The Effects of Tysabri Treatment on Vaccination Response and Lymphocyte Subsets in Subjects With Relapsing Forms of Multiple Sclerosis

Study Overview
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Brief Summary
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The primary objectives of this study were: to evaluate the effect of Tysabri® (natalizumab) on antibody responses after immunization with a neoantigen (keyhole limpet hemocyanin [KLH]) and a recall antigen (tetanus toxoid [Td]), and to evaluate the effect of Tysabri on circulating lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD56+) over time in participants with relapsing forms of multiple sclerosis (MS). The secondary objective was to assess alpha4-integrin saturation and alpha4-integrin expression levels over time.

Official Title
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A Randomized, Open-Label Study to Assess the Effects of Tysabri Treatment on Vaccination Response and Lymphocyte Subsets in Subjects With Relapsing Forms of Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: BG00002 (natalizumab)
* Biological: keyhole limpet hemocyanin (KLH)
* Biological: tetanus diphtheria toxoid vaccine (Td)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: able to give written informed consent diagnosis of a relapsing form of MS and must fall within the therapeutic indication stated in the approved label for Tysabri aged 18-60 years, inclusive at the time of consent free of signs and symptoms suggestive of any serious opportunistic infection, based on medical history, physical examination, or laboratory testing must have a known history of tetanus toxoid immunization Major Exclusion Criteria: tetanus toxoid vaccination less than 2 years prior to Screening known hypersensitivity to tetanus-diphtheria vaccine or KLH or any other administered vaccinations or their components (such as thimerosal) known allergy to shellfish history of active tuberculosis or undergoing treatment for tuberculosis previous exposure to KLH or vaccines containing KLH components (e.g., cancer vaccines) known history of human immunodeficiency virus (HIV), hepatitis C, or hepatitis B infection history of, or available abnormal laboratory results indicative of any significant disease history of malignancy history of organ transplantation (including anti-rejection therapy) history of severe allergic or anaphylactic reactions or known drug hypersensitivity a clinically significant infectious illness within 30 days prior to the Screening visit prior exposure to Tysabri, rituximab, any murine protein, or any therapeutic monoclonal antibody at any time receipt of intravenous (IV) or intramuscular (IM) immunoglobulin within 6 months of screening live virus, bacterial vaccines, or any other vaccines within 3 months of screening treatment with immunosuppressant medications within 6 months prior to screening treatment with cyclophosphamide within 1 year prior to screening treatment with immunomodulatory medications (interferon beta and glatiramer acetate) within 2 weeks prior to screening treatment with systemic corticosteroids within 4 weeks prior to screening treatment with any investigational product or approved therapy or vaccination for investigational use within 6 months prior to Screening women who are breastfeeding, pregnant, or planning to become pregnant during the study female subjects who are not postmenopausal for at least 1 year, surgically sterile (does not include tubal ligation), or willing to practice effective contraception during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tysabri Plus Vaccinations<br>Participants receive 9 monthly doses of Tysabri 300 mg intravenous (IV), and receive vaccinations with neoantigen and recall antigen (keyhole limpet hemocyanin [KLH] and tetanus diphtheria toxoid [Td], according to manufacturer's prescribing information) at Month 6 (following the 7th dose of Tysabri) for both KLH and Td, and 14 and 28 days later for KLH. | Biological: BG00002 (natalizumab)<br> <br> * Other names: Tysabri;Biological: keyhole limpet hemocyanin (KLH)<br>* KLH 1 mg administered subcutaneously (SC) in accordance with the Immucothel investigator's brochure.<br>* Other names: Immucothel;Biological: tetanus diphtheria toxoid vaccine (Td)<br>* Td administered in accordance with the manufacturer's prescribing information.<br>|
| Other: Vaccinations Only<br>Participants receive only vaccinations with neoantigen and recall antigen (KLH and Td, according to manufacturer's prescribing information) at Month 0 for both KLH and Td, and 14 and 28 days later for KLH. They do not receive any treatment for their MS and remain in the study through Month 2. | Biological: keyhole limpet hemocyanin (KLH)<br>* KLH 1 mg administered subcutaneously (SC) in accordance with the Immucothel investigator's brochure.<br>* Other names: Immucothel;Biological: tetanus diphtheria toxoid vaccine (Td)<br>* Td administered in accordance with the manufacturer's prescribing information.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Keyhole Limpet Hemocyanin (KLH) Responders at Day 28 Post-Vaccination | KLH responders were defined as those participants who had at least a 2-fold increase over pre-immunization level of anti-KLH antibodies in their blood at 28 days after vaccination with KLH. | 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group) | 
| Percentage of Tetanus Diphtheria Toxoid (Td) Responders at Day 28 Post-Vaccination | Tetanus responders were defined as participants who had at least a 2-fold increase over pre-immunization levels of anti-tetanus antibodies in their blood at 28 days after they were immunized with tetanus. | 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | The effect of Tysabri on circulating lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD56+) was calculated as a percentage change from baseline pre-treatment values (based on absolute count). | Month 0 (Baseline), Month 3 | 
| Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | The effect of Tysabri on circulating lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD56+) was calculated as a percentage change from baseline pre-treatment values (based on absolute count). | Month 0 (Baseline), Month 6 | 
| Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 | Measurement of the degree of natalizumab saturation of the alpha4 integrin on peripheral blood mononuclear cells was accomplished by staining cells with phycoerythrin conjugated anti human IgG4 antibody (hIgG4-PE) to label the cell-bound natalizumab, followed by flow cytometric detection and quantification. | Month 0 (Baseline), Month 3, and Month 6 | 
| Mean Alpha4-Integrin Expression at Baseline, Month 3, and Month 6 | Alpha4-integrin expression is the mean fluorescent intensity (MFI), a measure of fluorescence intensity often used to monitor changes in surface antigen modulation in flow cytometry. There is no reference range for this test, which was developed at Biogen Idec. | Month 0 (Baseline), Month 3, and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple sclerosis, MS, Relapsing forms of Multiple Sclerosis