Multiple Sclerosis
Conditions
Keywords
MS
Brief summary
To study the impact of cladribine on peripheral and intrathecal B-cell, plasma cells, T cells and Tregs
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.
Interventions
None listed
Sponsors
Queen Mary University of London
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Regulatory B Cells From Baseline to Week 96 | 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. |
| Percent Change in Class-switched Memory B Cells From Baseline to Week 96 nh | Baseline to week 96 | Percent change from baseline to Week 96 in class-switched memory B cells (CD19+/CD27+/IgD-) in participants with RRMS treated with oral cladribine. |
| Percent Change in Non Class-switched Memory B Cells From Baseline to Week 96 | 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. |
| Percent Change in Plasmablast From Baseline to Week 96 | Baseline to week 96 | Percent change from baseline to Week 96 in plasmablasts (CD19+/CD27+/CD38+) in participants with RRMS treated with oral cladribine. |
| Percent Change in Transitional B Cells From Baseline to Week 96 | 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. |
| Percent Change in CD4+ Central Memory T Cells From Baseline to Week 96 | 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. |
| Percent Change in CD4+ Naive T Cells From Baseline to Week 96 | 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. |
| Percent Change in CD4+ TEMRA Cells From Baseline to Week 96 | 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. |
| Percent Change in CD4+ Effector Memory T Cells From Baseline to Week 96 | 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. |
| Percent Change in CD8+ Central Memory T Cells From Baseline to Week 96 | 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. |
| Percent Change in CD8+ Naive T Cells From Baseline to Week 96 | 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. |
| Percent Change in CD8+ TEMRA Cells From Baseline to Week 96 | 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. |
| Percent Change in CD8+ TEM Cells From Baseline to Week 96 | 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. |
| Percent Change in Regulatory T Cells From Baseline to Week 96 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in CSF of κ Free Light Chain (KFLC) From Baseline to Week 48 and Week 96 | Baseline to 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. |
| Change in CSF Oligoclonal Band (OCB) Positivity From Baseline to Week 48 and Week 96 | Baseline to 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 |
| Changes in CSF of λ Free Light Chain (LFLC) Index From Baseline to Week 48 and Week 96 | Baseline to 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. |
| Change in CSF CXCL-13 Levels From Baseline to Week 96 | 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. |
| Change in Urine Neopterin Levels From Baseline to Week 96 | 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 |
| Change in CSF Neurofilament Light Chain (NfL) Levels From Baseline to Week 96 | Baseline to 96 weeks | 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 |
| Change in CSF Soluble CD138 Levels From Baseline to Week 96 | 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. |
| Changes in CSF Cytokine and Chemokine Levels From Baseline to Week 96 | 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. |
Countries
United Kingdom
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United Kingdom | 10 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
None listed