This study has been transitioned to CTIS with ID 2023-506516-40-00 check the CTIS register for the current data. The primary efficacy objective for this study is to demonstrate non-inferiority of ocrelizumab compared with fingolimod
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
primary endpoint to primary objective is:
• Protocol-defined annualized relapse rate (ARR)
The comparison of interest is the difference of protocol-defined ARR, as
measured through the rate ratio in counts during the double-blind period. The
primary comparison will be made in the hypothetical situation that patients do
not withdraw from the study treatment.
Secondary outcome
secondary endpoints to secondary objectives are:
- Number of new or enlarging T2-hyperintense lesions (T2 lesions) as detected
by brain MRI during the double-blind period
- Protocol-defined ARR by Week 96
- Number of T1 Gd lesions at Week 12
- Number of new or enlarging T2 lesions during the double-blind period
- Protocol-defined ARR during the double-blind period
All comparisons will be made in the hypothetical situation that patients do not
withdraw from the study treatment.
exploratory endpoints to exploratory objectives are:
• Time to the first relapse (Kaplan-Meier proportion of relapse-free patients)
• Time to the first new or enlarging T2 lesions (Kaplan-Meier proportion of
patients free of new or enlarging T2 lesions)
• Change in total T2 lesion volume from baseline to Weeks 24, 48 and 96
• Change in total T1-hypointense lesion (T1 lesion) volume from baseline to
Weeks 24, 48, and 96
• Change in the Symbol Digit Modalities Test (SDMT) from baseline to Weeks 48
and 96
• Time to 24-week confirmed 4-point worsening in the SDMT
• Annual rate of change from baseline in the EDSS during the double-blind
period
• Time to confirmed disability progression over the treatment period, defined
as an increase of * 1.0 point from baseline EDSS when the baseline score is *
5.5. EDSS will be confirmed at a regular scheduled visit at least 12 weeks or
24 weeks after the initial documentation of neurological worsening.
• Change in patient- and caregiver-reported Pediatric Quality of Life
Inventory* (PedsQL*) Generic Core Scale, Version 4.0, from baseline to Weeks 48
and 96
• Change in patient-reported fatigue, as measured by the PedsQL
Multidimensional Fatigue Scale (domain scores and total score) from baseline to
Week 48 and 96
• Change in EQ-5D-5L from baseline to Weeks 48 and 96
• Patient Global Impression of Change (PGIC) for fatigue, cognition, and
overall MS symptoms at Weeks 48 and 96
• Caregiver Global Impression of Change (CaGI-C) for fatigue, cognition, and
overall MS symptoms at Weeks 48 and 96
• Change in MS symptom severity and impact assessed by patient and caregiver
interviews at Weeks 48 and 96
SAFETY OBJECTIVES
Endpoints are:
• Incidence and severity of adverse events, with severity determined according
to National Cancer Institute Common Terminology Criteria for Adverse Events,
Version 5.0 (NCI CTCAE v5.0)
• Change from baseline in targeted vital signs and clinical significant
abnormalities in ECG following study treatment administration
• Change from baseline in targeted clinical laboratory test results
PHARMACOKINETIC AND PHARMACODYNAMIC OBJECTIVES
Endpoints are:
• Assess the pharmacokinetics of ocrelizumab in all children/adolescents
enrolled in this study
• Assess the pharmacodynamics in all children/adolescents enrolled in this
study, as measured by blood B-cell count
IMMUNOGENICITY OBJECTIVE
• Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs
during the study
The relationship between ADA status and pharmacokinetics, pharmacodynamics,
efficacy, and safety may also be explored.
BIOMARKER OBJECTIVE
Endpoints are:
• Level of neurofilament light (NfL) before and after ocrelizumab dosing at
indicated timepoints
• Relationship between biomarkers in serum and efficacy, safety, PK,
immunogenicity, or other biomarker endpoints
Background summary
Preventing the accrual of irreversible neurological impairment is a key goal of
MS therapy. It is particularly important in pediatric patients where the onset
of the disease is much earlier and patients reach higher EDSS milestones at a
younger age than in adult onset MS. Subclinical inflammatory activity and
neurodegenerative changes occur early and persist throughout the course of
RMS. Left untreated or undertreated, over time both clinically apparent and
subclinical disease activity result in CNS tissue damage, disability accrual,
and diminishing quality of life.
See protocol section 1.3 for the complete study rationale.
Study objective
This study has been transitioned to CTIS with ID 2023-506516-40-00 check the CTIS register for the current data.
The primary efficacy objective for this study is to demonstrate non-inferiority
of ocrelizumab compared with fingolimod
Study design
Description of Study
This Phase III randomized, double-blind, double-dummy, multicenter study will
evaluate the safety and efficacy of ocrelizumab administered by IV infusion
every 24 weeks compared with fingolimod taken PO QD, in children and
adolescents with RRMS aged >= 10 and < 18 years.
This study consists of the following study periods: a screening period, a
double-blind period, an optional OLE period, and a safety follow-up (SFU)
period. The study duration will vary for each patient.
Patients will be treated in the double-blind period for at least 96 weeks,
representing a minimum of four 24-week treatment cycles.
The study plans to enroll 171 patients in a 1:1 randomization
(ocrelizumab:fingolimod), globally. Randomization will be performed through an
interactive voice and web-based response system (IxRS) and will be stratified
by region (United States vs. rest of world [ROW]), pre-pubertal status (yes vs.
no), and presence of T1 Gd lesions at baseline (yes vs. no).
Patients with a body weight >= 40 kg will receive ocrelizumab or ocrelizumab
placebo 600 mg by IV infusion every 24 weeks and fingolimod placebo or
fingolimod PO QD. Patients with a body weight < 40 kg will only be enrolled in
this study once the data from the ongoing Phase II Study WA39085 allows
selection of an ocrelizumab dose in this patient subgroup.
An independent Data Monitoring Committee (iDMC) will be employed to monitor and
evaluate safety data throughout the study, until the primary analysis is
completed.
Intervention
Group A gets ocrelizumab, which is given every 6 months by infusion (a fluid
given slowly in your vein in your arm). The first dose is given as two
infusions of half the dose of ocrelizumab on Days 1 and 15, and following doses
are given as one infusion of ocrelizumab every 6 months.
Group B gets fingolimod, which is a capsule you take by mouth once every day at
home. On the first treatment day you will take the capsule at the hospital. The
capsule should be taken at about the same time each day (for example, at 8:00
every morning).
Whichever group the patient is in they will also take a dummy of the other type
of drug. This is called a placebo, that looks like the other drug, but it does
not contain any active ingredient.
Before every infusion of ocrelizumab (or placebo), the patient will receive
extra medicines (called premedications) to help avoid a reaction to the study
drug infusion.
Study burden and risks
The side effects associated with Ocrelizumab
The following side effects are very common (occurs in more than 10 out of 100
patients):
- Infusion related reactions (for example, itching of the skin, rash, throat
irritation or pain, flushing (reddening of the skin), headache, fever, hives,
chills, fatigue, nausea, vomiting, abnormally low blood pressure, rigors
(sudden feeling of being cold with shivers)
- Upper respiratory tract infections (common cold, sinus infection, inflamed
tonsils, sore throat)
- Influenza (flu)
- Decrease of blood antibody type M
The following side effects are common (occurs in 1-10 out of 100 patients):
- Sinus infection (sinusitis)
- Inflammation of the bronchial tubes leading to the lungs, causing coughing
(bronchitis)
- Inflammation of intestines causing diarrhea, vomiting, stomach pain, fever
(gastroenteritis)
- Cough
- Mucus in nose or throat (catarrh)
- Cold sore (oral herpes)
- Respiratory tract infection (common cold, sinus infection, inflamed tonsils,
sore throat, inflammation of the bronchial tubes leading to the lungs causing
coughing, inflammation of the lung)
- Viral infection
- Shingles or painful skin rash with blisters (herpes zoster)
- Eye infection or inflammation (conjunctivitis)
- Skin infection (cellulitis)
- Decrease of blood antibody type G
The following side effects are less common but important (occurs in fewer than
1 out of 100 patients):
- Serious infections related to decrease in blood antibodies
The following side effects are with unknown frequency:
- Delayed return of certain white blood cells (B cells) in your blood
- Decreased effectiveness of certain vaccines (due to lowering the number of B
cells)
- Allergic reactions
- Progressive multifocal leukoencephalopathy (PML), which is a very rare and
severe viral infection caused by the John Cunningham (JC) virus
- Increased risk of cancer (malignancy), including breast cancer
- Low levels of neutrophils (another type of white blood cells)
Ocrelizumab can also have side effects that we do not know about at the moment.
The side effects associated with Fingolimod
Fingolimod can also have side effects. The most important ones are:
- Bradyarrhythmia at the time of the first dose (short-term decrease in heart
rate usually without symptoms or mild to moderate symptoms of hypotension [low
blood pressure], dizziness, fatigue or palpitations)
- Infections (such as influenza, sinusitis)
- Leucopenia and lymphopenia (decrease in white blood cells and/or a subgroup
of white blood cells)
- Mood disorders (such as depression and anxiety)
- Blurred vision
- Macular edema (swelling of a yellow central area of the retina with or
without visual symptoms, symptoms include "blurred vision"*changes in the
eyesight, a lack of sharpness of vision)
- Increase of liver enzymes and bilirubin indicating a change to how the liver
is working
Grenzacherstrasse 124
Basel 4070
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Grenzacherstrasse 124
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Listed location countries
Age
Inclusion criteria
Patients must meet the following criteria for study entry:
• Informed consent for study participation signed by the parents or a legal
guardian, with patient assent obtained verbally and when possible, in writing,
from all pediatric patients old enough to fully comprehend the assent document
prior to any study-specific screening procedures, as per local requirements
• Able to comply with the study protocol, in the investigator's judgment
Patients who are unable to complete exploratory assessments (e.g., SDMT or
questionnaires) due to physical/disease limitations will not be excluded from
the study.
• Age between >= 10 to <18 years at randomization
• Body weight >= 25 kg
• Children and adolescents must have received all childhood vaccinations as per
local and/or national recommendations for childhood vaccination against
infectious diseases.
Patients negative for serological testing for varicella zoster will have the
full course of the vaccine for chickenpox completed before study start, except
patients who have already received the full course of the vaccine for
chickenpox, depending on local regulations.
• For female patients of childbearing potential: agreement to remain abstinent
(refrain from heterosexual intercourse) or use contraception, as defined below:
Female patients must remain abstinent or use two methods of contraception,
including at least one method with a failure rate of < 1% per year, during the
treatment period and for at least 24 weeks after the final dose of
ocrelizumab/ocrelizumab placebo and for 2 months after the final dose of
fingolimod/fingolimod placebo. Adherence to local requirement, if more
stringent, is required.
A female is considered to be of childbearing potential if she is postmenarcheal
and is not permanently infertile due to surgery (i.e., removal of ovaries,
fallopian tubes, and/or uterus) or another cause as determined by the
investigator (e.g., Müllerian agenesis). The definition of childbearing
potential may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of < 1% per year include
the following:
o Established hormonal contraception: combined (estrogen and progestogen
containing) hormonal contraception associated with inhibition of ovulation
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception
associated with inhibition of ovulation (oral, injectable, implantable)
o Intrauterine devices: intrauterine device, intrauterine hormone-releasing
system, and copper intrauterine device
A barrier method may be used as the second contraceptive method, such as the
following:
o A male or female condom with or without spermicide
o A cap, diaphragm, or sponge with spermicide
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception. If required per local guidelines or regulations, locally
recognized acceptable methods of contraception and information about the
reliability of abstinence will be described in the local Informed Consent Form.
Inclusion Criteria Related to Pediatric Multiple Sclerosis
Patients must meet the following criteria related to pediatric MS for study
entry:
• Diagnosis of RRMS in accordance with the International Pediatric Multiple
Sclerosis Study Group (IPMSSG) criteria for pediatric MS, Version 2012, or
McDonald criteria 2017 (or the most current revision of the IPMSSG criteria or
McDonald criteria at the time of study start)
Note: For the purpose of consistency, the same diagnostic criteria will be
used during the recruitment period regardless of revisions to the diagnostic
criteria.
• Confirmation of the diagnosis of Pediatric RRMS by the Independent Pediatric
MS Review Committee prior to randomization
• EDSS at screening: 0-5.5, both inclusive
• At least one relapse during the year prior to screening or two relapses in
the previous two years prior to screening or evidence of at least one Gd
enhancing lesion on MRI within 6 months prior to randomization (including
screening MRI)
Note: A relapse or an attack is a monophasic clinical episode with patient
reported symptoms and objective findings typical of multiple sclerosis,
reflecting a focal or multifocal inflammatory demyelinating event in the CNS,
developing acutely or subacutely, with duration of at least 24 hours, with or
without recovery, and in the absence of fever or infection. *Attack,*
*relapse,* and *exacerbation* are synonyms (Thompson et al. 2018).
Note: If a new MRI is required for re-screening, a new or enlarging T2 lesion
compared to the previous screening MRI is sufficient to fulfill the inclusion
criteria of recent disease activity even without gadolinium enhancement,
provided that both MRIs are done within 6 months prior to randomization.
Exclusion criteria
While participating in this study, patients are not allowed to take part in
other investigational research projects involving administration of any drug or
substance or involving any procedure that would place patients at risk or could
jeopardize this study results.
Exclusions Related to General Health
Patients who meet any of the following criteria related to general health will
be excluded from study entry:
• Pregnancy or lactation
• Known presence or suspicion (based on clinical or laboratory parameters) of
other neurologic disorders that may mimic MS, including, but not limited to,
acute disseminated encephalomyelitis (ADEM), neuromyelitis optica or
neuromyelitis optica spectrum disorders; and any neurological (other than MS),
somatic, or metabolic condition that could interfere with brain function or
normal cognitive or neurological development
In case of an ADEM like appearance of the first MS relapse, a second relapse
with clear MS like features is required.
• Patients that are aquaporin-4 positive and/or myelin oligodendrocyte
glycoprotein antibody positive at screening
• Clinical or laboratory findings at first presentation not typically for MS,
such as signs of infection; signs of encephalopathy such as confusion,
convulsion, reduced state of consciousness.
• Abnormal findings in the cerebrospinal fluid (CSF) at first MS presentation.
Protein * 100 mg/dL. Pleocytosis * 50 cells/mm3. Presence of neutrophils or
eosinophils above the normal reference range per local laboratory, or atypical
cells.
Note: CSF sampling is not mandated at screening and may be performed at
investigator discretion to confirm diagnosis of pediatric RRMS.
• Atypical MRI findings: ADEM like presentation of lesions; lesions in
atypical location for MS; bilateral optic neuritis; extensive spinal cord
lesions (* 3 spinal segments)
• Significant uncontrolled somatic diseases or any other significant condition
that may preclude patient from participating in the study
• Known active bacterial, viral, fungal, mycobacterial infection, or other
infection, excluding fungal infection of nail beds
• Infection requiring hospitalization or treatment with IV anti-infective
agents within 4 weeks prior to Day 1 visit or oral anti-infective agents within
2 weeks prior to Day 1 visit
• History or known presence of recurrent or chronic infection (e.g., HIV,
syphilis, tuberculosis)
• Receipt of any type of vaccine (e.g. live, live-attenuated vaccine, non-live)
within 6 weeks prior to treatment allocation. The patient's vaccination record
and a need for immunization should be carefully reviewed (scheduled
vaccinations should be completed at least 6 weeks prior to receiving
ocrelizumab, as per local guidelines).
• History or laboratory (local laboratory test) evidence of clinically
significant coagulation disorders (e.g., any coagulation disorder requiring
medical treatment).
• Peripheral venous access that precludes IV administration and venous blood
sampling as required per study protocol
• Inability to complete an MRI scan (e.g., due to weight, claustrophobia,
hypersensitivity to gadolinium, cochlear implants, presence of foreign
substances in the eye, or intracranial vascular clips)
• Teeth braces interfering with MRI acquisition
• History of cancer, including solid tumors, hematologic malignancies, and
carcinoma in situ (except basal cell and squamous cell carcinoma of the skin
that have been excised and cured)
• Currently active alcohol or drug abuse or history of alcohol or drug abuse
Exclusion Criteria Related to General Health Specific to Fingolimod Treatment
Patients who meet any of the following criteria related to general health
specific to fingolimod treatment will be excluded from study entry (for more
information also refer to the prescribing information):
• History of symptomatic bradycardia, recurrent syncope, significant QT
prolongation (corrected QT interval [QTc] * 460 msec [pediatric female] or *
450 msec [pediatric male]), patients having risk factors for QT prolongation
such as hypokalemia or congenital QT prolongation, and uncontrolled hypertension
• Patients who in the previous 6 months had myocardial infarction, unstable
angina pectoris, stroke/transient ischemic attack, decompensated heart failure
(requiring inpatient treatment), or New York Heart Association Class III/IV
heart failure
• Patients with severe cardiac arrhythmias requiring anti-arrhythmic treatment
with Class Ia or Class III anti-arrhythmic medicinal products.
• Patients with second-degree Mobitz type II atrioventricular (AV) block or
third*degree AV block, sick-sinus syndrome, or sinoatrial heart block
• Patients with a baseline QTc interval * 500 msec
• Presence of macular edema
• Presence of any pulmonary conditions, as determined by the investigator,
including severe asthma defined as per the 2010 World Health Organization
uniform definition on severe asthma (Bousquet et al. 2010)
• History of any type of epileptic seizure(s) as well as psychogenic
non-epileptic seizure(s) during the past 12 months before screening
• Patients with any of the following hepatic conditions
* Chronic liver or biliary disease, acute or chronic pancreatitis, with the
exception of Gilbert*s syndrome
* Liver enzymes, as per criteria in the exclusion criteria related to
laboratory findings
Exclusion Criteria Related to Medications
Patients who meet any of the following criteria related to medications will be
excluded from study entry:
• History of a severe allergic or anaphylactic reaction to humanized or murine
MAbs or known hypersensitivity to any component of ocrelizumab solution
• Contraindications to or intolerance of oral or IV corticosteroids,
antihistamines, or antipyretics according to the country label, including the
following:
* Psychosis not well controlled by a treatment
* Hypersensitivity to any of the constituents
• Treatment with any investigational agent within 24 weeks of screening or 5
half-lives, whichever is longer (or longer if indicated by the PD action of the
drug)
• Previous treatment with B-cell*targeted therapies (i.e., rituximab,
ocrelizumab, obinutuzumab, atacicept, belimumab, or ofatumumab)
• Any previous treatment with alemtuzumab, anti-CD4, cladribine, mitoxantrone,
daclizumab, laquinimod, total body irradiation, or bone marrow transplantation
• Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil,
cyclosporine, or methotrexate within 24 months prior to treatment allocation
• Treatment with natalizumab within 12 months prior to randomization
• Treatment with teriflunomide within 24 weeks prior to treatment allocation or
4 weeks prior to treatment allocation if an accelerated elimination procedure
is completed (with confirmation of drug plasma level of < 0.02mg/ml)
• Previous treatment with fingolimod
• Treatment with any other S1P receptor modulator (e.g., BAF312/siponimod)
within 24 weeks prior to treatment allocation
• Treatment with dimethyl fumarate within 4 weeks prior to treatment allocation
and lymphocyte count * lower limit of normal (LLN) for age- and sex-specific
reference range
• Treatment with intravenous immunoglobulin within 12 weeks prior to treatment
allocation
• Treatment with plasmapheresis within 4 weeks prior to treatment allocation
• Completion of systemic corticosteroid therapy within 30 days prior to
screening MRI scan
Exclusion Criteria Related to Medications Specific to Fingolimod Treatment
Patients who meet any of the following criteria related to medications specific
to fingolimod treatment will be excluded from study entry (for more information
also refer to the prescribing information
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-506516-40-00 |
| EudraCT | EUCTR2020-004128-41-NL |
| CCMO | NL78016.028.21 |