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

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.

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].

Study Overview

• Status: Completed
• Conditions: Relapsing Forms of Multiple Sclerosis
• Intervention / Treatment: Biological: tetanus diphtheria toxoids vaccine; Biological: 23-valent pneumococcal polysaccharide vaccine; Biological: meningococcal polysaccharide diphtheria conjugate vaccine (quadrivalent); Drug: non-pegylated interferon; Drug: dimethyl fumarate

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Research Site
  • Colorado
    • Thornton, Colorado, United States, 80233
      • Research Site
  • Florida
    • Fort Lauderdale, Florida, United States, 33312
      • Research Site
    • Sarasota, Florida, United States, 34243
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40513
      • Research Site
  • Maine
    • Auburn, Maine, United States, 04210
      • Research Site
  • New York
    • New York, New York, United States, 10016
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Research Site
  • Ohio
    • Akron, Ohio, United States, 44320
      • Research Site
    • Cleveland, Ohio, United States, 44195
      • Research Site
    • Dayton, Ohio, United States, 45417
      • Research Site
  • Texas
    • Round Rock, Texas, United States, 78761
      • Research Site
    • San Antonio, Texas, United States, 78258
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Non-Pegylated IFN Treated Plus Vaccinations; 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; Administered as described in the treatment arm; Other Names: Td; Tenivac; Biological: 23-valent pneumococcal polysaccharide vaccine; Administered as described in the treatment arm; Other Names: Pneumovax 23; PPSV23; Biological: meningococcal polysaccharide diphtheria conjugate vaccine (quadrivalent); Administered as described in the treatment arm; Other Names: Menveo; MCV4; Drug: non-pegylated interferon; Throughout the study participants will remain on their existing, stable dosing regimen of non-pegylated IFN.; Other Names: IFN
Experimental: Tecfidera Treated Plus Vaccinations; 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	Biological: tetanus diphtheria toxoids vaccine; Administered as described in the treatment arm; Other Names: Td; Tenivac; Biological: 23-valent pneumococcal polysaccharide vaccine; Administered as described in the treatment arm; Other Names: Pneumovax 23; PPSV23; Biological: meningococcal polysaccharide diphtheria conjugate vaccine (quadrivalent); Administered as described in the treatment arm; Other Names: Menveo; MCV4; Drug: dimethyl fumarate; Throughout the study participants will remain on their existing, stable dosing regimen of Tecfidera.; Other Names: BG00012; DMF; Tecfidera

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• von Hehn C, Howard J, Liu S, Meka V, Pultz J, Mehta D, Prada C, Ray S, Edwards MR, Sheikh SI. Immune response to vaccines is maintained in patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2017 Nov 15;5(1):e409. doi: 10.1212/NXI.0000000000000409. eCollection 2018 Jan.

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2015
• Primary Completion (Actual): May 2, 2016
• Study Completion (Actual): May 2, 2016

Study Registration Dates

• First Submitted: March 25, 2014
• First Submitted That Met QC Criteria: March 25, 2014
• First Posted (Estimate): March 27, 2014

Study Record Updates

• Last Update Posted (Actual): June 2, 2017
• Last Update Submitted That Met QC Criteria: May 1, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: vaccine; immune response; pneumococcal; meningococcal; tetanus diphtheria
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Interferons; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine; Dimethyl Fumarate
• Other Study ID Numbers: 109MS307