/depression, general contentment, thinking/fatigue and family/social well being) comprise 59 items, 44 of which are used for scoring on a Likert-type 5-point scale (ranging from *not at all* to *very much*) producing a score between 0 and 4 for each scored question. Assessments at month 6, 12, 24.
- Adverse events [ Time Frame: up to 24 months ] [ Designated as safety issue: Yes ]Recording and reporting according to regulations. Monthly assessments or if necessary.
| Estimated Enrollment: | 20 |
| Study Start Date: | June 2010 |
| Estimated Study Completion Date: | June 2013 |
| Estimated Primary Completion Date: | June 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Natalizumab
Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.
|
Drug: Natalizumab
Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 months at study entry. Natalizumab continues to be administered every four weeks by intravenous infusion from the beginning of the study as indicated by the manufacturers' instructions.
Other Name: Tysabri
|
|
Experimental: Interferon-beta-1b
250 mcg (8 MIU) subcutaneous injections every other day
|
Drug: interferon beta-1b
Eligible patients to this study have been treated with monthly infusions of natalizumab for at least 12 month at study entry. After a wash-out period of one month, interferon-beta-1b will be administered subcutaneously every other day as indicated by the manufacturers' instructions including the stepwise up-titration scheme as recommended for treatment start. The final dose of interferon beta-1b is 250 mcg (8 million International Units [MIU])
Other Name: Betaferon®
|
Detailed Description:
At present, there is no cure for multiple sclerosis and the management of MS-patients requires treatment with disease-modifying agents such as interferon-beta or glatiramer acetate, monoclonal antibodies such as natalizumab or immunsuppressants such as mitoxantrone, azathioprine or methotrexate. Acute relapses are usually treated with corticosteroids. Natalizumab is a humanized monoclonal antibody directed against α4-integrin, a component of VLA-4 (very late antigen-4) present on leukocytes. Following submission of additional safety data, the agencies such as Swissmedic or EMEA have issued approval of natalizumab for treatment of relapsing MS with a number of restrictions. The preparation has been available in Switzerland since 2006. According to the current scientific information, natalizumab (Tysabri®) is indicated as a "disease-modifying monotherapy of highly active relapsing MS" for the following patient groups: 1) patients showing high levels of disease activity despite treatment with an IFN-β preparation, or 2) untreated/treatment-naive patients with rapidly progressing relapsing-remitting MS (at least two serious relapses per year).
The primary objective of this pilot study is to generate first data and hypotheses on the concept of de-escalating natalizumab-treated relapsing-remitting multiple sclerosis patients to interferon-beta-1b e.o.d compared to continuous treatment on natalizumab for planning of further clinical studies regarding safety and efficacy.
As secondary objectives, clinical, neuropsychological parameters, MRI and laboratory parameter and safety aspects will be assessed in accordance to the protocol available for the management of patient on natalizumab at our service.
This is a prospective, controlled, randomized, rater-blinded, parallel-group, monocentric, two arm, phase IV pilot study. Patients with relapsing-remitting forms of MS, respecting all inclusion/exclusion criteria, will be randomized into two equal-size parallel arms for de-escalation to interferon beta-1b (after a month wash-out) or for continued treatment on natalizumab.
it is planned to enrol 20 patients (1/2 in the natalizumab group, 1/2 in the interferon beta-1b group. Patients providing written informed consent will be treated for 12 months; pre-planned follow-up of further 12 month
Eligibility| Ages Eligible for Study: | 18 Years to 60 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Female or male patients with relapsing-remitting forms of multiple sclerosis (according to McDonald's criteria)
- Age between 18 and 60 years
- Natalizumab-treatment for at least 12 month following the current Swiss guidelines for treatment initiation
- Eligible patients are clinically stable (free from relapses and 6-month confirmed disability progression for at least 6 months) while on natalizumab-treatment
- Women of potential childbearing with active contraceptive methods
- Patients who are willing to undergo study procedures
- Patients who are willing and able to sign informed consent
Exclusion Criteria:
- Patients who have previously entered this study
- Natalizumab-treatment for less than 12 month following the current Swiss guidelines for treatment initiation
- Sign of clinical disease activity within the 6 month
- One or more relapses and/or 6-month confirmed disability progression during the 6 months prior to the study
- Any disease other than multiple sclerosis that would better explain the patient's signs and symptoms
- Secondary progressive MS
- Primary progressive MS
- Pregnancy - Urine pregnancy test at baseline visit - or breast feeding
- Uncontrolled, clinically significant heart diseases, such as arrhythmias, angina, or uncompensated congestive heart failure
- History of severe depression or attempted suicide or current suicidal ideation
- Medical or psychiatric conditions that compromise the ability to give informed consent, to comply with the protocol, or to complete the study
- Uncontrolled seizure disorder
- Myopathy or clinically significant liver disease
- Inability, in the opinion of the principal investigator or staff, to comply with protocol requirements for the duration of the study
- Known hypersensitivity to interferon-beta or other human proteins including albumin
- Any contraindication for MRI or contrast administration
- A history of drug abuse in the 6 months prior to screening
- Treatment with any of the following in the 30 days before day 1: systemic corticosteroids, ACTH, or other investigational drugs.
- Participation in any other study involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study
- Current participation on other clinical trials
- Treatment with drugs which might interfere with the evaluation of study drugs during the study protocol
- Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol
Contacts and Locations| Switzerland | |
| Neurocenter of Southern Switzerland, Ospedale Civico Lugano | |
| Lugano, Ticino, Switzerland, 6900 | |
| Principal Investigator: | Claudio Gobbi, Dr med. | Neurocenter of Southern Switzerland, Ospedale Civico Lugano |
More Information
Additional Information:
Publications:
| Responsible Party: | Claudio Gobbi, Dr med., Neurocenter of Southern Switzerland |
| ClinicalTrials.gov Identifier: | NCT01144052 History of Changes |
| Other Study ID Numbers: | EOC.NC.09.01 |
| Study First Received: | June 11, 2010 |
| Last Updated: | August 4, 2011 |
| Health Authority: | Switzerland: Swissmedic |
Keywords provided by Ospedale Civico, Lugano:
|
Natalizumab Interferon-beta 1b De-escalation Ticino |
Additional relevant MeSH terms:
|
Multiple Sclerosis Sclerosis Multiple Sclerosis, Relapsing-Remitting Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases Pathologic Processes Interferon-beta |
Interferons Interferon beta-1b Antiviral Agents Anti-Infective Agents Therapeutic Uses Pharmacologic Actions Immunologic Factors Physiological Effects of Drugs Antineoplastic Agents Adjuvants, Immunologic |
ClinicalTrials.gov processed this record on May 16, 2013