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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tysabri Plus Vaccinations | Experimental | 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. |
|
| Vaccinations Only | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BG00002 (natalizumab) | Biological |
|
| |
| keyhole limpet hemocyanin (KLH) |
| 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) |
| 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 |
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Inclusion Criteria:
Major Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Biogen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site 1 | Fullerton | California | 92835 | United States | ||
| Research Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24731783 | Background | Kaufman M, Pardo G, Rossman H, Sweetser MT, Forrestal F, Duda P. Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis. J Neurol Sci. 2014 Jun 15;341(1-2):22-7. doi: 10.1016/j.jns.2014.03.035. Epub 2014 Mar 26. |
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Participants were enrolled in the study at 10 investigational sites in the US. Study enrollment began on 07 January 2008.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Biological |
KLH 1 mg administered subcutaneously (SC) in accordance with the Immucothel investigator's brochure. |
|
|
| tetanus diphtheria toxoid vaccine (Td) | Biological | Td administered in accordance with the manufacturer's prescribing information. |
|
| 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 |
| Centennial |
| Colorado |
| 80112 |
| United States |
| Research site | Farmington Hills | Michigan | 48334 | United States |
| Research Site | Patchogue | New York | 11772 | United States |
| Research Site 3 | Charlotte | North Carolina | 28207 | United States |
| Research Site 5 | Oklahoma City | Oklahoma | 73130 | United States |
| Research Site | Franklin | Tennessee | 37064 | United States |
| Research Site | Dallas | Texas | 75214 | United States |
| Research Site 2 | Seattle | Washington | 98122 | United States |
| Research Site 4 | Charleston | West Virginia | 25301 | United States |
| FG001 | 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. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
| |||||||||||||||
| Gender | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Number | participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Number | participants |
| ||||||||||||||||
| Time Since First MS Symptoms | Median | Full Range | years |
| |||||||||||||||
| Time Since First MS Diagnosis | Median | Full Range | years |
| |||||||||||||||
| Number of Relapses in 3 Years Prior to Screening | Mean | Standard Deviation | relapses |
| |||||||||||||||
| Number of Relapses in 12 Months Prior to Screening | Mean | Standard Deviation | relapses |
| |||||||||||||||
| Expanded Disability Status Scale at Screening | The Expanded Disability Status Scale (EDSS) measures physical disability on a scale from 0.0 (no disability) to 10.0 (death due to disability) in 0.5-point increments. | Median | Full Range | scores on a scale |
| ||||||||||||||
| Circulating Lymphocyte Subsets | Circulating lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD56+) at Baseline | Mean | Standard Deviation | lymphocyte count/µL |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Participants with an assessment at Day 28. No imputation methods were used in the primary analyses. | Posted | Jul 2011 | Number | percentage of participants | 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group) |
|
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| ||||||||||||||||||||||||||||
| 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. | 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. | Posted | Jul 2011 | Number | percentage of participants | 28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group) |
| ||||||||||||||||||||||||||||||
| 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). | 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. | Posted | Mean | Standard Deviation | percent change | Month 0 (Baseline), Month 3 |
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| 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). | 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. | Posted | Mean | Standard Deviation | percent change | Month 0 (Baseline), Month 6 |
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| |||||||||||||||||||||||||||||
| 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. | 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. | Posted | Mean | Standard Deviation | percent saturation | Month 0 (Baseline), Month 3, and Month 6 |
|
| |||||||||||||||||||||||||||||
| 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. | 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. | Posted | Mean | Standard Deviation | mean fluorescent intensity (MFI) | Month 0 (Baseline), Month 3, and Month 6 |
|
|
Adverse events were collected from dosing at the Baseline Visit (Month 0) until the participant's End of Study Visit (Month 8). Serious adverse events were collected from screening until 12 weeks following the participant's last dose of Tysabri.
Data for the Tysabri Plus Vaccinations group covers the entire study period, and data for the Vaccines Only group covers only the immunization period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 specified timepoints following the 7th dose. | 3 | 30 | 25 | 30 | ||
| EG001 | Vaccinations Only | Participants received only vaccinations with neoantigen and recall antigen (KLH and Td, according to manufacturer's prescribing information) at specified timepoints. They did not receive any treatment for their MS. | 2 | 30 | 19 | 30 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| multiple sclerosis relapse | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
| |
| herpes zoster disseminated | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| basal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (12.0) | Systematic Assessment |
| |
| angina unstable | Cardiac disorders | MedDRA (12.0) | Systematic Assessment |
| |
| gastroenteritis | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| influenza | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| bronchitis | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| vomiting | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
| |
| pruritis | Skin and subcutaneous tissue disorders | MedDRA (12.0) | Systematic Assessment |
| |
| vision blurred | Eye disorders | MedDRA (12.0) | Systematic Assessment |
| |
| nasopharyngitis | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| fatigue | General disorders | MedDRA (12.0) | Systematic Assessment |
| |
| diarrhoea | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
| |
| oral herpes | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| injection site erythrema | General disorders | MedDRA (12.0) | Systematic Assessment |
| |
| injection site pain | General disorders | MedDRA (12.0) | Systematic Assessment |
| |
| cough | Respiratory, thoracic and mediastinal disorders | MedDRA (12.0) | Systematic Assessment |
| |
| injection site swelling | General disorders | MedDRA (12.0) | Systematic Assessment |
| |
| paraesthesia | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
| |
| injection site warmth | General disorders | MedDRA (12.0) | Systematic Assessment |
| |
| urticaria | Skin and subcutaneous tissue disorders | MedDRA (12.0) | Systematic Assessment |
| |
| sinusitis | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| pyrexia | General disorders | MedDRA (12.0) | Systematic Assessment |
| |
| muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (12.0) | Systematic Assessment |
| |
| hypoaesthesia | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
| |
| pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (12.0) | Systematic Assessment |
| |
| upper respiratory tract infection | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| urinary tract infection | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| otitis media | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
| |
| fall | Injury, poisoning and procedural complications | MedDRA (12.0) | Systematic Assessment |
| |
| depression | Psychiatric disorders | MedDRA (12.0) | Systematic Assessment |
| |
| nausea | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
| |
| arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (12.0) | Systematic Assessment |
| |
| multiple sclerosis relapse | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
| |
| headache | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
|
Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Biogen Idec Medical Director | Biogen Idec Inc. | clinicaltrials@biogenidec.com |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000069442 | Natalizumab |
| C032808 | keyhole-limpet hemocyanin |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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| Male |
|
| Not Hispanic or Latino |
|
| Asian |
|
| Black or African American |
|
| White |
|
| CD4+; n=24 |
|
| CD8+; n=24 |
|
| CD16+; n=24 |
|
| CD19+; n=24 |
|
| Units | Counts |
|---|---|
| Participants |
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