Clinical trial NCT01144052: Natalizumab De-escalation With Interferon Beta-1b
Official title: De-escalation After Natalizumab Treatment With Interferon-beta-1b in Patients With Relapsing-remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Relapsing-remitting Multiple Sclerosis
Keywords: Natalizumab
Interferon-beta 1b
De-escalation
Ticino
Lead sponsor: Ospedale Civico, Lugano
Sponsor class: OTHER_GOV
Collaborators: name: Ospedale Civico, Lugano
First posted: 2010-06-15
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 criteria: 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

Primary outcomes:
measure: Number of Days Until First On-study Relapse
timeFrame: 12 months
Secondary outcomes:
measure: Number of Participants With Relapses
timeFrame: 12 months
measure: Number of Relapses
timeFrame: 12 months
measure: Proportion of Relapse Free Patients
timeFrame: 12 months
measure: Severity of Relapses
timeFrame: 12 months vs baseline
measure: MRI Parameters
timeFrame: 12 months
measure: Number of Patients With Adverse Events
timeFrame: 12 months
measure: Number of Infections
timeFrame: 12 months
Other outcomes:
Locations:
city: Lugano
country: Switzerland
facility: Neurocenter of Southern Switzerland, Ospedale Civico Lugano
state: Ticino
Study officials:
affiliation: Neurocenter of Southern Switzerland, Ospedale Civico Lugano
name: Claudio Gobbi, Dr med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Multiple Sclerosis Therapy Consensus Group (MSTCG); Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008 Oct;255(10):1449-63. doi: 10.1007/s00415-008-0061-1. Epub 2008 Oct 29.
citation: Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):911-23. doi: 10.1056/NEJMoa044396.
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citation: Paty DW, Li DK; UBC MS/MRI Study Group and IFNB Multiple Sclerosis Study Group. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology. 2001 Dec;57(12 Suppl 5):S10-5. No abstract available.
citation: Putzki N, Yaldizli O, Tettenborn B, Diener HC. Multiple sclerosis associated fatigue during natalizumab treatment. J Neurol Sci. 2009 Oct 15;285(1-2):109-13. doi: 10.1016/j.jns.2009.06.004. Epub 2009 Jun 26.
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citation: Gobbi C, Meier DS, Cotton F, Sintzel M, Leppert D, Guttmann CR, Zecca C. Interferon beta 1b following natalizumab discontinuation: one year, randomized, prospective, pilot trial. BMC Neurol. 2013 Aug 2;13:101. doi: 10.1186/1471-2377-13-101.
citation: Zecca C, Riccitelli GC, Calabrese P, Pravata E, Candrian U, Guttmann CR, Gobbi C. Treatment satisfaction, adherence and behavioral assessment in patients de-escalating from natalizumab to interferon beta. BMC Neurol. 2014 Feb 28;14:38. doi: 10.1186/1471-2377-14-38.