Oral Cladribine B-cell Study

To study the impact of cladribine on peripheral and intrathecal B-cell, plasma cells, T cells and Tregs

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis

Detailed Description

Primary: To quantify the temporal changes of memory B cells (CD19+/CD27+/IgD-/+), plasmablasts (CD19-/CD138+/CD38+) and T cells (CD4/CD45RA-/+, CCR7-/+, CD8+/CD45RA-/+/CCR7-/+), Tregs (CD4/CD8)/CD25+/CD127-/Fox3 P+) in the peripheral venous blood of pwMS with RRMS over 96w of treatment with oral cladribine.

These will be compared to the populations of non-memory or class-switched B cells (immature/transitional B cells CD10+/CD38+/CD19+, immature regulatory B cells CD10+/CD38+/CD19+/CD24+/IL-10+, mature B cells CD10-/CD38+/CD19+).

Secondary:

1. To study the effects of oral cladribine on:

   1. CSF OCBs and free immunoglobulin kappa and lambda light chain levels (FLC).
   2. CSF markers of inflammation, in particular CXCL-13 and urine markers of inflammation (neopterin).
   3. CSF markers of neuroaxonal damage, in particular free neurofilament light chains.
   4. On the peripheral repertoire B-cells (immunoglobulin) and T-cells (T cell receptor) and plasma cells (soluble receptors).
2. To compare CSF OCB positivity and CSF light chain levels with a contemporary control group of alemtuzumab treated pwMS (historical data).

Tertiary:

1. To compare B and T cell repertoire with a contemporary control group of alemtuzumab treated pwMS (historical data).
2. To evaluate the effect of changes in the immune cell profile on clinical measures of disability, MRI activity and PROMS.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Barts Health NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Relapsing-remitting MS

Description

Inclusion Criteria:

• Patients with MS who are being treated with oral cladribine at Barts Health NHS Trust will be approached to participate in this study.
• Patients must be willing and able to undergo lumbar punctures
• Patients who are OCB positive in their CSF (previous diagnostic lumbar puncture)

Exclusion Criteria:

• Ineligible for oral cladribine under NHS England prescribing guidelines and those participating in MAGNIFY-MS study (cladribine tablets in active MS)
• Unsuitable to have a lumbar puncture, for example spinal deformity, tethered cord syndrome or the use of aspirin or anticoagulants, and those unable to comply with study requirements, including frequency of visits and lumbar punctures.
• Presence of comorbidities in which the administration of cladribine is contraindicated.
• Abnormal baseline investigations (WBC<3 x 10*9/l, lymphocytes <1.0 x 10*9/l, neutrophil count <1.5 x 10*9/l, platelet count <100 x 10*9, haemoglobin <110g/l, LFT>/3x upper limit of normal of site reference ranges, potassium <2.8mmol/l or >5.5mmol/l, sodium <125 mmol/l, creatinine >130 umol/l)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Cladribine (Mavenclad, Merck Serono Ltd); In the summary of product characteristics the recommended cumulative dose is 3.5 mg/kg body weight over 2 years, taken as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, 1 at the beginning of the first month and 1 at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient takes 10 mg or 20 mg (1 or 2 tablets) as a single daily dose, depending on body weight

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Class-switched Memory B Cells From Baseline to Week 96 nh	Percent change from baseline to Week 96 in class-switched memory B cells (CD19+/CD27+/IgD-) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in Non Class-switched Memory B Cells From Baseline to Week 96	Percent change from baseline to Week 96 in non class-switched memory B cells (CD19+/CD27+/IgD+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in Plasmablast From Baseline to Week 96	Percent change from baseline to Week 96 in plasmablasts (CD19+/CD27+/CD38+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in Transitional B Cells From Baseline to Week 96	Percent change from baseline to Week 96 in transitional B cells (CD19+ IgD+ CD10+ CD27-) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in Regulatory B Cells From Baseline to Week 96	Percent change from baseline to Week 96 in regulatory B cells (CD19+/CD24+/CD38+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD4+ Central Memory T Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD4+ central memory T cells (CD45RA- CCR7+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD4+ Naive T Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD4+ naive T cells (CD45RA+ CCR7+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD4+ TEMRA Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD4+ TEMRA cells (CD45RA+ CCR7-) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD4+ Effector Memory T Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD4+ effector memory T cells (CD45RA- CCR7-) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD8+ Central Memory T Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD8+ central memory T cells (CD45RA- CCR7+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD8+ Naive T Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD8+ naive T cells (CD45RA+ CCR7+) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD8+ TEMRA Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD8+ TEMRA cells (CD45RA+ CCR7-) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in CD8+ TEM Cells From Baseline to Week 96	Percent change from baseline to Week 96 in CD8+ effector memory T cells (CD45RA- CCR7-) in participants with RRMS treated with oral cladribine.	Baseline to week 96
Percent Change in Regulatory T Cells From Baseline to Week 96	Percent change from baseline to Week 96 in regulatory T cells (CD4+ CD25+ FOXP3+) in participants with RRMS treated with oral cladribine.	Baseline to week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in CSF of κ Free Light Chain (KFLC) From Baseline to Week 48 and Week 96	The CSF κ Free Light Chain (KFLC) Index and λ Free Light Chain (LFLC) Index were measured at baseline, Week 48, and Week 96. KFLC and LFLC concentrations in cerebrospinal fluid and serum were obtained using Optilite. The KFLC Index and LFLC Index were calculated as (CSF FLC / serum FLC) ÷ (CSF albumin / serum albumin). These indices provide quantitative measures of intrathecal free light chain synthesis. Values are continuous laboratory measurements and do not use a score or scale.	Baseline to week 96
Change in CSF Oligoclonal Band (OCB) Positivity From Baseline to Week 48 and Week 96	CSF and matched serum samples were analysed for IgG oligoclonal bands using isoelectric focusing followed by immunoblotting. OCB positivity was defined as ≥1 IgG band present in CSF but absent in serum (CSF-restricted bands). Reported values include the number of OCB-positive and OCB-negative participants at each time point (baseline, Week 48, Week 96). Higher values indicate increased intrathecal IgG synthesis	Baseline to week 96
Changes in CSF of λ Free Light Chain (LFLC) Index From Baseline to Week 48 and Week 96	The CSF κ Free Light Chain (KFLC) Index and λ Free Light Chain (LFLC) Index were measured at baseline, Week 48, and Week 96. KFLC and LFLC concentrations in cerebrospinal fluid and serum were obtained using Optilite. The KFLC Index and LFLC Index were calculated as (CSF FLC / serum FLC) ÷ (CSF albumin / serum albumin). These indices provide quantitative measures of intrathecal free light chain synthesis. Values are continuous laboratory measurements and do not use a score or scale.	Baseline to week 96
Change in CSF CXCL-13 Levels From Baseline to Week 96	CXCL-13 concentrations in cerebrospinal fluid (CSF) were measured at baseline, Week 48, and Week 96 using immunoassay methods. Values are continuous laboratory measurements and are reported numerically (mean and standard deviation). No scoring system or clinical scale applies.	Baseline to week 96
Change in Urine Neopterin Levels From Baseline to Week 96	Urine neopterin concentrations were measured at baseline, Week 48, and Week 96 using immunoassay methods. Values are continuous laboratory measurements and are reported numerically (mean and standard deviation). No scoring system or clinical scale applied	Baseline to week 96
Change in CSF Neurofilament Light Chain (NfL) Levels From Baseline to Week 96	CSF neurofilament light chain (NfL) concentrations were measured at baseline, Week 48, and Week 96 using immunoassay methods. NfL is reported as a continuous laboratory value. Results are presented as numerical measurements (mean and standard deviation). No clinical scoring system or scale applies	Baseline to 96 weeks
Change in CSF Soluble CD138 Levels From Baseline to Week 96	Soluble CD138 concentrations in cerebrospinal fluid (CSF) were measured at baseline, Week 48, and Week 96 using immunoassay methods. Values are continuous laboratory measurements and are reported numerically (mean and standard deviation). No clinical scoring system or scale applies.	Baseline to week 96
Changes in CSF Cytokine and Chemokine Levels From Baseline to Week 96	Cerebrospinal fluid (CSF) cytokines and chemokines were measured at baseline, Week 48, and Week 96 using immunoassays. Analytes included IFN-γ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-5, IL-8, and TNF-α. Values are continuous laboratory measurements and are reported numerically (mean and standard deviation). No clinical scoring system or scale applies. Results for each analyte are presented in separate rows of the results table.	Baseline to week 96

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare the data of T and B cells from the CladB study versus Alemtuzumab	To compare B and T cell repertoire with a contemporary control group of alemtuzumab treated pwMS (historical data	2 years

Collaborators and Investigators

• Sponsor: Queen Mary University of London

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): January 31, 2024
• Study Completion (Actual): January 31, 2024

Study Registration Dates

• First Submitted: April 3, 2024
• First Submitted That Met QC Criteria: May 14, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: February 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: MS
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis
• Other Study ID Numbers: 262436

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No