Addition of Belimumab to B-cell Depletion in Relapsing-remitting Multiple Sclerosis

NCT04767698 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: IRB00246563
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

Multiple sclerosis is the most common inflammatory disease of the central nervous system and a common cause of disability in young adults. Depleting B cells from the circulation with an anti-cluster of differentiation (CD) 20 antibodies has proven to be an effective strategy in reducing relapses and disability in patients with the relapsing-remitting disease. However, continuous and long-term depletion of B-cells can result in reduced immunoglobulin levels, immunosuppression, and an increased tendency for severe infections and perhaps, even malignancy. Blocking B-cell Activating Factor (BAFF) is effective for the treatment of several autoimmune disorders. Belimumab, a BAFF blocking antibody, has been approved by the Food and Drug Administration for the treatment of systemic lupus erythematosus. Belimumab has been shown to have immunomodulatory properties, without resulting in overt immunosuppression. The investigators hypothesize that belimumab, given to patients who received a short course of treatment with B-cell depleting antibody (ocrelizumab), will be safe and equally effective in reducing MS disease activity (as compared to patients receiving continuous treatment with ocrelizumab); while resulting in less immunosuppression, as measured by antibody response to pneumococcal vaccination. Currently, available treatment strategies in relapsing MS sacrifice higher efficacy for long-term safety or vice versa. The proposed strategy in this application combines the long-term safety and high efficacy to treat patients with relapsing-remitting multiple sclerosis (RRMS) and, if eventually proven effective, can be adopted in a large proportion of patients with this chronic disease. This is a randomized, open-labeled trial. Forty eligible participants will be randomized 1:1 to either receiving a form of standard of care, ocrelizumab (300 mg two infusions two weeks apart at baseline and then 600 mg as a single infusion every six months) or belimumab (200 mg subcutaneous (SC) weekly for 36 months) plus two courses of ocrelizumab (300 mg two infusions two weeks apart at baseline and 600 mg as a single infusion six months later). Co-primary outcomes of the study include pneumococcal vaccine antibody response, the return of MS disease activity, and proportions of patients with adverse events and serious adverse events.

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (2)

• Pneumococcal Vaccine Antibody Response

  The proportion of patients with positive antibody responses to \>/=1 of the 23 pneumococcal vaccine serotypes measured four weeks post-vaccination (vaccination given at month 24). A positive antibody response is defined as a two-fold increase from pre-vaccination levels against \>/=1 of the 23 pneumococcal serotypes measured.

  Month 25

• Safety as Assessed by Adverse Events

  Adverse events (AEs) and serious adverse events (SAEs), including AEs of special interest (opportunistic infections, herpes zoster, malignancies, hypersensitivity and infusion reactions, suicidal ideation, intent or behavior and all-cause mortality).

  24 months

Secondary Outcomes (12)

• Difference Between the Two Treatment Groups in GM-CSF/IL-10 Ratio

  Month 36

• Difference Between the Two Treatment Groups in IL-6/IL-10 Ratio

  Month 36

• Assessment of Return of Disease Activity by Month 24

  Month 24

• Assessment of Return of Disease Activity by Month 36

  Month 36

• Assessment of Clinical Disease Activity by Month 24

  Month 24

Study Arms (2)

Belimumab + short-term Ocrelizumab

EXPERIMENTAL

Participants will receive Belimumab and Ocrelizumab.

Drug: Belimumab; Drug: Short-course Ocrelizumab

Continued Ocrelizumab

ACTIVE COMPARATOR

Participants will receive Ocrelizumab only.

Drug: Continued Ocrelizumab

Interventions

Belimumab DRUG

200 mg SC weekly for 36 months

Belimumab + short-term Ocrelizumab

Short-course Ocrelizumab DRUG

300 mg, two infusions two weeks apart and then 600 mg as a single infusion after six months (only one time) (total of two courses of treatment)

Belimumab + short-term Ocrelizumab

Continued Ocrelizumab DRUG

300 mg, two infusions two weeks apart and then 600 mg as a single infusion every six months for a total of 36 months

Continued Ocrelizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of RRMS based on McDonald criteria 2017
• Age \> 18
• A clinical relapse in the past 12 months OR an enhancing lesion on brain/ spinal cord MRI in the past 6 months OR a new T2/FLAIR lesion on a brain/spinal cord MRI obtained in the past 6 months (compared to a previous MRI obtained within one year from the latest MRI)
• Pre-existing pneumococcal antibody titers (\>1.0 mg/mL) to =\<9 of 23 vaccine serotypes
• Female Subjects: Not pregnant or nursing and at least one of the following conditions apply: a. Non- childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea. b. Child-bearing potential and agrees to use one of the contraception methods as described by the investigator or designee, from Day 0 until 24 weeks after the last dose of study medications (See details below).
• Liver function at the time of screening: alanine aminotransferase (ALT) \< 2x upper limit of normal (ULN); bilirubin \<= 1.5x ULN (isolated bilirubin \>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

You may not qualify if:

• Prior therapy at any time: has ever received any of the following: a) B-cell targeted therapy (e.g., rituximab, ocrelizumab, other anti-cluster of differentiation (CD)20 agents, anti-CD22 \[epratuzumab\], anti-CD52 \[alemtuzumab\], B lymphocyte stimulator (BLyS)-receptor fusion protein \[BR3\], Transmembrane activator and calcium-modulating ligand (CAML) interaction (TACI) fragment, crystallizable (Fc), or belimumab)
• Prior use of cladribine, mitoxantrone, cyclophosphamide, or hematopoietic stem cell transplantation (HSCT)
• Lymphopenia: a lymphocyte count \<500/ millimeter (mm)\^3
• Neutrophils \<1.5x 10E9/L.
• Drug sensitivity: a history of sensitivity to any of the study medications, or components thereof or a history of drug or other allergies including a previous anaphylactic reaction to parenteral administration contrast agents, human or murine proteins or monoclonal antibodies
• Treatment with steroids in the last 30 days
• Clinically unstable medical or psychiatric disorder
• Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, poses a significant suicide risk
• Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
• Substance abuse: has evidence of current drug or alcohol abuse or dependence
• Day prior therapy: has received a biologic investigational agent other than B-cell targeted therapy \[e.g., abetimus sodium, anti CD40L antibody (e.g., BG9588/ IDEC-131; investigational agent applies to any drug not approved for sale in the country in which it is being used\]
• Day prior therapy: has received any of the following within 30 days before Day 0: a) Any other MS disease-modifying therapy, not mentioned above (including fumaric acid esters, sphingosine-1-phosphate (S1P) receptor modulators, teriflunomide, and natalizumab). Glatiramer acetate and interferons are permitted up to the day of starting the investigational medication. Intravenous, oral, and Inhaled steroids and new topical immunosuppressive agents (e.g., eye drops, topical creams) are allowed.
• Day prior therapy: has received a live virus vaccine or a non-biologic investigational agent.
• Malignancy: has a history of malignancy in the past 5 years except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
• Have a history of a primary immunodeficiency

Sponsors & Collaborators

• Johns Hopkins University: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

belimumab

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Limitations and Caveats

Study was prematurely terminated and therefore there was no data collected nor analysis performed.

Results Point of Contact

• Title: Dimitrios Ladakis
• Organization: Johns Hopkins University, School of Medicine

dladaki1@jhmi.edu

410-614-1522

Study Officials

• Pavan Bhargava, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2021
• First Posted: February 23, 2021
• Study Start: October 1, 2021
• Primary Completion: May 10, 2022
• Study Completion: May 10, 2022
• Last Updated: March 7, 2023
• Results First Posted: March 7, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)