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

Hoffmann-La Roche26 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Multiple Sclerosis Clinically Isolated Syndrome

Interventions

OcrelizumabDRUG

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.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 40 Years

Medical Language ↔ Plain English

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

Locations (8)

University of California San Francisco

San Francisco, California, United States

University Of Colorado

Aurora, Colorado, United States

Northwestern Memorial Hospital

Chicago, Illinois, United States

Brigham and Womens Hospital

Outcomes

Primary Outcomes

Percentage of Infants With B Cell Levels (Cluster of Differentiation 19 [CD19+] Cells) Below the Lower Limit of Normal (LLN) Measured at Day 30 After the Mother's First Ocrelizumab Postpartum Infusion

Infant blood samples were collected at Day 30 after the mothers received their first postpartum ocrelizumab infusion (regardless of whether women receive a 600 mg or a 2x300 mg dose). The percentage of infants with B cell levels below LLN are reported with the two-sided Clopper Pearson 95% confidence interval (CI). B-cell reference ranges by week of life (absolute and percentage counts) are defined by Borriello et al. 2022.

Time frame: At Day 30

Estimated Average Oral Daily Infant Dosage (ADID)

ADID was calculated as the arithmetic mean of the mother's daily ocrelizumab milk concentration (micrograms/milliliters \[µg/mL\]) over 60 days post-ocrelizumab infusion 1 multiplied by an estimated infant milk intake of 150 milliliters/kilograms/day (mL/kg/day) and based on the weight \[kilograms (kg)\] recorded at the Day 30 visit. Ocrelizumab concentrations reported as below the lower limit of quantification \[LLQ=160 nanograms/millilitres (ng/mL)\] are imputed to zero for the calculation ADID.

Time frame: Up to Day 60

Secondary Outcomes

Absolute CD19+ B Cell Count in the Infant

Infant blood samples were collected at Day 30 after the mothers received their first postpartum ocrelizumab infusion (regardless of whether women receive a 600 mg or a 2x300 mg dose).

Time frame: At Day 30

Percentage of CD19+ B Cell in the Infant

Infant blood samples were collected at Day 30 after the mothers received their first postpartum ocrelizumab infusion (regardless of whether women receive a 600 mg or a 2x300 mg dose).

Time frame: At Day 30

Area Under the Milk Concentration-Time Curve (AUC) of Ocrelizumab in Mature Breastmilk

Data from ClinicalTrials.gov

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Boston, Massachusetts, United States

Memorial Healthcare Institute for Neurosciences and Multiple Sclerosis

Owosso, Michigan, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Hosp. Clinico San Carlos

Madrid, Spain

Queen Mary University of London

London, United Kingdom

Time frame: One 600 mg infusion: before infusion and at 24 hours (Day 1), Days 7, 30 and 60 post-infusion; Two 300 mg infusions: before infusion 1 and at 24 hours (Day 1), Days 7, 14, 15 (24 hours after infusion 2), 21, 30 and 60 post-infusion 1

Average Concentration of Ocrelizumab in Breastmilk (Cmean)

Maximum Concentration (Cmax) of Ocrelizumab in Breastmilk

Time of Maximum Concentration (Tmax) of Ocrelizumab in Breastmilk

Estimated Maximum Oral Daily Infant Dosage (MDID)

MDID was calculated at the subject level as the peak ocrelizumab milk concentration (μg/mL) multiplied by an estimated infant milk intake of 150 mL/kg/day measured over 60 days after the mother's first postpartum ocrelizumab infusion.

Time frame: Up to Day 60

Average Relative Infant Dose (RID)

Average RID over 60 days was calculated as the ADID (mg/kg/day) divided by the maternal dosage (mg/kg/day) over 60 days multiplied by 100.

Time frame: Up to Day 60

Serum Concentration of Ocrelizumab in the Infant at Day 30

Serum concentration of ocrelizumab in the infant measured at Day 30 after the mother's first ocrelizumab postpartum infusion. Concentrations reported as below the lower limit of quantification (LLQ=156 ng/mL) are set to zero for calculation of summary statistics.

Time frame: At Day 30

Percentage of Mothers With Adverse Events (AEs)

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and regardless of causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product.

Time frame: Up to approximately 73.3 weeks after first ocrelizumab dose

Percentage of Infants With AEs

Time frame: Up to approximately 73.3 weeks after first ocrelizumab dose administered to mother

Mean Titers of Measles, Immunoglobin G (IgG) Antibody in Response to Measles, Mumps, and Rubella (MMR) Vaccination

The immune response to MMR vaccine was assessed 1 month after the first dose of MMR vaccine (if the first dose is administered at 11 months of age or later) or 1 month after the second dose of MMR vaccine (if the first dose is administered before 11 months of age), or at Month 13 of chronological age if MMR vaccine was not planned to be administered. This was to evaluate whether infants can mount humoral immune responses to clinically relevant vaccines. mIU/mL=milli-international units per milliliter.