Vaccination Response in Tecfidera-Treated Versus Interferon-Treated Participants With Relapsing Forms of Multiple Sclerosis.

Study Overview
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Brief Summary
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Primary objective is to evaluate the immune response to vaccination with tetanus diphtheria toxoids vaccine (Td) in participants with relapsing forms of Multiple Sclerosis (MS) who have been treated with Tecfidera (BG00012) versus those treated with non pegylated interferon (IFN). Secondary objective is to evaluate the immune response to vaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV23) [a mostly T cell-independent humoral response] and meningococcal polysaccharide diphtheria conjugate vaccine, quadrivalent (MCV4) [T cell-dependent neoantigen response].

Official Title
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An Open-Label Study to Assess the Immune Response to Vaccination in Tecfidera® (BG00012)-Treated Versus Interferon-Treated Subjects With Relapsing Forms of Multiple Sclerosis.

Conditions
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Relapsing Forms of Multiple Sclerosis

Intervention / Treatment
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* Drug: dimethyl fumarate
* Biological: tetanus diphtheria toxoids vaccine
* Biological: 23-valent pneumococcal polysaccharide vaccine
* Biological: meningococcal polysaccharide diphtheria conjugate vaccine (quadrivalent)
* Drug: non-pegylated interferon


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have a confirmed diagnosis of relapsing remitting MS per the 2010 McDonald criteria. Must have a known tetanus immunization history with most recent tetanus vaccination given 2 to 15 years prior to Screening and an anti-tetanus serum immunoglobulin titer at Screening that is less than or equal to one-half the upper limit of detection for the assay. Must have been on a stable approved dose of Tecfidera (240 mg twice daily [BID]) [Group 1] for ≥6 months or on a stable approved dose of a non-pegylated IFN (e.g., Avonex, Betaseron, Rebif, Extavia) [Group 2] for ≥3 months prior to Day 1. Key Exclusion Criteria: Clinical relapse requiring treatment within 30 days prior to Day 1. Pneumococcal vaccination within 5 years prior to Screening. Previous exposure to meningococcal vaccines. Known hypersensitivity to Td, PPSV23, or MCV4 or their components. NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Non-Pegylated IFN Treated Plus Vaccinations<br>Participants on a stable approved dose of a non pegylated IFN for ≥3 months will receive 3 vaccinations on Day 1 intramuscularly in the specified order: Td 0.5 mL PPSV23 0.5 mL MCV4 0.5 mL | Biological: tetanus diphtheria toxoids vaccine<br>* Administered as described in the treatment arm<br>* Other names: Tenivac;Biological: 23-valent pneumococcal polysaccharide vaccine<br>* Administered as described in the treatment arm<br>* Other names: PPSV23;Biological: meningococcal polysaccharide diphtheria conjugate vaccine (quadrivalent)<br>* Administered as described in the treatment arm<br>* Other names: Menveo;Drug: non-pegylated interferon<br>* Throughout the study participants will remain on their existing, stable dosing regimen of non-pegylated IFN.<br>* Other names: IFN;|
| Experimental: Tecfidera Treated Plus Vaccinations<br>Participants on a stable approved dose of Tecfidera (240 mg BID) for ≥6 months will receive 3 vaccinations on Day 1 intramuscularly in the specified order: Td 0.5 mL PPSV23 0.5 mL MCV4 0.5 mL | Drug: dimethyl fumarate<br>* Throughout the study participants will remain on their existing, stable dosing regimen of Tecfidera.<br>* Other names: Tecfidera;Biological: tetanus diphtheria toxoids vaccine<br>* Administered as described in the treatment arm<br>* Other names: Tenivac;Biological: 23-valent pneumococcal polysaccharide vaccine<br>* Administered as described in the treatment arm<br>* Other names: PPSV23;Biological: meningococcal polysaccharide diphtheria conjugate vaccine (quadrivalent)<br>* Administered as described in the treatment arm<br>* Other names: Menveo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Tetanus Responders (≥ 2-Fold Rise) at Day 28 Compared to Prevaccination Level | Percentage of participants with a ≥ 2-fold rise in anti-tetanus serum immunoglobulin G (IgG) levels (responders) from prevaccination to 4 weeks after Td vaccination. | Up to Week 4 (Day 28) postvaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Tetanus Responders (≥ 4-Fold Rise) at Day 28 Compared to Prevaccination Level | Percentage of participants with a ≥ 4-fold rise in anti-tetanus serum IgG levels (responders) from prevaccination to 4 weeks after Td vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Percentage of Pneumococcal Serotype 3 (≥ 2-Fold Rise) Responders Compared to Prevaccination Level | Percentage of participants with a ≥ 2-fold rise in anti-pneumococcal serum IgG levels against serotype 3 from prevaccination to 4 weeks (28 days) after PPSV23 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Percentage of Pneumococcal Serotype 3 (≥ 4-Fold Rise) Responders Compared to Prevaccination Level | Percentage of participants with a ≥ 4-fold rise in anti-pneumococcal serum IgG levels against serotype 3 from prevaccination to 4 weeks (28 days) after PPSV23 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Percentage of Pneumococcal Serotype 8 (≥ 2-Fold Rise) Responders Compared to Prevaccination Level | Percentage of participants with a ≥ 2-fold rise in anti-pneumococcal serum IgG levels against serotype 8 from prevaccination to 4 weeks (28 days) after PPSV23 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Percentage of Pneumococcal Serotype 8 (≥ 4-Fold Rise) Responders Compared to Prevaccination Level | Percentage of participants with a ≥ 4-fold rise in anti-pneumococcal serum IgG levels against serotype 8 from prevaccination to 4 weeks (28 days) after PPSV23 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Percentage of Meningococcal Serogroup C Responders (≥ 2-Fold Rise) Compared to Prevaccination Level | Percentage of participants with a ≥ 2-fold rise in anti-meningococcal serum IgG levels against serotype C from prevaccination to 4 weeks after MCV4 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Percentage of Meningococcal Serogroup C Responders (≥ 4-Fold Rise) Compared to Prevaccination Level | Percentage of participants with a ≥ 4-fold rise in anti-meningococcal serum IgG levels against serotype C from prevaccination to 4 weeks after MCV4 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Ratio of Serum Tetanus Level at Day 28 to Prevaccination | Median serum titer ratios from prevaccination to 4 weeks after Td vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Ratio of Serum Pneumococcal Antibodies (Serotype 3) Level at Day 28 to Prevaccination | Median serum titer ratios from prevaccination to 4 weeks after PPSV23 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Ratio of Serum Pneumococcal Antibodies (Serotype 8) Level at Day 28 to Prevaccination | Median serum titer ratios from prevaccination to 4 weeks after PPSV23 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Ratio of Serum Meningococcal Antibodies (Serogroup C) Level at Day 28 to Prevaccination | Median serum titer ratios from prevaccination to 4 weeks after MCV4 vaccination. | Up to Week 4 (Day 28) postvaccination | 
| Number of Participants Experiencing Vaccination-Emergent Adverse Events (AEs) and Serious AEs | An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. A serious AE was any untoward medical occurrence that at any dose: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, could have jeopardized the participant or required intervention to prevent one of the other outcomes listed in the definition above. | Day 1 to Week 4 | 
| Number of Participants With Shifts From Baseline in Hematology | Shift to low includes normal to low, high to low, and unknown to low. Shift to high includes normal to high, low to high, and unknown to high. | Screening to Week 4 | 
| Number of Participants With Shifts From Baseline in Blood Chemistry | Shift to low includes normal to low, high to low, and unknown to low. Shift to high includes normal to high, low to high, and unknown to high. | Screening to Week 4 | 
| Number of Participants With Abnormalities in Vital Signs | Temperature increase: > 38 celcius (C) or ≥ 1 C increase from baseline. Pulse increase: > 120 beats per minute (bpm) or > 20 bpm increase from baseline. Pulse decrease: < 50 bpm or > 20 bpm decrease from baseline. Systolic blood pressure (SBP) increase: > 180 millimeters of mercury (mmHg) or > 40 mmHg from baseline. SBP decrease: < 90 mmHg or > 30 mmHg decrease from baseline. Diastolic blood pressure (DBP) increase: > 105 mmHg or > 30 mmHg increase from baseline. DBP decrease: < 50 mmHg or > 20 mmHg decrease from baseline. | Screening to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine, pneumococcal, meningococcal, tetanus diphtheria, immune response