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 Relapsing Multiple Sclerosis
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 864
- 试验地点
- 203
- 主要终点
- Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12)
研究概览
简要总结
This is a randomized, double-blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and PK of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks (Q24W) in participants with RMS, in comparison to the approved 600 milligrams (mg) dose of ocrelizumab.
详细描述
Participants will be treated for a minimum of 120 weeks in the double-blind treatment (DBT) phase. Upon positive primary results after the DBT phase, an optional higher dose extension treatment, open-label extension (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 low level 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 LLN.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of RMS
- •At least two documented clinical relapses within the last 2 years prior to screening, or one clinical relapse in the year prior to screening. No relapse 30 days prior to screening and at baseline
- •Participants must be neurologically stable for at least 30 days prior to randomization and baseline
- •EDSS score, at screening and baseline, from 0 to 5.5 inclusive
- •Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
- •Average 9HPT score over four trials at screening and over four trials at baseline respectively, up to 250 (inclusive) seconds
- •Documented magnetic resonance imaging (MRI) of brain with abnormalities consistent with MS at screening
- •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
- •Females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods
- •Female participants without reproductive potential may be enrolled e.g. if post-menopausal or if surgically sterile
排除标准
- •History of primary 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 infusion-related reaction (IRRs)
- •Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
- •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 within 24 weeks prior to screening or treatment with any experimental procedure for MS
- •Previous use of anti- cluster of differentiation 20 (CD20s) (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy
- •Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
- •Previous treatment with natalizumab within 4.5 months of baseline
- •Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
- •Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab - 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 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 (including excipients) of ocrelizumab
- •Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above
研究组 & 干预措施
Ocrelizumab Higher Dose
Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight <75 kilograms [kg]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional 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.
干预措施: Methylprednisolone (Drug)
Ocrelizumab Approved Dose
Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W 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.
干预措施: Methylprednisolone (Drug)
Ocrelizumab Higher Dose
Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight <75 kilograms [kg]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional 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.
干预措施: Ocrelizumab (Drug)
Ocrelizumab Approved Dose
Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W 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.
干预措施: Antihistamine (Drug)
Ocrelizumab Approved Dose
Participants will be randomized to receive a minimum of 5 treatment doses of 600 mg ocrelizumab administered by IV infusion Q24W 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.
干预措施: Ocrelizumab (Drug)
Ocrelizumab Higher Dose
Participants will be randomized to receive a minimum of 5 higher treatment doses based on their body weight at baseline: 1200 mg (participant's body weight <75 kilograms [kg]) or 1800 mg (participant's body weight ≥ 75 kg) of ocrelizumab administered by IV infusion Q24W in the DBT phase. During the optional 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.
干预措施: Antihistamine (Drug)
结局指标
主要结局
Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12)
时间窗: Up to approximately 4 years
Time to onset of 12-week cCDP=first occurrence of a 12-week cCDP according to at least 1 of the 3 criteria: 1) CDP=12-week confirmed increase (CI) from baseline (FB) in expanded disability status scale (EDSS) score of ≥1.0 point in participants with baseline EDSS score of ≤5.5 or 12-week CI≥0.5 point in participants with baseline EDSS score of \>5.5 OR 2) 12-week CI of ≥20% FB in Timed 25-foot Walk Test (T25FWT) score OR 3)12-week CI of ≥ 20% FB in 9-hole Peg Test (9-HPT) score. EDSS = disability scale that ranges in 0.5-point steps from 0 \[normal\]-10.0 \[death\]. In T25FWT test participants walked to a 25 foot course as quickly \& safely as possible. Score = average of 2 completed trials (in seconds). In 9-HPT, participants had to place \& remove pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the amount of time (in seconds) required was recorded. In T25FWT \& 9-HPT the longer it took complete test= higher scores, indicating deterioration.
次要结局
- Time to Onset of 24-week cCDP (cCDP24)(Up to approximately 4 years)
- Time to Onset of 48-week cCDP (cCDP48)(Up to approximately 4 years)
- Time to Onset of cCDP12 Independent of Protocol-defined Relapses (PDR) or Progression Independent of Relapse Activity (PIRA)(Up to approximately 4 years)
- Time to Onset of 12-week Confirmed Disability Progression (CDP12)(Up to approximately 4 years)
- Time to ≥ 20% Increase in 12-week Confirmed T25FWT(Up to approximately 4 years)
- Annual Rate of Percent Change From Baseline in Total Brain Volume(Up to approximately 4 years)
- Time to Onset of 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT)(Up to approximately 4 years)
- Time to Onset of 24-week Confirmed 8-point Increase in 12-item Multiple Sclerosis Walking Scale (MSWS-12)(Up to approximately 4 years)
- Fold Change From Baseline in Neurofilament Light (NfL) Chain at Week 48 for Participants Assigned to the Higher Dose Ocrelizumab Group(Week 48)
- Fold Change From Baseline in NfL Chain at Week 48 for Participants Assigned to the Approved Dose Ocrelizumab Group(Week 48)
- Number of Participants With Adverse Events (AEs)(From initiation of study drug up to approximately 4 years)
- Area Under the Serum Concentration-Time Curve (AUC) of Ocrelizumab Over the First Dosing Interval(Day 1 to Week 24)
- B-cell Levels in Blood(Baseline, Weeks 2, 24, 48, 72, 96, 120, 144, 168, and 192)
- Percent Change From Baseline in B-cell Levels(Weeks 2, 24, 48, 72, 96, 120, 144, 168, and 192)
- Percentage of Participants Who Achieved ≤ 5 B-cells/μL of Blood(Baseline, Weeks 2, 24, 48, 72, 96, 120, 144, 168, and 192)
- Percentage of Participants With Anti-drug Antibodies (ADAs) to Ocrelizumab(Baseline up to approximately 4 years)