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A Study to Evaluate the Effects of Ocrelizumab on Immune Responses In Participants With Relapsing Forms of Multiple Sclerosis

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ClinicalTrials.gov Identifier: NCT02545868
Recruitment Status : Active, not recruiting
First Posted : September 10, 2015
Results First Posted : June 5, 2018
Last Update Posted : November 2, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This multicenter, randomized, open-label study will evaluate the immune response to vaccines (tetanus toxoid [TT]-containing adsorbed vaccine, 23-valent pneumococcal polysaccharide vaccine [23-PPV] either unboosted or boosted with 13-valent pneumococcal conjugate vaccine [13-PCV], influenza vaccine, keyhole limpet hemocyanin [KLH]) after administration of a dose of ocrelizumab (OCR) in participants with relapsing multiple sclerosis (RMS).

Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Relapsing-Remitting Biological: 23-PPV Biological: 13-PCV Booster Biological: Influenza Vaccine Biological: KLH Drug: OCR Biological: TT Vaccine Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: A Phase IIIB, Multicenter, Randomized, Parallel-Group, Open-Label Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Patients With Relapsing Forms of Multiple Sclerosis
Actual Study Start Date : October 27, 2015
Actual Primary Completion Date : February 14, 2017
Estimated Study Completion Date : December 10, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Ocrelizumab

Arm Intervention/treatment
Experimental: Group A: OCR + Vaccines
Participants will receive dual infusion of OCR 300 milligrams (mg) on Day 1 and then on Day 15, and then participants will further receive immunization course (TT-containing adsorbed vaccine, 23-PPV either unboosted or boosted with 13-PCV, influenza vaccine, and repeated administration with KLH) at 12 weeks post-OCR treatment until Week 24. Participants who complete the 24-week immunization study period will have the option for retreatment with a single infusion of 600 mg OCR on Day 169 and subsequent single infusions (600 mg OCR) at intervals of 24 weeks. Participants who have received one or more infusions of OCR will enter the 48-week safety follow-up period.
Biological: 23-PPV
The 23-PPV vaccine will be given as a 0.5-milliliter (mL) intramuscular (IM) injection in the deltoid muscle on Day 112 (Group A) or Day 28 (Group B).

Biological: 13-PCV Booster
The 13-PCV booster will be given as an IM injection in the deltoid muscle on Day 140 (select participants in Group A).

Biological: Influenza Vaccine
The influenza vaccine will be given as an IM injection in the deltoid muscle at any time between Day 85 and Day 144 (select participants in Group A) or any time between Day 1 and Day 85 (Group B).

Biological: KLH
KLH will be given as a 1-mg subcutaneous (SC) injection on Days 84, 112, and 140 (Group A) or Days 1, 28, and 56 (Group B).

Drug: OCR
OCR will be given as an intravenous (IV) infusion at a dose of 600 mg, with the first dose given as two infusions of 300mg 14 days apart, according to the specifications described in the corresponding Group A and Group B arms.
Other Name: RO4964913, PRO70769, rhuMAb 2H7

Biological: TT Vaccine
The TT-containing adsorbed vaccine will be given as a 0.5-mL IM injection in the deltoid muscle on Day 85 (Group A) or Day 1 (Group B).

Group B: Vaccines (Optional OCR in Extension)
Participants will receive immunizations (TT-containing adsorbed vaccine, 23-PPV, influenza vaccine, and repeated administration with KLH) on Day 1 until Week 12 of the immunization period. Participants who complete the 12-week immunization study period will have the option to receive two single infusions of OCR 300 mg, on Day 84 and Day 98, and subsequent single infusions (600 mg OCR) at intervals of 24 weeks. Participants who have received one or more infusions of OCR will enter the 48-week safety follow-up period.
Biological: 23-PPV
The 23-PPV vaccine will be given as a 0.5-milliliter (mL) intramuscular (IM) injection in the deltoid muscle on Day 112 (Group A) or Day 28 (Group B).

Biological: Influenza Vaccine
The influenza vaccine will be given as an IM injection in the deltoid muscle at any time between Day 85 and Day 144 (select participants in Group A) or any time between Day 1 and Day 85 (Group B).

Biological: KLH
KLH will be given as a 1-mg subcutaneous (SC) injection on Days 84, 112, and 140 (Group A) or Days 1, 28, and 56 (Group B).

Drug: OCR
OCR will be given as an intravenous (IV) infusion at a dose of 600 mg, with the first dose given as two infusions of 300mg 14 days apart, according to the specifications described in the corresponding Group A and Group B arms.
Other Name: RO4964913, PRO70769, rhuMAb 2H7

Biological: TT Vaccine
The TT-containing adsorbed vaccine will be given as a 0.5-mL IM injection in the deltoid muscle on Day 85 (Group A) or Day 1 (Group B).




Primary Outcome Measures :
  1. Percentage of Participants With Positive Response to TT Vaccine Measured 8 Weeks After TT Vaccine [ Time Frame: 8 weeks after TT vaccine ]
    For participants with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive response was defined as an antibody titer >/= 0.2 IU/mL measured 8 weeks after vaccination. For participants with pre-vaccination tetanus antibody titers >/= 0.1 IU/mL, a positive response was defined as at least a 4-fold increase in antibody titers measured 8 weeks after vaccination compared with pre-vaccination levels.


Secondary Outcome Measures :
  1. Percentage of Participants With Positive Response to TT Vaccine Measured 4 Weeks After TT Vaccine [ Time Frame: 4 weeks after TT vaccine ]
    For participants with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive response was defined as an antibody titer >/= 0.2 IU/mL measured 4 weeks after vaccination. For participants with pre-vaccination tetanus antibody titers >/= 0.1 IU/mL, a positive response was defined as at least a 4-fold increase in antibody titers measured 4 weeks after vaccination compared with pre-vaccination levels.

  2. Percentage of Participants With Tetanus Antibody Titer >/=0.2 IU/mL or 2-Fold Increase in Tetanus Antibody Titers [ Time Frame: 4 weeks after TT vaccine ]
    For participants with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive response was defined as an antibody titer >/= 0.2 IU/mL measured 4 weeks after vaccination. For participants with pre-vaccination tetanus antibody titers >/= 0.1 IU/mL, a positive response was defined as at least a 2-fold increase in antibody titers measured 4 weeks after vaccination compared with pre-vaccination levels.

  3. Mean Levels of Anti-Tetanus Antibody [ Time Frame: Immediately prior to and at 4 and 8 weeks after TT vaccine ]
    Anti-tetanus antibody levels were assessed by enzyme-linked immunosorbent assay (ELISA).

  4. Mean Levels of Anti-KLH Antibody: Immunoglobulin (Ig) G [ Time Frame: Immediately prior to first KLH administration and 4, 8, and 12 weeks after first KLH administration ]
    Anti-KLH antibody levels were assessed by ELISA.

  5. Mean Levels of Anti-KLH Antibody: Ig M [ Time Frame: Immediately prior to first KLH administration and 4, 8, and 12 weeks after first KLH administration ]
    Anti-KLH antibody levels were assessed by ELISA.

  6. Percentage of Participants With Positive Response Against Individual Pneumococcal Serotypes in 23-PPV [ Time Frame: 4 weeks after 23-PPV ]
    Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or greater than (>) 1 microgram per milliliter (mcg/mL) rise compared with pre-vaccination levels.

  7. Percentage of Participants With Positive Response Against >/=2 Pneumococcal Serotypes [ Time Frame: 4 weeks after 23-PPV ]
    Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or > 1 mcg/mL rise compared with pre-vaccination levels.

  8. Percentage of Participants With Positive Response Against >/=12 Pneumococcal Serotypes [ Time Frame: 4 weeks after 23-PPV ]
    Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or > 1 mcg/mL rise compared with pre-vaccination levels.

  9. Mean Levels of Anti-Pneumococcal Antibody [ Time Frame: Immediately prior to and 4 weeks after 23-PPV ]
    Serotype-specific antibody levels (IgG) were assessed by bead-based multi-analyte immunodetection (MAID).

  10. Percentage of Participants With Positive Response Against Individual Pneumococcal Serotypes in 13-PCV [ Time Frame: 8 weeks after 23-PPV, which was 4 weeks after Group A1 participants received 13-PCV ]
    Positive response against a serotype was defined as a 2-fold increase in anti-pneumococcal antibody level or > 1 mcg/mL rise compared with pre-vaccination levels.

  11. Mean Level of Anti-Pneumococcal Antibody [ Time Frame: Immediately prior to 23-PPV and 4 and 8 weeks after 23-PPV ]
    Serotype-specific antibody levels (IgG) were assessed by bead-based multi-analyte immunodetection (MAID).

  12. Percentage of Participants With Seroprotection [ Time Frame: 4 weeks after seasonal influenza vaccine administration ]
    Seroprotection was defined as specific hemagglutination inhibition (HI) titers >40 at 4 weeks after vaccination.

  13. Percentage of Participants With 2-Fold Increase in Strain-Specific HI Titers [ Time Frame: 4 weeks after seasonal influenza vaccine administration ]
    2-fold increase from prevaccination HI titer.

  14. Percentage of Participants With 4-Fold Increase in Strain-Specific HI Titers [ Time Frame: 4 weeks after seasonal influenza vaccine administration ]
    4-fold increase from prevaccination HI titer.

  15. Percentage of Participants With Seroconversion [ Time Frame: 4 weeks after influenza immunization ]
    Seroconversion at 4 weeks after vaccination defined, as per protocol, as a prevaccination HI titer <10 and an HI titer >40 at 4 weeks after vaccination. Seroconversion at 4 weeks after vaccination, defined per FDA guidance, as either a) a pre-vaccination HI titer <10 and HI titer >/= 40 at 4 weeks after vaccination, or b) a pre-vaccination HI titer >/= 10 and at least 4-fold increase in HI antibody titer at 4 weeks after vaccination.

  16. Strain-Specific Geometric Mean Titer Levels [ Time Frame: Baseline and Week 4 ]
    Geometric mean titers (GMTs) in participants in Groups A2 and B were measured 4 weeks after vaccination.

  17. Ratio of Strain-Specific Geometric Mean Titer Levels Postvaccination to Prevaccination [ Time Frame: Immediately prior to and 4 weeks after influenza vaccine ]
    Strain-specific GMT ratios were calculated as post-vaccination : pre-vaccination.

  18. Magnetic Resonance Imaging (MRI) Parameters: Volume of T2 Lesions [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  19. MRI Parameters: Number of T2 Lesions [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  20. MRI Parameters: Categorical Number of T2 Lesions [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  21. MRI Parameters: Number of Gadolinium (Gd)-Enhancing T1 Lesions [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  22. MRI Parameters: Categorical Number of Gd-enhancing T1 Lesions [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  23. MRI Parameters: Normalized Brain Volume [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  24. MRI Parameters: Volume of T2 Lesions: White Matter Volume [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  25. MRI Parameters: Cortical Grey Matter Volume [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  26. MRI Parameters: T1 Unenhancing Lesion Volume [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  27. MRI Parameters: Total Number of Lesions [ Time Frame: Baseline ]
    MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.

  28. Cellular Immune Response Assessed by Flow Cytometry [ Time Frame: Days 1, 15, 85, 112, 140 and 169 ]

    Flow cytometry is a laser-based technology commonly used for cell counting and sorting. In this study, this outcome measure is focusing on a single variable, CD19 count (total B cells). LLN = 80 cells/ul.

    Repleted is defined as CD19 >= LLN or baseline, whichever is lower.


  29. Total Immunoglobulin [ Time Frame: Days 1, 85, and 169 ]
  30. Percentage of Participants With Anti-Drug Antibody Formation [ Time Frame: Up to 24 Weeks (ISP) ]
    Anti-Drug Antibodies (ADA) may induce unwanted side effects, especially in biotechnology-derived pharmaceuticals, such as therapeutic antibodies and growth factors.

  31. Percentage of Participants With Adverse Events (AEs), Serious AEs, or AEs Leading to Study Discontinuation [ Time Frame: During ISP (24 weeks for Group A and 12 weeks for Group B) ]
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious AE is any AE that is fatal, life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug, or is a significant medical event in the investigator's judgment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of RMS in accordance with the revised McDonald criteria
  • Received at least one previous immunization against TT or tetanus and diphtheria (DT/Td) or tetanus, diphtheria, and acellular pertussis (DTaP/Tdap)
  • Expanded Disability Status Scale (EDSS) at Screening from 0 to 5.5 points, inclusive
  • For sexually active female participants of reproductive potential, use of reliable means of contraception

Exclusion Criteria:

  • Contraindications for or intolerance to oral or IV corticosteroids, including IV methylprednisolone, according to the country label
  • Known presence of other neurologic disorders
  • Treatment with any investigational agent within 24 weeks of screening or 5 half-lives of the investigational drug, whichever is longer, or treatment with any experimental procedure for multiple sclerosis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02545868


  Show 23 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Statistical Analysis Plan  [PDF] November 7, 2016
Study Protocol  [PDF] March 1, 2016


Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02545868     History of Changes
Other Study ID Numbers: BN29739
2015-001357-32 ( EudraCT Number )
First Posted: September 10, 2015    Key Record Dates
Results First Posted: June 5, 2018
Last Update Posted: November 2, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs