A Study Evaluating B Cell Levels In Infants Of Lactating Women With CIS Or MS Receiving Ocrelizumab

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the pharmacokinetics of ocrelizumab in the breastmilk of lactating women with clinically isolated syndrome (CIS) or multiple sclerosis (MS) [in line with the locally approved indications] treated with ocrelizumab, by assessing the concentration of ocrelizumab in mature breastmilk, as well as the corresponding exposure and pharmacodynamic effects (blood B cell levels) in the infants.

Official Title
-----------------
A Phase IV Multicenter, Open-Label Study Evaluating B Cell Levels In Infants Of Lactating Women With CIS Or MS Receiving Ocrelizumab

Conditions
-----------------
Multiple Sclerosis, Clinically Isolated Syndrome

Intervention / Treatment
-----------------
* Drug: Ocrelizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Woman is between 18 and 40 years of age at screening Woman is willing to breastfeed for at least 60 days after the first post-partum ocrelizumab infusion (this decision is to be taken prior to and independent from study participation) Woman is willing to provide breastmilk samples 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 post-partum dose of ocrelizumab For women who received commercial ocrelizumab (OCREVUS) before enrolment: documentation that last exposure to ocrelizumab occurred more than 3 months before the last menstrual period (LMP) and was given at the approved dose of 2 x 300 mg or 1 x 600 mg Woman agrees to use acceptable contraceptive methods during the study Exclusion Criteria related to the Mother: Hypersensitivity to ocrelizumab or to any of its excipients Received last dose of ocrelizumab <3 months before the LMP or during pregnancy Active infections (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 Known active malignancies, or being actively monitored for recurrence of malignancy History of breast implants, breast augmentation, breast reduction surgery or mastectomy Prior or current history of chronic alcohol abuse or drug abuse Positive screening tests for hepatitis B Treatment with a DMT for CIS or MS during pregnancy and/or first weeks post-partum, with the exception of formulations of interferon-beta, glatiramer acetate or pulsed corticosteroids Treatment with drugs known to transfer to the breastmilk and with established or potential deleterious effects for the infant Treatment with any investigational agent within 6 months or five half-lives of the investigational drug prior to the LMP Exclusion Criteria related to the Infant: >24 weeks of life at the time of the mother's first dose of ocrelizumab Any abnormality that may interfere with breastfeeding or milk absorption Active infection (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 At least one documented brief resolved unexplained event (BRUE), as defined by the 2016 Guidelines of the American Academy of Pediatrics

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Women with CIS or MS<br>Lactating women with CIS or MS (in line with the locally approved indications) who decided together with their treating physician to continue on, or start treatment with, OCREVUS (ocrelizumab) post-partum. Women resuming treatment with ocrelizumab post-partum will be included only if the last exposure to ocrelizumab occurred more than 3 months before the last menstrual period to exclude any interference between fetal exposure and exposure via lactation. | Drug: Ocrelizumab<br>* Women will receive the ocrelizumab dose regimen as per the locally-approved label. The ocrelizumab dose will be administered as an initial split dose of two 300 mg infusions separated by 14 days or a single 600 mg infusion according to the local prescribing information.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of infants with B cell levels (CD19+ cells) below the lower limit of normal (LLN) |  | Day 30 after the mother's first post-partum ocrelizumab infusion | 
| Estimated average oral daily infant dosage (ADID) |  | Over 60 days after the mother's first post-partum ocrelizumab infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| B cell levels (CD19+ cells) in the infant |  | Day 30 after the mother's first post-partum ocrelizumab infusion | 
| Area under the milk concentration-time curve (AUC) of ocrelizumab in mature breastmilk |  | Over 60 days after the mother's first post-partum ocrelizumab infusion | 
| Average ocrelizumab milk concentration |  | Over 60 days after the mother's first post-partum ocrelizumab infusion | 
| Peak ocrelizumab milk concentration |  | Over 60 days after the mother's first post-partum ocrelizumab infusion | 
| Time to reach peak ocrelizumab milk concentration |  | Over 60 days after the mother's first post-partum ocrelizumab infusion | 
| Estimated maximum oral daily infant dosage (MDID) |  | Over 60 days after the mother's first post-partum ocrelizumab infusion | 
| Serum concentration of ocrelizumab in the infant |  | Day 30 after the mother's first post-partum ocrelizumab infusion | 
| Mean titers of antibody immune responses to Mumps, Measles and Rubella vaccination |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Proportion of infants with positive humoral response (seroprotective titers; as defined for the individual vaccine) to Measles, Mumps and Rubella vaccines |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Mean titers of antibody immune responses to Diphtheria-Tetanus-Pertussis Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Proportion of infants with positive humoral response to Diphtheria-Tetanus-Pertussis Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Mean titers of antibody immune responses to Haemophilus influenzae type B Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Proportion of infants with positive humoral response to Haemophilus influenzae type B Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Mean titers of antibody immune responses to Hepatitis B Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Proportion of infants with positive humoral response to Hepatitis B Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Mean titers of antibody immune responses to Pneumococcal conjugate Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Proportion of infants with positive humoral response to Pneumococcal conjugate Vaccine |  | 1 month after the first or second dose of measles, mumps, and rubella (MMR) vaccine, or at Month 13, in case MMR vaccine is not planned to be administered | 
| Rate and nature of adverse events in the infant |  | Baseline up to 16 months | 
| Rate and nature of adverse events in the mother |  | Baseline up to 16 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ocrelizumab, OCREVUS, breastmilk transfer, breast milk transfer, lactation