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: N/A

• 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
To study B cells subsets changes	The temporal changes of memory B cells (CD19+/CD27+/IgD-/+), plasmablasts (CD19-/CD138+/CD38+) T cells (CD4/CD45RA-/+, CCR7-/+, CD8+/CD45RA-/+/CCR7-/+) and Tregs (CD4/CD8)/CD25+/CD127-/Fox3 P+), will be performed in the peripheral venous blood of pwMS with RRMS over 96w of treatment with oral cladribine, using Flow Cytometry. These populations of cells 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+).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in OCBs and free immunoglobulin kappa and lambda light chain levels (FLC)	To study the effects of oral cladribine on CSF OCBs and FLC between baseline, 48kws and 96 wks	2 years
Measure of CXCL-13 and urine markers of inflammation (neopterin)	To study the effects of oral cladribine on CSF markers of inflammation, in particular CXCL-13 and neopterin between baseline, 48kws and 96 wks	2 years
Measure of Neurofilament light chain (NFL)	To study the effects of oral cladribine on CSF NFL between baseline, 48kws and 96 wks	2 years
Measure of soluble CD138	o study the effects of oral cladribine on CSF sCD138 between baseline, 48kws and 96 wks	2 years
Measure of cytokines and chemokines	o study the effects of oral cladribine on CSF cytokines and chemokines between baseline, 48kws and 96 wks	2 years

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): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 14, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: MS
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune 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