Trial Outcomes & Findings for The Effects of Tysabri Treatment on Vaccination Response and Lymphocyte Subsets in Subjects With Relapsing Forms of Multiple Sclerosis (NCT NCT00536120)

Last Updated: 2017-02-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

60 participants

Primary outcome timeframe

28 days after immunization (Day 28 for Vaccinations Only Group/Day 196 for Tysabri Plus Vaccinations Group)

Results posted on

2017-02-15

Participant Flow

Participants were enrolled in the study at 10 investigational sites in the US. Study enrollment began on 07 January 2008.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	30	30
Overall Study COMPLETED	24	27
Overall Study NOT COMPLETED	6	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Lost to Follow-up	1	0
Overall Study Positive for Anti-natalizumab Antibodies	3	0
Overall Study Non-compliance	1	0
Overall Study Sponsor Decision Due to Lab Values	1	0
Overall Study Steroid Use	0	2
Overall Study Missed Study Visit	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tysabri Plus Vaccinations n=30 Participants 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.	Vaccinations Only n=30 Participants 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.	Total n=60 Participants Total of all reporting groups
Age, Continuous	43.1 Years STANDARD_DEVIATION 8.34 • n=99 Participants	40.4 Years STANDARD_DEVIATION 9.86 • n=107 Participants	41.8 Years STANDARD_DEVIATION 9.16 • n=206 Participants
Gender Female	23 Participants n=99 Participants	28 Participants n=107 Participants	51 Participants n=206 Participants
Gender Male	7 Participants n=99 Participants	2 Participants n=107 Participants	9 Participants n=206 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	30 participants n=99 Participants	29 participants n=107 Participants	59 participants n=206 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants
Race/Ethnicity, Customized Asian	1 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants
Race/Ethnicity, Customized Black or African American	1 participants n=99 Participants	4 participants n=107 Participants	5 participants n=206 Participants
Race/Ethnicity, Customized White	27 participants n=99 Participants	26 participants n=107 Participants	53 participants n=206 Participants
Time Since First MS Symptoms	8.0 years n=99 Participants	8.5 years n=107 Participants	8.0 years n=206 Participants
Time Since First MS Diagnosis	6.0 years n=99 Participants	5.0 years n=107 Participants	5.5 years n=206 Participants
Number of Relapses in 3 Years Prior to Screening	3.0 relapses STANDARD_DEVIATION 2.65 • n=99 Participants	2.4 relapses STANDARD_DEVIATION 1.83 • n=107 Participants	2.7 relapses STANDARD_DEVIATION 2.27 • n=206 Participants
Number of Relapses in 12 Months Prior to Screening	1.4 relapses STANDARD_DEVIATION 1.07 • n=99 Participants	1.0 relapses STANDARD_DEVIATION 0.85 • n=107 Participants	1.2 relapses STANDARD_DEVIATION 0.98 • n=206 Participants
Expanded Disability Status Scale at Screening	2.75 scores on a scale n=99 Participants	3.00 scores on a scale n=107 Participants	3.00 scores on a scale n=206 Participants
Circulating Lymphocyte Subsets CD3+; n=24	1261.5 lymphocyte count/µL STANDARD_DEVIATION 309.47 • n=99 Participants	NA lymphocyte count/µL STANDARD_DEVIATION NA • n=107 Participants	1261.5 lymphocyte count/µL STANDARD_DEVIATION 309.47 • n=206 Participants
Circulating Lymphocyte Subsets CD4+; n=24	905.2 lymphocyte count/µL STANDARD_DEVIATION 299.51 • n=99 Participants	NA lymphocyte count/µL STANDARD_DEVIATION NA • n=107 Participants	905.2 lymphocyte count/µL STANDARD_DEVIATION 299.51 • n=206 Participants
Circulating Lymphocyte Subsets CD8+; n=24	344.6 lymphocyte count/µL STANDARD_DEVIATION 123.91 • n=99 Participants	NA lymphocyte count/µL STANDARD_DEVIATION NA • n=107 Participants	344.6 lymphocyte count/µL STANDARD_DEVIATION 123.91 • n=206 Participants
Circulating Lymphocyte Subsets CD16+; n=24	179.2 lymphocyte count/µL STANDARD_DEVIATION 106.12 • n=99 Participants	NA lymphocyte count/µL STANDARD_DEVIATION NA • n=107 Participants	179.2 lymphocyte count/µL STANDARD_DEVIATION 106.12 • n=206 Participants
Circulating Lymphocyte Subsets CD19+; n=24	269.8 lymphocyte count/µL STANDARD_DEVIATION 123.00 • n=99 Participants	NA lymphocyte count/µL STANDARD_DEVIATION NA • n=107 Participants	269.8 lymphocyte count/µL STANDARD_DEVIATION 123.00 • n=206 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tysabri Plus Vaccinations n=19 Participants 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.	Vaccinations Only n=23 Participants 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.
Percentage of Keyhole Limpet Hemocyanin (KLH) Responders at Day 28 Post-Vaccination	89 percentage of participants	83 percentage of participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tysabri Plus Vaccinations n=16 Participants 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.	Vaccinations Only n=24 Participants 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.
Percentage of Tetanus Diphtheria Toxoid (Td) Responders at Day 28 Post-Vaccination	94 percentage of participants	100 percentage of participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Tysabri Plus Vaccinations n=23 Participants 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.	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.
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 82.80	—
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	—
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	—
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	—
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	—

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Tysabri Plus Vaccinations n=20 Participants 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.	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.
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 73.20	—
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	—
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	—
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	—
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	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tysabri Plus Vaccinations n=30 Participants 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.	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.
Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 Baseline; n=27	9.9 percent saturation Standard Deviation 16.72	—
Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 Month 3; n=28	72.7 percent saturation Standard Deviation 28.93	—
Mean Alpha4-Integrin Saturation at Baseline, Month 3, and Month 6 Month 6; n=24	80.5 percent saturation Standard Deviation 24.46	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tysabri Plus Vaccinations n=30 Participants 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.	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.
Mean Alpha4-Integrin Expression at Baseline, Month 3, and Month 6 Baseline; n=27	633.7 mean fluorescent intensity (MFI) Standard Deviation 139.73	—
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	—
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	—

Adverse Events

Tysabri Plus Vaccinations

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Vaccinations Only

Serious events: 2 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tysabri Plus Vaccinations n=30 participants at risk 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.	Vaccinations Only n=30 participants at risk 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.
Nervous system disorders multiple sclerosis relapse	0.00% 0/30 • 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.	3.3% 1/30 • 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.
Infections and infestations herpes zoster disseminated	3.3% 1/30 • 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.	0.00% 0/30 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) basal cell carcinoma	3.3% 1/30 • 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.	0.00% 0/30 • 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.
Cardiac disorders angina unstable	0.00% 0/30 • 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.	3.3% 1/30 • 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.
Infections and infestations gastroenteritis	3.3% 1/30 • 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.	0.00% 0/30 • 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.

Other adverse events

Additional Information

Biogen Idec Medical Director

Biogen Idec Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER