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

Phase 4

Completed

Conditions: Clinically Isolated Syndrome
Multiple Sclerosis

Interventions: Drug: Ocrelizumab

Registration Number: NCT04998851

Lead Sponsor: Hoffmann-La Roche

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 26

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Women with CIS or MS	Ocrelizumab	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.

Primary Outcome Measures

Name	Time	Method
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	At Day 30	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.
Estimated Average Oral Daily Infant Dosage (ADID)	Up to Day 60	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.

Secondary Outcome Measures

Name	Time	Method
Mean Titers of Antibody Immune Responses to Measles, Mumps, and Rubella (MMR) Vaccination	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	The immune response to MMR vaccine will be 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 is not planned to be administered. This is to evaluate whether infants can mount humoral immune responses to clinically relevant vaccines.
Absolute CD19+ B Cell Count in the Infant	At Day 30	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).
Area Under the Milk Concentration-Time Curve (AUC) of Ocrelizumab in Mature Breastmilk	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
Maximum Concentration (Cmax) of Ocrelizumab in Breastmilk	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
Time of Maximum Concentration (Tmax) of Ocrelizumab in Breastmilk	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
Estimated Maximum Oral Daily Infant Dosage (MDID)	Up to Day 60	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.
Number of AEs in Infants	Up to 16 months	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.
Mean Titers of Antibody Immune Responses to Diphtheria-Tetanus-Pertussis (DTP) Vaccine	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	The immune response to DTP vaccine will be 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 is not planned to be administered. This is to evaluate whether infants can mount humoral immune responses to clinically relevant vaccines.
Mean Titers of Antibody Immune Responses to Haemophilus Influenzae Type B (Hib) Vaccine	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	The immune response to Hib vaccine will be 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 is not planned to be administered. This is to evaluate whether infants can mount humoral immune responses to clinically relevant vaccines.
Percentage of CD19+ B Cell in the Infant	At Day 30	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).
Average Concentration of Ocrelizumab in Breastmilk (Cmean)	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
Percentage of Infants With Positive Humoral Response to MMR Vaccination	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	Percentage of infants with positive humoral response (seroprotective titers as defined for the individual vaccine) will be presented for each immunoglobulin G (IgG) antibody titer. Seroprotective titer based on vaccine tests for MMR vaccine are as follows: Anti-Measles Vir IgG(-70)CL: ≥ 120 milli-international units/milliliter (mIU/mL); Anti-MumpsAT Vir iGG(-70)CL: ≥ 17 units per milliliters (U/mL); Anti-Rub Vir IgG(-70)RUOCL: ≥ 10 international units/milliliters (IU/mL)
Mean Titers of Antibody Immune Responses to Hepatitis B Vaccine (HBV)	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	The immune response to HBV vaccine will be 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 is not planned to be administered. This is to evaluate whether infants can mount humoral immune responses to clinically relevant vaccines.
Average Relative Infant Dose (RID)	Up to Day 60	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.
Serum Concentration of Ocrelizumab in the Infant at Day 30	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.
Mean Titers of Antibody Immune Responses to 13-valent Pneumococcal Conjugate Vaccine (PCV-13)	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	The immune response to PCV-13 vaccine will be 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 is not planned to be administered. This is to evaluate whether infants can mount humoral immune responses to clinically relevant vaccines.
Percentage of Mothers With of Adverse Events (AEs)	Up to 16 months	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.
Percentage of Infants With Positive Humoral Response to Hib Vaccine	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	Percentage of infants with positive humoral response (seroprotective titers as defined for the individual vaccine) will be presented for each IgG antibody titer. Seroprotective titer based on vaccine tests for Hib vaccine are as follows: Hib, IgG: ≥ 0.15 µg/mL.
Percentage of Infants With Positive Humoral Response to DTP Vaccine	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	Percentage of infants with positive humoral response (seroprotective titers as defined for the individual vaccine) will be presented for each IgG antibody titer. Seroprotective titer based on vaccine tests for DTP vaccine are as follows: Anti-Diphtheria IgG(-70)CL and Anti-Tetanus Toxoid IgG(-70)RUO: ≥ 0.01 IU/mL; Bordetella pertussis antibodies, IgG: \> 1.04 cut-off index (COI).
Percentage of Infants With Positive Humoral Response to HBV	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	Percentage of infants with positive humoral response (seroprotective titers as defined for the individual vaccine) will be presented for each IgG antibody titer. Seroprotective titer based on vaccine tests for HBV vaccine are as follows: Anti-HBs: ≥ 10 mIU/mL.
Percentage of Infants With Positive Humoral Response to PCV-13	Up to 1 month after the first or second dose of MMR vaccine (at approximately Month 13)	Percentage of infants with positive humoral response (seroprotective titers as defined for the individual vaccine) will be presented for each IgG antibody titer. Seroprotective titer based on vaccine tests for PCV-13 vaccine are as follows: 13 Valent anti-pneumococcal antibody panel: ≥ 0.35 µg/ml.

Trial Locations

Locations (8): University of California San Francisco
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San Francisco, California, United States
University Of Colorado
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Aurora, Colorado, United States
Northwestern Memorial Hospital
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Chicago, Illinois, United States
Brigham and Womens Hospital
🇺🇸
Boston, Massachusetts, United States
Hospital of the University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Memorial Healthcare Institute for Neurosciences and Multiple Sclerosis
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Owosso, Michigan, United States
Universitaetsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪
Dresden, Germany
Queen Mary University of London
🇬🇧
London, United Kingdom