Natalizumab De-escalation With Interferon Beta-1b

This study has been completed.
Sponsor:
Collaborator:
Ospedale Civico, Lugano
Information provided by (Responsible Party):
Claudio Gobbi, Ospedale Civico, Lugano
ClinicalTrials.gov Identifier:
NCT01144052
First received: June 11, 2010
Last updated: March 13, 2014
Last verified: March 2014
  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

Resource links provided by NLM:


Further study details as provided by Ospedale Civico, Lugano:

Primary Outcome Measures:
  • Number of Days Until First On-study Relapse [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Number of Relapses [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Proportion of Relapse Free Patients [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Severity of Relapses [ Time Frame: 12 months vs baseline ] [ Designated as safety issue: No ]
    Change of Expanded Disability Status Scale (EDSS 1-10). Higher values represent a worser outcome.

  • MRI Parameters [ Time Frame: 12 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.

  • Number of Patients With Adverse Events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Recording and reporting according to regulations. Monthly assessments or if necessary.

  • Number of Infections [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Enrollment: 19
Study Start Date: June 2010
Study Completion Date: November 2011
Primary Completion Date: November 2011 (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
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01144052

Locations
Switzerland
Neurocenter of Southern Switzerland, Ospedale Civico Lugano
Lugano, Ticino, Switzerland, 6900
Sponsors and Collaborators
Claudio Gobbi
Ospedale Civico, Lugano
Investigators
Principal Investigator: Claudio Gobbi, Dr med. Neurocenter of Southern Switzerland, Ospedale Civico Lugano
  More Information

Additional Information:
Publications:

Responsible Party: Claudio Gobbi, Dr. med., Ospedale Civico, Lugano
ClinicalTrials.gov Identifier: NCT01144052     History of Changes
Other Study ID Numbers: EOC.NC.09.01
Study First Received: June 11, 2010
Results First Received: October 31, 2013
Last Updated: March 13, 2014
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 July 20, 2014