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

• ClinicalTrials.gov Identifier: NCT02545868
• Recruitment Status: Completed
• First Posted: September 10, 2015
• Results First Posted: June 6, 2018
• Last Update Posted: April 28, 2022
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 8, 2015
• First Posted Date: September 10, 2015
• Results First Submitted Date: February 13, 2018
• Results First Posted Date: June 6, 2018
• Last Update Posted Date: April 28, 2022
• Actual Study Start Date: October 27, 2015
• Actual Primary Completion Date: February 14, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 2, 2018)

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.

• Original Primary Outcome Measures (submitted: September 8, 2015): Percentage of Participants in With Positive Response to TT Vaccine Measured 8 Weeks After TT Vaccine [ Time Frame: 8 weeks after TT vaccine ]

Current Secondary Outcome Measures (submitted: May 2, 2018)

• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• MRI Parameters: Number of T2 Lesions [ Time Frame: Baseline ]
  MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
• MRI Parameters: Categorical Number of T2 Lesions [ Time Frame: Baseline ]
  MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
• 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.
• 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.
• MRI Parameters: Normalized Brain Volume [ Time Frame: Baseline ]
  MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
• 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.
• MRI Parameters: Cortical Grey Matter Volume [ Time Frame: Baseline ]
  MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
• MRI Parameters: T1 Unenhancing Lesion Volume [ Time Frame: Baseline ]
  MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
• MRI Parameters: Total Number of Lesions [ Time Frame: Baseline ]
  MRI assessments done to evaluate the long-term effects of ocrelizumab on MRI parameters.
• 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.
• Total Immunoglobulin [ Time Frame: Days 1, 85, and 169 ]
• 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.
• 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.

Original Secondary Outcome Measures (submitted: September 8, 2015)

• Percentage of Participants in With Positive Response to TT Vaccine Measured 4 Weeks After TT Vaccine [ Time Frame: 4 weeks after TT vaccine ]
• Percentage of Participants in With Positive Response to 23-PPV Measured 4 Weeks After 23-PPV [ Time Frame: 4 weeks after 23-PPV ]
• Percentage of Participants in With KLH Immunization Measured 4 Weeks After KLH Vaccine [ Time Frame: 4 weeks after KLH vaccine ]
• Percentage of Participants in With Positive Response to Pneumococcal Conjugate Booster Measured 4 Weeks After the Booster 13-PCV [ Time Frame: 4 weeks after the booster 13-PCV ]
• Percentage of Participants in With Influenza Vaccine Response Measured 4 Weeks After the Influenza Vaccine [ Time Frame: 4 weeks after the influenza vaccine ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Effects of Ocrelizumab on Immune Responses In Participants With Relapsing Forms of Multiple Sclerosis
• 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
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Supportive Care
• Condition: Multiple Sclerosis, Relapsing-Remitting

Intervention

• 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).

Study Arms

• 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.
  Interventions:

  • Biological: 23-PPV
  • Biological: 13-PCV Booster
  • Biological: Influenza Vaccine
  • Biological: KLH
  • Drug: OCR
  • Biological: TT Vaccine
• 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.
  Interventions:

  • Biological: 23-PPV
  • Biological: Influenza Vaccine
  • Biological: KLH
  • Drug: OCR
  • Biological: TT Vaccine

• Publications *: Bar-Or A, Calkwood JC, Chognot C, Evershed J, Fox EJ, Herman A, Manfrini M, McNamara J, Robertson DS, Stokmaier D, Wendt JK, Winthrop KL, Traboulsee A. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology. 2020 Oct 6;95(14):e1999-e2008. doi: 10.1212/WNL.0000000000010380. Epub 2020 Jul 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 3, 2016): 102
• Original Estimated Enrollment (submitted: September 8, 2015): 100
• Actual Study Completion Date: October 9, 2021
• Actual Primary Completion Date: February 14, 2017 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT02545868
• Other Study ID Numbers: BN29739; 2015-001357-32 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: April 2022