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    Summary
    EudraCT Number:2021-000062-14
    Sponsor's Protocol Code Number:MN42988
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-08-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2021-000062-14
    A.3Full title of the trial
    A PHASE IV MULTICENTER, OPEN-LABEL STUDY EVALUATING B CELL LEVELS IN INFANTS POTENTIALLY EXPOSED TO OCRELIZUMAB DURING PREGNANCY – THE MINORE STUDY
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate B Cell Levels in Infants Potentially Exposed to Ocrelizumab During Pregnancy - The Minore Study
    A.4.1Sponsor's protocol code numberMN42988
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ocrevus
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOcrelizumab
    D.3.9.1CAS number 637334-45-3
    D.3.9.2Current sponsor codeRO4964913
    D.3.9.3Other descriptive nameOCRELIZUMAB
    D.3.9.4EV Substance CodeSUB121707
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typehumanized monoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Sclerosis (MS) or Clinically Isolated Syndrome (CIS) [in line with the locally approved indications]
    E.1.1.1Medical condition in easily understood language
    MS is a chronic disease in which the immune system attacks the insulation and support around the nerve cells in the brain, spinal cord and optic nerves, causing inflammation and consequent damage.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10071068
    E.1.2Term Clinically isolated syndrome
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate whether infants potentially exposed to ocrelizumab during pregnancy present with postpartum B cell depletion
    E.2.2Secondary objectives of the trial
    • To evaluate B cell levels in infants potentially exposed to ocrelizumab during pregnancy
    • To evaluate whether there is placental transfer of ocrelizumab from the mother to the infant
    • To evaluate whether infants potentially exposed to ocrelizumab during pregnancy are able to mount humoral immune responses to clinically relevant vaccines
    • To evaluate the levels of ocrelizumab in the mother during pregnancy
    • To evaluate the safety of ocrelizumab in the mother, and the safety of infants potentially exposed to ocrelizumab
    • To evaluate pregnancy and neonatal outcomes
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • An informed consent form (ICF) for participation of the maternal subject and her unborn (for collection of blood samples, infant demographics and AE data) is signed and dated by the subject. Where applicable, the written ICF with respect to the infant is also signed and dated by the holder of parental rights as designated by the maternal subject
    • Able and willing to comply with the study protocol, in the Investigator’s judgment
    • Age 18-40 years, inclusive, at screening
    • Have a diagnosis of MS or CIS (in line with the locally approved indications)
    • Currently pregnant with singleton pregnancy at gestational week <=30 at enrolment
    • Documentation that first (12-week) and second (18 to 20-week) obstetric ultrasound (prenatal screening) has been conducted before enrolment
    • Documentation that the last exposure to ocrelizumab occurred up to 6 months before the LMP before the woman became pregnant OR during the first trimester of pregnancy (up to gestational week 13 inclusive)
    E.4Principal exclusion criteria
    • Last exposure to ocrelizumab >6 months before the woman’s LMP or later than the first trimester (after gestational week 13)
    • Gestational age at enrolment >30 weeks
    • Non-singleton pregnancy
    • Received last dose of ocrelizumab at a different posology other than per the LPI
    • Social circumstances that may preclude a woman from participating in the study
    Exclusions related to obstetric and gynecological health
    • Lack of access to ultrasound pre-natal care as part of standard clinical practice
    • Women in whom aneuploid disorders or genetic disorders that cause major congenital malformations have been detected during first trimester prenatal screening (e.g.ultrasound, amniocentesis, genetic testing, nuchal translucency screening, chorionic villus sampling),or in whom any fetal anomalies (i.e., fetal biometry, fetal anatomy) have been detected during the morphology scan at around or before gestational week 18-20
    • Documented history of disorders associated with adverse pregnancy outcomes, including but not limited to:
    o History of preterm birth (gestational age <37 weeks) for any indication with or without fetal malformations
    o History of spontaneous abortion (miscarriage) after the 1st trimester (i.e. after gestational week 13)
    o History of stillbirth (defined as fetal loss after gestational week 22)
    o History of pre-eclampsia/eclampsia
    o History of a cervical pathology or intervention which may increase the risk of cervical incompetence (e.g. history of cervical cerclage, prior cervical conization or loop electrosurgical excision procedure)
    • Prior or current history of any other gynecological or obstetric disease considered by the investigator to be associated with a high risk of adverse pregnancy outcomes in the current pregnancy
    Exclusions related to general health
    • Lack of peripheral venous access
    • Pre-pregnancy body mass index >35 kilograms per square meter
    • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
    • Prior or current history of primary or secondary immunodeficiency, or woman in an otherwise severely immunocompromised state. The woman may be re-screened and included if condition resolves significant and uncontrolled disease, such as cardiovascular, pulmonary, neurological, psychiatric, renal, hepatic, endocrine, or gastrointestinal or any other significant disease that may preclude a woman from participating in the study
    • Women with known active malignancies or being actively monitored for recurrence of malignancy including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin). Women with in situ carcinoma of the cervix of the uterus, even if excised and resolved with documented clean margins on pathology, are excluded from the study
    • Prior or current history of alcohol or drug abuse, or current use of tobacco
    Exclusions Related to Laboratory Findings
    • Any abnormal screening laboratory value that is clinically relevant will be retested only once in order to rule out any progressive or uncontrolled underlying condition. The last value before study entry must meet study criteria
    • Women with positive screening tests for hepatitis B, determined by a positive HBsAg result (current infection) or positive HBcAb titers (previous infection) will be excluded. Women with documented history of hepatitis B virus vaccination or positive hepatitis B surface antibody titers are eligible
    Exclusions Related to Medications
    Absolute exclusions
    • Drugs known to have teratogenic effects including but not limited to certain anticonvulsants (even if used for pain management), antibiotics such as tetracyclines or fluoroquinolones
    • Planned treatment with interferons, glatiramer acetate, or pulsed corticosteroids as a bridging therapy after the last ocrelizumab dose before enrolment and throughout pregnancy
    Relative exclusions
    • Treatment with one of the following agents prior to the last ocrelizumab dose or prior to the LMP, whichever occurred first:
    − Treatment with siponimod or ponesimod within 10 days
    − Treatment with mycophenolate within 6 weeks
    − Treatment with fingolimod within 2 months
    − Treatment with ozanimod within 3 months
    − Treatment with alemtuzumab within 4 months
    − Treatment with mitoxantrone, methotrexate, rituximab, ofatumumab or cladribine within 6 months
    − Treatment with cyclophosphamide within 12 months
    • Treatment with natalizumab within 12 weeks prior to the LMP
    • Treatment with teriflunomide within the last 2 years, unless measured plasma concentrations are less than 0.02 mg/L. If levels are above 0.02 mg/L or not known, an accelerated elimination procedure will be implemented before screening visit
    • Treatment with any investigational agent within 6 months or 5 half-lives of the investigational drug (whichever is longer) prior to the last ocrelizumab dose or prior to the LMP whichever occurred first
    E.5 End points
    E.5.1Primary end point(s)
    1. Proportion of infants with B cell levels (CD19+ cells, absolute counts) below the lower limit of normal (LLN), measured at week 6 of life
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. At Week 6 of life
    E.5.2Secondary end point(s)
    1. B cell levels (CD19+ cells, absolute counts and percentage of lymphocytes) measured at week 6 of life
    2. Serum concentration of ocrelizumab in the umbilical cord blood at birth
    3. Serum concentration of ocrelizumab in the infant at week 6 of life
    4. Mean titers of antibody immune response(s) to vaccination to common childhood vaccinations with full or partial doses given prior to 1 year, which may include but not be limited to responses to DTaP, Hib, PCV-13, MMR, and HBV
    5. Proportion of infants with positive humoral response (seroprotective titers; as defined for the individual vaccine) to vaccines
    6. Serum concentration of ocrelizumab in the mother during pregnancy (time frame of blood sampling: Week 24-30, Week 35) and at delivery (time frame of blood sampling: within 24 hours after delivery)
    7. Rate and nature of adverse events (AEs) in the mother throughout the study, including changes in clinical and laboratory results
    8. Rate and nature of AEs in the infant throughout the study, including infections and hospitalizations
    9. Proportion of pregnancies resulting in live births (term and preterm, with and without congenital anomalies), therapeutic abortions, or stillbirths
    10. Infant characteristics at birth, including but not limited to body weight, head circumference and length
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. At Week 6 of life
    2. Within 1 hour after delivery
    3. At Week 6 of life
    4-5. 1 month after the first or second dose of MMR vaccine, or at month 13 of age in case MMR vaccine is not planned to be administered
    6. At Weeks 24-30, Week 35 and within 24 hours after delivery
    7.-8. Throughout the study
    9.-10. At birth
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    exposure effects
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    United States
    France
    Spain
    Switzerland
    Germany
    Italy
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study is defined as the date of the last assessment (vaccine response titers measured 1 month [+ 30 days] after the 1st or 2nd dose of MMR vaccine, or at Month 13 (of age (+ 30 days) if MMR is not planned to be administered for the last infant.
    Total length of study, from screening of the first woman to the end of the study, is expected to be approximately 25 months. This includes an enrollment period of approximately 8 months and subject participation period of approx. 17 months.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 44
    F.1.1.1In Utero Yes
    F.1.1.1.1Number of subjects for this age range: 44
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 44
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    44 in utero/newborns
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 44
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-09-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-25
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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