Relapsing-remitting Multiple Sclerosis
Conditions
Keywords
pediatric Multiple Sclerosis, pediatric MS, children MS, children Multiple Sclerosis, pediatric ocrelizumab
Brief summary
This double-blind, double-dummy study will evaluate the safety and efficacy of ocrelizumab compared with fingolimod in children and adolescents with RRMS aged between 10 and \< 18 years over a flexible duration. The double-blind period will last until after the last participant randomized has completed 24 weeks.
Detailed description
This Phase III randomized, double-blind, double-dummy, multicenter study will evaluate the safety and efficacy of ocrelizumab administered as intravenous (IV) infusion every 24 weeks (Q24W) compared with fingolimod taken orally (PO), once daily (QD), in children and adolescents with RRMS aged between 10 and \< 18 years. Participants will be randomized in a 1:1 ratio (ocrelizumab:fingolimod), globally. This study consists of a double-blind, double dummy period in which participants will be treated with either active ocrelizumab or active fingolimod for a flexible duration. Participants who complete the double-blind period will be offered the possibility to enter an optional open-label extension (OLE) treatment period of at least 144 weeks with ocrelizumab.
Interventions
DRUGOcrelizumab
Ocrelizumab, 300 milligrams (mg) will be administered as IV infusion to participants who weigh \< 35 kilograms (kg), and ocrelizumab 600 mg, IV will be administered to participants who weigh ≥ 35 kg on Days 1 and 15 (half the dose, 2 weeks apart), and Q24W thereafter.
OTHEROcrelizumab Placebo
Ocrelizumab matching placebo will be administered as IV infusion on Day 1 and Day 15, and Q24W thereafter.
DRUGFingolimod
Fingolimod will be administered QD as a capsule per the prescribing information (0.25 mg to participants who weigh ≤ 40 kg and 0.5 mg to participants who weigh \> 40 kg).
OTHERFingolimod Placebo
Fingolimod matching placebo will be administered QD as a capsule.
Sponsors
Hoffmann-La Roche
PPD Development, LP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Body weight ≥ 25 kg * Diagnosis of RRMS in accordance with the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for pediatric multiple sclerosis (MS), Version 2012, or McDonald criteria 2017 * Expanded Disability Status Scale (EDSS) at screening: 0-5.5, inclusive * For all countries except Germany, at least one MS relapse during the previous year or two MS relapses in the previous 2 years or evidence of at least one Gd-enhancing lesion on MRI within 6 months prior to randomization Inclusion Criteria for Optional OLE Period: -Participants in Group A (ocrelizumab in the DBP) and Group B (fingolimod in the DBP) who, in the opinion of the investigator, may benefit from switching to ocrelizumab and who have completed the DBP with study treatment (ocrelizumab/fingolimod), may participate in the OLE period
Exclusion criteria
* Known presence or suspicion of other neurologic disorders that may mimic MS * Significant uncontrolled somatic diseases, known active infection or any other significant condition that may preclude participant from participating in the study * Participants with severe cardiac disease or significant findings on the screening electrocardiograph (ECG)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Protocol-defined Annualized Relapse Rate (ARR) | Up to after the last participant randomized completed 24 weeks since first study treatment administration (up to approximately 160 weeks) | The population-level summary is rate ratio of ARR. The ARR is calculated as the total number of protocol-defined relapses divided by the total patient-years. Protocol-defined relapse is the occurrence of new/worsening neurological symptoms attributable to multiple sclerosis (MS) and immediately preceded by relatively stable or improving neurological state for ≥ 30 days. Symptoms must persist for \>24 hours \& should not be attributable to confounding clinical factors. The new/worsening neurological symptoms must be accompanied by objective neurological worsening consistent with an increase of at least half a step on the expanded disability status scale (EDSS) score, or 2 points on one of the appropriate functional system (FS) scores, or 1 point on two or more of the appropriate FS scores. The change must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory, or visual). Adjusted values were reported. OM assessed non inferiority of ocrelizumab vs fingolimod. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Protocol-defined ARR | Up to after the last participant randomized completed 24 weeks since first study treatment administration (up to approximately 160 weeks) | The population-level summary is rate ratio of ARR. The ARR is calculated as the total number of protocol-defined relapses divided by the total patient-years. Protocol-defined relapse is the occurrence of new/worsening neurological symptoms attributable to multiple sclerosis (MS) and immediately preceded by relatively stable or improving neurological state for ≥ 30 days. Symptoms must persist for \>24 hours \& should not be attributable to confounding clinical factors. The new/worsening neurological symptoms must be accompanied by objective neurological worsening consistent with an increase of at least half a step on the expanded disability status scale (EDSS) score, or 2 points on one of the appropriate functional system (FS) scores, or 1 point on two or more of the appropriate FS scores. The change must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory, or visual). Adjusted values were reported. OM assessed non superiority of ocrelizumab vs fingolimod. |
| Number of New or Enlarging T2-hyperintense Lesions (T2 Lesions), as Detected by Brain Magnetic Resonance Imaging (MRI) | Up to after the last participant randomized completed 24 weeks since first study treatment administration (up to approximately 160 weeks) | Number of new or enlarging T2 lesions for each participant was calculated as the sum of the individual number of new or enlarging T2 lesions as detected by brain MRI. |
| Number of T1 Gd Lesions at Week 12 | At Week 12 | Brain MRI with and without a Gd-contrast agent were performed to assess the number of Gd lesions. |
| Number of Participants With Adverse Events (AEs) | Up to approximately 7 years | An AE was defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Maximum Serum Concentration (Cmax) of Ocrelizumab | Cycle (1 Cycle=24 weeks) | — |
| Area Under the Plasma Concentration-time Curve Over a Dosing Interval (AUC Tau) of Ocrelizumab | Cycle 1 (1 Cycle=24 weeks) | — |
| Number of Participants With Anti-drug Antibodies (ADAs) to Ocrelizumab | Up to approximately 7 years | Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (treatment-enhanced ADA response). The total number of participants who developed ADAs to atezolizumab was determined by summing the ADA-positive participants across all timepoints. |
| Levels of Cluster of Differentiation 19 (CD19) + B-cell Count in Blood | Up to approximately 7 years | CD19+ B-cell count in blood will be assessed using flow cytometry. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Estonia, France, Germany, Greece, Hungary, India, Italy, Latvia, Mexico, Morocco, Poland, Portugal, Romania, Serbia, Spain, Switzerland, Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 187 participants with relapsing-remitting multiple sclerosis (RRMS) took part in the study at 79 investigative sites across 25 countries.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either ocrelizumab + fingolimod placebo or fingolimod + ocrelizumab placebo. The study is still ongoing.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 15.0 years STANDARD_DEVIATION 1.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 38 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 20 Participants |
| Race (NIH/OMB) White | 123 Participants |
| Sex: Female, Male Female | 129 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 93 | 0 / 92 |
| other Total, other adverse events | 76 / 93 | 65 / 92 |
| serious Total, serious adverse events | 6 / 93 | 8 / 92 |
Outcome results
None listed