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A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)

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ClinicalTrials.gov Identifier: NCT04548999
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : November 18, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 9, 2020
First Posted Date  ICMJE September 16, 2020
Last Update Posted Date November 18, 2020
Estimated Study Start Date  ICMJE November 17, 2020
Estimated Primary Completion Date February 23, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 9, 2020)
Time to Onset of Composite Confirmed Disability Progression (cCDP) Sustained for at least 12 Weeks [ Time Frame: Baseline up to approximately 4.3 years ]
Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2020)
  • Time to Onset of 24-week cCDP (cCDP24) [ Time Frame: Baseline up to approximately 4.3 years ]
    Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression event measured by EDSS, T25FWT or 9-HPT.
  • Time to Onset of 12-week CDP (CDP12) [ Time Frame: Baseline up to approximately 4.3 years ]
    CDP, defined as a sustained increase from baseline in EDSS score of >/=1.0 point in participants with a baseline EDSS score of </=5.5 or a sustained increase of >/=0.5 points in participants with a baseline EDSS score of >5.5.
  • Time to Onset of 24-week CDP (CDP24) [ Time Frame: Baseline up to approximately 4.3 years ]
    CDP, defined as a sustained increase from baseline in EDSS score of >/=1.0 point in participants with a baseline EDSS score of </=5.5 or a sustained increase of >/=0.5 points in participants with a baseline EDSS score of >5.5.
  • Time to >/= 20% Increase in 12-week Confirmed by Timed 25-Foot Walk Test (T25FWT) [ Time Frame: Baseline up to approximately 4.3 years ]
    The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible.
  • Time to >/= 20% Increase in 24-week Confirmed T25FWT [ Time Frame: Baseline up to approximately 4.3 years ]
    The T25FWT is a performance measure used to assess walking speed based on a timed 25-foot walk. The participant is directed to start at one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible.
  • Time to >/= 20% Increase in 12-week Confirmed by 9-Hole Peg Test (9-HPT) [ Time Frame: Baseline up to approximately 4.3 years ]
    The 9-HPT is a performance measure used to assess upper extremity (arm and hand) function. The test consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. The participant is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the participant is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded.
  • Time to >/= 20% Increase in 24-week Confirmed by 9-HPT [ Time Frame: Baseline up to approximately 4.3 years ]
    The 9-HPT is a performance measure used to assess upper extremity (arm and hand) function. The test consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. The participant is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the participant is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded.
  • Change from Baseline in the Multiple Sclerosis Impact Scale (MSIS 29) Score at Week 120 [ Time Frame: Baseline to Week 120 ]
    The MSIS-29 is a 29-item participant-reported measure of the physical and psychological impacts of MS. Participants are asked to rate how much their functioning and well-being has been impacted over the past 14 days on a 4-point scale, from "Not at all" (1) to "Extremely" (4).
  • Percent Change in Total Brain Volume from Week 24 to Week 120 [ Time Frame: Week 24 to Week 120 ]
  • Time to 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) [ Time Frame: Baseline up to approximately 4.3 years ]
    The SDMT is a performance measure that has demonstrated sensitivity in detecting not only the presence of cognitive impairment but also changes in cognitive functioning over time and in response to treatment. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses will be collected orally. A four-point change from baseline is typically considered clinically meaningful.
  • Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to approximately 4.3 years ]
    Severity of an adverse event is determined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
  • Serum Concentration of Ocrelizumab at Specified Timepoints [ Time Frame: Baseline up to approximately 4.3 years ]
  • Change in B-cell Levels in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
  • Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood [ Time Frame: Baseline up to approximately 4.3 years ]
  • Proportion of Participants Achieving 5 or Less B-cells per Microliter of Blood in Participants with the High versus Low Affinity Fcgamma Receptor 3A (FcgR3A) Genotype per Arm [ Time Frame: Baseline up to approximately 4.3 years ]
  • Change from Baseline in the Anti-Drug Antibody (ADA) Levels [ Time Frame: Baseline up to approximately 4.3 yearsv ]
  • Levels of Neurofilament Light Chain (NfL) in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
  • Levels of Interleukin-6 (IL-6) in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
  • Levels of Blood B-cells [ Time Frame: Baseline up to approximately 4.3 years ]
    Levels of blood B-cells is based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
  • Levels of Lymphocytes in Blood [ Time Frame: Baseline up to approximately 4.3 years ]
  • Proportion of Participants with Different DNA Genotypes [ Time Frame: Baseline up to approximately 4.3 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)
Official Title  ICMJE A Phase IIIB Multicenter, Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis
Brief Summary This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks in participants with PPMS, in comparison to the approved 600 mg dose of ocrelizumab.
Detailed Description Participants will be treated for a minimum of 120 weeks in the double-blind phase. Upon positive primary results after the double-blind phase, an optional higher dose extension treatment (OLE phase) is planned for eligible participants. The OLE will be carried out for approximately 96 weeks. Participants will be followed for safety for 48 weeks thereafter. Participants whose B-cell levels still did not replete to their baseline level or the lower limit of normal (LLN), whichever is lower, will move into the B-cell monitoring (BCM) phase following the safety follow-up phase. The study will end when all participants who were not treated with an alternative B-cell depleting therapy have repleted their B-cells to the baseline value or the lower limit of normal.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE
  • Drug: Ocrelizumab
    The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants's body weight <75 kg) or 1800 mg (participant's body weight >/=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks.
    Other Name: Ocrevus
  • Drug: Ocrelizumab
    Ocrelizumab will be administered at a dose of 600 milligram (mg) every 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg IV infusion every 24 weeks.
    Other Name: Ocrevus
  • Drug: Antihistamine
    Premedication with oral or IV antihistaminic drug (i.e., diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered prior to each ocrelizumab infusion.
    Other Name: Non-Investigational Medicinal Product
  • Drug: Methylprednisolone
    Premedication with 100 mg of methylprednisolone (or equivalent) will be administered by IV infusion prior to each ocrelizumab infusion.
    Other Name: Non-Investigational Medicinal Product
Study Arms  ICMJE
  • Experimental: Ocrelizumab Higher Dose
    Participants will be randomized to receive a minimum of 5 higher treatment doses (1200 mg or 1800 mg) of ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the double blind treatment (DBT) phase. During the optional open-label extension (OLE) phase, participants will continue with their assigned dose of ocrelizumab (either 1200 or 1800 mg) for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
    Interventions:
    • Drug: Ocrelizumab
    • Drug: Antihistamine
    • Drug: Methylprednisolone
  • Active Comparator: Ocrelizumab Approved Dose
    Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by intravenous (IV) infusion every 24 weeks in the DBT phase. During the optional OLE phase, participants will be offered a higher dose of ocrelizumab (either 1200 or 1800 mg), based on their body weight at OLE baseline, for approximately 96 weeks (4 doses in total). Mandatory methylprednisolone (or equivalent) and antihistaminic drug (e.g., diphenhydramine or equivalent) will be administered approximately 30-60 minutes prior to the start of each ocrelizumab infusion.
    Interventions:
    • Drug: Ocrelizumab
    • Drug: Antihistamine
    • Drug: Methylprednisolone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 9, 2020)
699
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 8, 2028
Estimated Primary Completion Date February 23, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of primary progressive multiple sclerosis (PPMS).
  • Expanded disability status scale (EDSS) score at screening and baseline, from 3 to 6.5 inclusive.
  • Score of >/= to 2.0 on the Functional Systems scale for the pyramidal system that was due to lower extremity findings.
  • Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization.
  • Participants must be neurologically stable for at least 30 days prior to randomization and baseline.
  • Disease duration from the onset of MS symptoms, less than 15 years in participants with an EDSS score at screening >5.0, less than 10 years in participants with an EDSS score at screening </=5.0.
  • Documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands.
  • For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods.
  • For female participants without reproductive potential, may be enrolled if post-menopausal unless receiving a hormonal therapy for her menopause or if surgically sterile.

Exclusion Criteria:

  • History of relapsing remitting or secondary progressive MS at screening.
  • Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening.
  • History of confirmed or suspected progressive multifocal leukoencephalopathy.
  • History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening.
  • Immunocompromised state.
  • Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization.
  • Inability to complete an MRI or contraindication to gadolinium administration.
  • Contraindications to mandatory pre-medications for IRRs.
  • Known presence of other neurologic disorders.
  • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study.
  • Significant, uncontrolled disease that may preclude participant from participating in the study.
  • History of or currently active primary or secondary, non-drug-related, immunodeficiency.
  • Pregnant or breastfeeding or intending to become pregnant.
  • Lack of peripheral venous access.
  • History of alcohol or other drug abuse within 12 months prior to screening.
  • Treatment with any investigational agent or treatment with any experimental procedure for MS.
  • Previous use of anti-CD20s if in the last 2 years before screening, or if B-cell count is not normal, or if treatment was stopped due to safety reasons or lack of efficacy.
  • Previous use of mitoxantrone, cladribine, atacicept, and alemtuzumab.
  • Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label.
  • If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication.
  • Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation.
  • Any previous history of transplantation or anti-rejection therapy.
  • Treatment with intravenous (IV) immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization.
  • Systemic corticosteroid therapy within 4 weeks prior to screening.
  • Positive screening tests for active, latent, or inadequately treated hepatitis B
  • Sensitivity or intolerance to any ingredient of ocrelizumab.
  • Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: BN42083 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) Global-Roche-Genentech-Trials@gene.com
Listed Location Countries  ICMJE Argentina,   Belgium,   Brazil,   Canada,   Czechia,   Denmark,   France,   Germany,   Greece,   Hungary,   Italy,   Mexico,   Peru,   Poland,   Portugal,   Russian Federation,   Spain,   Switzerland,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04548999
Other Study ID Numbers  ICMJE BN42083
2020-000894-26 ( 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  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP