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Natalizumab De-escalation With Interferon Beta-1b

Primary Purpose

Relapsing-remitting Multiple Sclerosis

Status

Completed

Phase

Phase 4

Locations

Switzerland

Study Type

Interventional

Intervention

interferon beta-1b

Natalizumab

About this trial

This is an interventional treatment trial for Relapsing-remitting Multiple Sclerosis focused on measuring Natalizumab, Interferon-beta 1b, De-escalation, Ticino

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Neurocenter of Southern Switzerland, Ospedale Civico Lugano

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Natalizumab

Interferon-beta-1b

Arm Description

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.

250 mcg (8 MIU) subcutaneous injections every other day

Outcomes

Primary Outcome Measures

Number of Days Until First On-study Relapse

Patients were followed-up during 12 months and time to first on-study relapse from randomization was recorded.

Secondary Outcome Measures

Number of Participants With Relapses

Number of Relapses

Proportion of Relapse Free Patients

Severity of Relapses

Change of Expanded Disability Status Scale (EDSS 1-10). Higher values represent a worser outcome.

MRI Parameters

Number of new T2-hyperintense lesions, Number of Gd-enhancing lesions on T1-weighted images. Assessments at month 3, 6, 9, 12, 18, 24.

Number of Patients With Adverse Events

Recording and reporting according to regulations. Monthly assessments or if necessary.

Number of Infections

Full Information

NCT ID

NCT01144052

First Posted

June 11, 2010

Last Updated

March 13, 2014

Sponsor

Claudio Gobbi

Collaborators

Ospedale Civico, Lugano

1. Study Identification

Unique Protocol Identification Number

NCT01144052

Brief Title

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

2. Study Status

Record Verification Date

March 2014

Overall Recruitment Status

Completed

Study Start Date

June 2010 (undefined)

Primary Completion Date

November 2011 (Actual)

Study Completion Date

November 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Claudio Gobbi

Collaborators

Ospedale Civico, Lugano

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Relapsing-remitting Multiple Sclerosis

Keywords

Natalizumab, Interferon-beta 1b, De-escalation, Ticino

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

19 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Natalizumab

Arm Type

Active Comparator

Arm Description

Arm Title

Interferon-beta-1b

Arm Type

Experimental

Arm Description

250 mcg (8 MIU) subcutaneous injections every other day

Intervention Type

Drug

Intervention Name(s)

interferon beta-1b

Other Intervention Name(s)

Betaferon®

Intervention Description

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])

Intervention Type

Drug

Intervention Name(s)

Natalizumab

Other Intervention Name(s)

Tysabri

Intervention Description

Primary Outcome Measure Information:

Title

Number of Days Until First On-study Relapse

Description

Patients were followed-up during 12 months and time to first on-study relapse from randomization was recorded.

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Number of Participants With Relapses

Time Frame

12 months

Title

Number of Relapses

Time Frame

12 months

Title

Proportion of Relapse Free Patients

Time Frame

12 months

Title

Severity of Relapses

Description

Change of Expanded Disability Status Scale (EDSS 1-10). Higher values represent a worser outcome.

Time Frame

12 months vs baseline

Title

MRI Parameters

Description

Number of new T2-hyperintense lesions, Number of Gd-enhancing lesions on T1-weighted images. Assessments at month 3, 6, 9, 12, 18, 24.

Time Frame

12 months

Title

Number of Patients With Adverse Events

Description

Recording and reporting according to regulations. Monthly assessments or if necessary.

Time Frame

12 months

Title

Number of Infections

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Claudio Gobbi, Dr med.

Organizational Affiliation

Neurocenter of Southern Switzerland, Ospedale Civico Lugano

Official's Role

Principal Investigator

Facility Information:

Facility Name

Neurocenter of Southern Switzerland, Ospedale Civico Lugano

City

Lugano

State/Province

Ticino

ZIP/Postal Code

6900

Country

Switzerland

12. IPD Sharing Statement

Citations:

PubMed Identifier

19005625

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.

Results Reference

background

PubMed Identifier

16510745

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.

Results Reference

background

PubMed Identifier

16510744

Citation

Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910. doi: 10.1056/NEJMoa044397.

Results Reference

background

PubMed Identifier

11902592

Citation

IFNB Multiple Sclerosis Study Group. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology. 2001 Dec;57(12 Suppl 5):S3-9. No abstract available.

Results Reference

background

PubMed Identifier

11902589

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.

Results Reference

background

PubMed Identifier

19560168

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.

Results Reference

background

PubMed Identifier

16189528

Citation

Ransohoff RM. Natalizumab and PML. Nat Neurosci. 2005 Oct;8(10):1275. doi: 10.1038/nn1005-1275. No abstract available.

Results Reference

background

PubMed Identifier

8467424

Citation

Sadovnick AD, Ebers GC. Epidemiology of multiple sclerosis: a critical overview. Can J Neurol Sci. 1993 Feb;20(1):17-29. doi: 10.1017/s0317167100047351.

Results Reference

background

PubMed Identifier

23915113

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.

Results Reference

result

PubMed Identifier

24576156

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.

Results Reference

result

Links:

URL

http://www.eoc.ch

Description

Homepage of the hospital organisation in Ticino

URL

http://www.multiplesklerose.ch

Description

Homepage of the Swiss Society of Multiple Sclerosis

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Natalizumab De-escalation With Interferon Beta-1b

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