Multiple Sclerosis
Conditions
Keywords
MS, Multiple sclerosis, Relapsing forms of Multiple Sclerosis
Brief summary
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.
Interventions
BIOLOGICALBG00002 (natalizumab)
BIOLOGICALkeyhole limpet hemocyanin (KLH)
KLH 1 mg administered subcutaneously (SC) in accordance with the Immucothel investigator's brochure.
BIOLOGICALtetanus diphtheria toxoid vaccine (Td)
Td administered in accordance with the manufacturer's prescribing information.
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Keyhole Limpet Hemocyanin (KLH) Responders at Day 28 Post-Vaccination | 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group) | 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. |
| Percentage of Tetanus Diphtheria Toxoid (Td) Responders at Day 28 Post-Vaccination | 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | Month 0 (Baseline), Month 3 | 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). |
| Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | Month 0 (Baseline), Month 6 | 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). |
| Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 | Month 0 (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. |
| Mean Alpha4-Integrin Expression at Baseline, Month 3, and Month 6 | Month 0 (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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled in the study at 10 investigational sites in the US. Study enrollment began on 07 January 2008.
Participants by arm
| Arm | Count |
|---|---|
| Tysabri Plus Vaccinations Participants received 9 monthly doses of Tysabri 300 mg intravenous (IV), and received 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. | 30 |
| Vaccinations Only Participants received 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 did not receive any treatment for their MS and remained in the study through Month 2. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Missed Study Visit | 0 | 1 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Positive for Anti-natalizumab Antibodies | 3 | 0 |
| Overall Study | Sponsor Decision Due to Lab Values | 1 | 0 |
| Overall Study | Steroid Use | 0 | 2 |
Baseline characteristics
| Characteristic | Vaccinations Only | Tysabri Plus Vaccinations | Total |
|---|---|---|---|
| Age, Continuous | 40.4 Years STANDARD_DEVIATION 9.86 | 43.1 Years STANDARD_DEVIATION 8.34 | 41.8 Years STANDARD_DEVIATION 9.16 |
| Circulating Lymphocyte Subsets CD16+; n=24 | NA lymphocyte count/µL | 179.2 lymphocyte count/µL STANDARD_DEVIATION 106.12 | 179.2 lymphocyte count/µL STANDARD_DEVIATION 106.12 |
| Circulating Lymphocyte Subsets CD19+; n=24 | NA lymphocyte count/µL | 269.8 lymphocyte count/µL STANDARD_DEVIATION 123 | 269.8 lymphocyte count/µL STANDARD_DEVIATION 123 |
| Circulating Lymphocyte Subsets CD3+; n=24 | NA lymphocyte count/µL | 1261.5 lymphocyte count/µL STANDARD_DEVIATION 309.47 | 1261.5 lymphocyte count/µL STANDARD_DEVIATION 309.47 |
| Circulating Lymphocyte Subsets CD4+; n=24 | NA lymphocyte count/µL | 905.2 lymphocyte count/µL STANDARD_DEVIATION 299.51 | 905.2 lymphocyte count/µL STANDARD_DEVIATION 299.51 |
| Circulating Lymphocyte Subsets CD8+; n=24 | NA lymphocyte count/µL | 344.6 lymphocyte count/µL STANDARD_DEVIATION 123.91 | 344.6 lymphocyte count/µL STANDARD_DEVIATION 123.91 |
| Expanded Disability Status Scale at Screening | 3.00 scores on a scale | 2.75 scores on a scale | 3.00 scores on a scale |
| Gender Female | 28 Participants | 23 Participants | 51 Participants |
| Gender Male | 2 Participants | 7 Participants | 9 Participants |
| Number of Relapses in 12 Months Prior to Screening | 1.0 relapses STANDARD_DEVIATION 0.85 | 1.4 relapses STANDARD_DEVIATION 1.07 | 1.2 relapses STANDARD_DEVIATION 0.98 |
| Number of Relapses in 3 Years Prior to Screening | 2.4 relapses STANDARD_DEVIATION 1.83 | 3.0 relapses STANDARD_DEVIATION 2.65 | 2.7 relapses STANDARD_DEVIATION 2.27 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 4 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 29 participants | 30 participants | 59 participants |
| Race/Ethnicity, Customized White | 26 participants | 27 participants | 53 participants |
| Time Since First MS Diagnosis | 5.0 years | 6.0 years | 5.5 years |
| Time Since First MS Symptoms | 8.5 years | 8.0 years | 8.0 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 30 | 19 / 30 |
| serious Total, serious adverse events | 3 / 30 | 2 / 30 |
Outcome results
Primary
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.
Time frame: 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group)
Population: Participants with an assessment at Day 28. No imputation methods were used in the primary analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tysabri Plus Vaccinations | Percentage of Keyhole Limpet Hemocyanin (KLH) Responders at Day 28 Post-Vaccination | 89 percentage of participants |
| Vaccinations Only | Percentage of Keyhole Limpet Hemocyanin (KLH) Responders at Day 28 Post-Vaccination | 83 percentage of participants |
Primary
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.
Time frame: 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group)
Population: Participants with an assessment at Day 28 and a pre-immunization antibody value ≤ 3.5 IU/mL. No imputation methods were used in the primary analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tysabri Plus Vaccinations | Percentage of Tetanus Diphtheria Toxoid (Td) Responders at Day 28 Post-Vaccination | 94 percentage of participants |
| Vaccinations Only | Percentage of Tetanus Diphtheria Toxoid (Td) Responders at Day 28 Post-Vaccination | 100 percentage of participants |
Secondary
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.
Time frame: Month 0 (Baseline), Month 3, and Month 6
Population: Participants who had received at least 1 dose of Tysabri and had at least 1 post-baseline assessment. n=number of participants with measurement at given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri Plus Vaccinations | Mean Alpha4-Integrin Expression at Baseline, Month 3, and Month 6 | Baseline; n=27 | 633.7 mean fluorescent intensity (MFI) | Standard Deviation 139.73 |
| Tysabri Plus Vaccinations | Mean Alpha4-Integrin Expression at Baseline, Month 3, and Month 6 | Month 3; n=28 | 419.5 mean fluorescent intensity (MFI) | Standard Deviation 158.95 |
| Tysabri Plus Vaccinations | Mean Alpha4-Integrin Expression at Baseline, Month 3, and Month 6 | Month 6; n=24 | 434.3 mean fluorescent intensity (MFI) | Standard Deviation 167.93 |
Secondary
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.
Time frame: Month 0 (Baseline), Month 3, and Month 6
Population: Participants who received at least 1 dose of Tysabri and had at least 1 post-baseline assessment. n=number of participants with measurement at given timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri Plus Vaccinations | Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 | Baseline; n=27 | 9.9 percent saturation | Standard Deviation 16.72 |
| Tysabri Plus Vaccinations | Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 | Month 3; n=28 | 72.7 percent saturation | Standard Deviation 28.93 |
| Tysabri Plus Vaccinations | Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 | Month 6; n=24 | 80.5 percent saturation | Standard Deviation 24.46 |
Secondary
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).
Time frame: Month 0 (Baseline), Month 3
Population: Participants who had received at least 3 doses of Tysabri per protocol; those with insufficient Tysabri dosing or protocol violations were excluded from the relevant analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | CD3+ | 39.6 percent change | Standard Deviation 26.84 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | CD4+ | 35.7 percent change | Standard Deviation 26.83 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | CD8+ | 51.8 percent change | Standard Deviation 36.68 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | CD16+/CD56+ | 68.7 percent change | Standard Deviation 79.83 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 3 of Tysabri Therapy | CD19+ | 135.2 percent change | Standard Deviation 82.8 |
Secondary
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).
Time frame: Month 0 (Baseline), Month 6
Population: Participants who had received at least 3 doses of Tysabri per protocol; those with insufficient Tysabri dosing or protocol violations were excluded from the relevant analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | CD3+ | 52.4 percent change | Standard Deviation 34.19 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | CD4+ | 48.2 percent change | Standard Deviation 32.71 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | CD8+ | 67.1 percent change | Standard Deviation 42.41 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | CD16+/CD56+ | 73.5 percent change | Standard Deviation 73.2 |
| Tysabri Plus Vaccinations | Mean Percentage Change From Baseline in Circulating Lymphocyte Subsets CD3+, CD4+, CD8+, CD19+, and CD56+ at Month 6 of Tysabri Therapy | CD19+ | 164.8 percent change | Standard Deviation 85.21 |