E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple Sclerosis (MS) or Clinically Isolated Syndrome (CIS) [in line with the locally approved indications] |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071068 |
E.1.2 | Term | Clinically isolated syndrome |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate whether infants of lactating women with CIS or MS receiving ocrelizumab postpartum present with B cell depletion • To evaluate the exposure to ocrelizumab in infants of lactating women with CIS or MS receiving ocrelizumab postpartum
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E.2.2 | Secondary objectives of the trial |
• To evaluate B cell levels in infants of lactating women with CIS or MS receiving ocrelizumab postpartum • To evaluate transfer of ocrelizumab into breastmilk of lactating women with CIS or MS receiving ocrelizumab postpartum • To evaluate the relative and maximum exposure to ocrelizumab in infants of lactating women with CIS or MS receiving ocrelizumab postpartum • To evaluate whether there is transfer of ocrelizumab from the mother to the infant via breastmilk • To evaluate whether infants of lactating women with CIS or MS receiving ocrelizumab postpartum are able to mount humoral immune responses to clinically relevant vaccines • To evaluate the safety of ocrelizumab in lactating women with CIS or MS receiving ocrelizumab postpartum and in their respective infants |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• An Informed Consent Form (ICF) for participation of the maternal subject and her infant (for collection of blood, infant demographic and AE data) is signed and dated by the subject. Where applicable, the written Informed Consent form (ICF) with respect to the infant is also signed and dated by the holder of parental rights as designated by the maternal subject • Woman is able and willing to comply with the study protocol, according to the judgment of the Investigator, in particular: 1] Woman is willing to breastfeed (either exclusively, or with formula supplementation) for at least 60 days after the first postpartum ocrelizumab infusion (this decision is to be taken prior to and independent from study participation) 2] Woman is willing to provide breastmilk samples before and after their first and, if applicable, second postpartum ocrelizumab infusion. Exposure to ocrelizumab includes administration of an initial split dose of two 300 mg infusions (in 250 mL 0.9% sodium chloride) separated by 14 days for women initiating treatment with ocrelizumab, or a single 600 mg infusion (in 500 mL 0.9% sodium chloride) for women already on treatment with ocrelizumab. • Woman is between 18 and 40 years of age at screening • Woman has a diagnosis of MS or CIS (in line with the locally approved indications) • Woman has delivered a healthy term singleton infant (>=37 weeks gestation) • Infant is between 2-24 weeks of age at the time of the mother’s first postpartum dose of ocrelizumab • For women who received commercial ocrelizumab (OCREVUS) before enrolment: documentation that last exposure ocrelizumab occurred more than 3 months before the last menstrual period (LMP) (i.e. excluded a potential fetal exposure) and was given at the approved dose of 2x300 mg or 1x600 mg • Woman agrees to use acceptable contraceptive methods or alternative methods during the study |
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E.4 | Principal exclusion criteria |
Exclusions related to the mother • Hypersensitivity to ocrelizumab or to any of its excipients • Woman received last dose of ocrelizumab <3 months before the LMP or during pregnancy (i.e. there was a potential fetal exposure to ocrelizumab) • Active infections (note: the woman may be included once the infection is treated and is resolved; women with bilateral mastitis infection should not have samples collected until the infection is completely resolved) • Prior or current history of primary or secondary immunodeficiency, or woman in an otherwise severely immunocompromised state. Woman may be re-screened and included if condition resolves • Woman 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 high risk of breast malignancies undergoing prophylactic treatment with drugs such as tamoxifen are excluded • Woman has history of breast implants, breast augmentation, breast reduction surgery or mastectomy • Woman has prior or current history of chronic alcohol abuse or drug abuse • Woman has any medical, obstetrical or psychiatric condition that, in the opinion of the Investigator, would compromise the woman's ability to participate in this study • Treatment with a disease-modifying therapy (DMT) for CIS or MS during pregnancy and/or first weeks postpartum, with the exception of formulations of interferon-beta, glatiramer acetate or pulsed corticosteroids • Drugs known to transfer to the breastmilk and with established or potential deleterious effects for the infant, including but not limited to aspirin (risk of Reye’s syndrome), tetracyclines or fluoroquinolones • Treatment with any investigational agent within 6 months or five half-lives of the investigational drug (whichever is longer) prior to the LMP, unless the investigational agent is ocrelizumab administered >3 months prior to the LMP in the context of a study or registry sponsored by Roche
Exclusions related to the infant • Infant is >24 weeks of age at the time of the mother’s first postpartum dose of ocrelizumab • Infant has any abnormality that may interfere with breastfeeding or milk absorption, including but not limited to cleft palate and/or lip, congenital diaphragmatic hernia and esophageal atresia • Infant has an active infection. Infant may be included once the infection resolves • Infant has any other medical condition or abnormality that, in the opinion of the investigator, could compromise the infant’s ability to participate in this study, including interference with the interpretation of study results • Infant has at least one documented brief resolved unexplained event (BRUE), as defined by the 2016 Guidelines of the American Academy of Pediatrics
Exclusions Related to Laboratory Findings • Mother with any abnormal screening laboratory value that is clinically relevant should 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 • Mother with positive screening tests for hepatitis B, determined by a positive hepatitis B surface antigen (HBsAg) result (current infection) or positive hepatitis B core antibody (HBcAb) titers (previous infection) will be excluded. Women with documented history of hepatitis B virus (HBV) vaccination or positive hepatitis B surface antibody (HBsAb) titers are eligible |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Proportion of infants with B cell levels (CD19+ cells, absolute counts in blood) below the lower limit of normal (LLN), measured at Day 30 days after the mother’s first ocrelizumab postpartum infusion 2. Estimated average oral daily infant dosage (ADID), calculated as the ocrelizumab average milk concentration over 60 days post-ocrelizumab infusion 1 multiplied by an estimated infant milk intake of 150 mL/kg/day
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At 30 days after the mother’s first ocrelizumab postpartum infusion 2. Over 60 days after the mother’s first ocrelizumab postpartum infusion |
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E.5.2 | Secondary end point(s) |
1. B cell levels (CD19+ cells, absolute counts and percentage of lymphocytes) measured at Day 30 after the mother’s first ocrelizumab postpartum infusion 2. Area under the milk concentration-time curve (AUC) of ocrelizumab in mature breastmilk (i.e. milk produced after day 14 postpartum) over 60 days after the first postpartum ocrelizumab infusion 3. Average and peak ocrelizumab milk concentration as well as time to reach peak milk concentration, measured over 60 days after the mother’s first postpartum ocrelizumab infusion 4. Estimated maximum oral daily infant dosage (MDID) calculated as the peak ocrelizumab milk concentration multiplied by an estimated infant milk intake of 150 mL/kg/day measured over 60 days after the mother’s first postpartum ocrelizumab infusion 5. Average relative infant dose (RID) over 60 days, calculated as the ADID (mg/kg/day) divided by the maternal dosage (mg/kg/day) multiplied by 100 6. Serum concentration of ocrelizumab in the infant measured at Day 30 after the mother’s first ocrelizumab postpartum infusion 7. Mean titers of antibody immune response(s) to vaccination against common childhood vaccinations with full or partial doses given prior to 1 year, which include responses to MMR, diphtheria, tetanus, pertussis, Hib, HBV, and PCV-13 8. Proportion of infants with positive humoral response (seroprotective titers; as defined for the individual vaccine) to vaccines 9. Rate and nature of adverse events (AEs) in the mother throughout the study, including changes in clinical and laboratory results 10. Rate and nature of AEs in the infant throughout the study, including infections and hospitalizations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Day 30 after the mother’s first ocrelizumab postpartum infusion 2. For 1x600 mg: before infusion and at 24 hours (Day 1), Day 7 , Day 30 and Day 60 post-infusion; For 2x300 mg: before infusion 1 and at 24 hours (Day 1), Day 7, Day 14, Day 15 (24 hours after infusion 2), Day 21, Day 30 and Day 60 post-infusion 1 3-5. Over 60 days after the mother’s first ocrelizumab postpartum infusion 6. 30 days after the mother’s first ocrelizumab postpartum infusion 7-8. 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 9-10. Throughout the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Switzerland |
Australia |
Canada |
France |
Germany |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial 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
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The end of the study is defined as the date of the last assessment (vaccine response titers measured 1 month [+ 30 days] after the first or second dose of MMR vaccine, or at Month 13 of age [+30 days] if MMR vaccine is not planned to be administered) for the last infant. The primary analysis will be conducted at the end of the Treatment and Sampling Period (Day 60 [+ 2 days]).
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |