Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
The purpose of this study is to better understand the mechanism of action (MoA) of cladribine tablets by exploring the effect on central nervous system (CNS) and blood biomarkers relevant in the relapsing forms of multiple sclerosis (RMS; to include relapsing-remitting MS \[RRMS\] or active secondary progressive MS).
Detailed description
This is an open label, randomized, multicenter collaborative research Phase 4 biomarker study, designed to generate hypotheses to better understand the MoA of cladribine tablets in RMS (to include RRMS or active secondary progressive MS). The study is designed to generate hypotheses regarding the impact and relevance of cladribine tablet activity in the CNS by assessing the cerebrospinal (CSF) levels of lymphocyte subsets, other immune cells, neuronal injury markers and soluble immunological markers in study participants with RMS before and during treatment with cladribine tablets, and the association of these CSF markers with corresponding blood markers and with clinical outcomes.
Interventions
DRUGCladribine
All participants will receive cladribine 10 mg tablets at a cumulative dosage of 3.5 mg/kg divided into 2 treatment courses as per the United States Prescribing Information (USPI) (1.75 mg/kg per treatment course; Year 1 and Year 2 treatment). Patients will be randomized 1:2:2:1 to receive a total of 2 Lumbar Punctures at specific time points during the treatment cycle.
Sponsors
Gregory Wu
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
All patients will receive cladribine treatment per standard of care. Patients will be randomized 1:2:2:1 to receive a total of 2 Lumbar Punctures (LP) according to 1 of the 4 following schedules: Group 1: Baseline and end of Week 5; Group 2: Baseline and end of Week 10; Group 3: Baseline and end of Year 1; Group 4: Baseline and end of Year 2 . Patients in Groups 1-3 will have the option to undergo a third LP at the end of Year 2.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Have a relapsing form of multiple sclerosis (RMS; to include RRMS or active secondary progressive MS) 2. Are willing and able to receive at least 2 lumbar punctures 3. Have an EDSS of 0 to ≤ 5.5 during the screening period 4. Had at least 1 relapse or 1 gadolinium-enhancing or 1 new or enlarged T2 lesion in the last 12 months 5. Have absolute lymphocyte count (ALC) within normal range of the local laboratory or assessed as normal by the investigator within the 3 week screening period and meet all other eligibility criteria for cladribine tablet treatment 6. Capable of giving signed informed consent
Exclusion criteria
1. Have any contraindication for lumbar puncture 2. Have current malignancy 3. Are infected with human immunodeficiency virus (HIV) 4. Have active chronic infections (e.g. hepatitis or tuberculosis) 5. Have signs or symptoms suggestive of progressive multifocal leukoencephalopathy (PML) in MRI 6. Have history of hypersensitivity to cladribine or any of the excipients listed in the cladribine tablets US Prescribing Information 7. Allergy or hypersensitivity to gadolinium and/or any other contraindication to perform a MRI 8. Have any other comorbid conditions that preclude participation 9. Have been previously treated with cladribine 10. Have previously been treated with ocrelizumab, alemtuzumab, rituximab, or daclizumab 11. Have received treatment with natalizumab during the last 6 months 12. Are currently receiving immunosuppressive or myelosuppressive therapy, e.g., methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic treatment with systemic corticosteroids 13. Have received treatment with immunosuppressive or myelosuppressive therapy during the last 6 months 14. Have received chronic treatment with systemic corticosteroids during the last 4 weeks 15. Have moderate or severe hepatic impairment (Child-Pugh score \>6) 16. Have moderate or severe renal impairment (creatinine clearance \<60 mL per minute) 17. Are pregnant or unwilling or unable to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course 18. Are intending to breastfeed on a cladribine tablet treatment day and/or during the 10 days after the last cladribine tablet dose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in CD3+ T Cells % From Baseline to Week 5 | Baseline to Week 5 (5 weeks after first cladribine dose) | Change in CSF level of CD3+ T lymphocytes from Baseline to second LP at Week 5, using quality-controlled flow cytometry and assays. Within-group differences from baseline to Week 5 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cell percentage and a negative number indicates decrease in CD3+ T cell percentage. |
| Change in CD3+ T Cells % From Baseline to Week 10 | Baseline to Week 10 (10 weeks after first cladribine dose) | Change in CSF level of CD3+ T lymphocytes from Baseline to second LP at Week 10, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Week 10 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cell percentage and a negative number indicates decrease in CD3+ T cell percentage. |
| Change in CD3+ T Cells % From Baseline to Year 1 | Baseline to Year 1 (45 weeks after first cladribine dose) | Change in CSF level of CD3+ T lymphocytes from Baseline to second LP at Year 1, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 1 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cell percentage and a negative number indicates decrease in CD3+ T cell percentage. |
| Change in CD3+ T Cells % From Baseline to Year 2 | Baseline to Year 2 (45 weeks after last cladribine dose) | Change in CSF level of CD3+ T lymphocytes from Baseline to second LP at Year 2, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 2 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cell percentage and a negative number indicates decrease in CD3+ T cell percentage. |
| Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Week 5 | Baseline to Week 5 | Change in CSF level of CD3+ T cells absolute numbers from Baseline to second LP at Week 5, using quality-controlled flow cytometry and assays. Within-group differences from baseline to Week 5 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cells absolute numbers and a negative number indicates decrease in CD3+ T cells absolute numbers. |
| Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Week 10 | Baseline to Week 10 (10 weeks after first cladribine dose) | Change in CSF level of CD3+ T cells absolute numbers from Baseline to second LP at Week 10, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Week 10 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cells absolute numbers and a negative number indicates decrease in CD3+ T cells absolute numbers. |
| Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Year 1 | Baseline to Year 1 (45 weeks after first cladribine dose) | Change in CSF level of CD3+ T cells absolute numbers from Baseline to second LP at Year 1, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 1 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cells absolute numbers and a negative number indicates decrease in CD3+ T cells absolute numbers. |
| Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Year 2 | Baseline to Year 2 (45 weeks after last cladribine dose) | Change in CSF level of CD3+ T cells absolute numbers from Baseline to second LP at Year 2, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 2 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD3+ T cells absolute numbers and a negative number indicates decrease in CD3+ T cells absolute numbers. |
| Change in CD19+ B Cells % From Baseline to Week 5 | Baseline to Week 5 (5 weeks after first cladribine dose) | Change in CSF level of CD19+ B lymphocytes from Baseline to second LP at Week 5, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Week 5 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cell percentage and a negative number indicates decrease in CD19+ B cell percentage. |
| Change in CD19+ B Cells % From Baseline to Week 10 | Baseline to Week 10 (10 weeks after first cladribine dose) | Change in CSF level of CD19+ B lymphocytes from Baseline to second LP at Week 10, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Week 10 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cell percentage and a negative number indicates decrease in CD19+ B cell percentage. |
| Change in CD19+ B Cells % From Baseline to Year 1 | Baseline to Year 1 (45 weeks after first cladribine dose) | Change in CSF level of CD19+ B lymphocytes from Baseline to second LP at Year 1, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 1 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cell percentage and a negative number indicates decrease in CD19+ B cell percentage. |
| Change in CD19+ B Cells % From Baseline to Year 2 | Baseline to Year 2 (45 weeks after last cladribine dose) | Change in CSF level of CD19+ B lymphocytes from Baseline to second LP at Year 2, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 2 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cell percentage and a negative number indicates decrease in CD19+ B cell percentage. |
| Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Week 5 | Baseline to Week 5 (5 weeks after first cladribine dose) | Change in CSF level of CD19+ B cells absolute numbers from Baseline to second LP at Week 5, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Week 5 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cells absolute numbers and a negative number indicates decrease in CD19+ B cells absolute numbers. |
| Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Week 10 | Baseline to Week 10 (10 weeks after first cladribine dose) | Change in CSF level of CD19+ B cells absolute numbers from Baseline to second LP at Week 10, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Week 10 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cells absolute numbers and a negative number indicates decrease in CD19+ B cells absolute numbers. |
| Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Year 1 | Baseline to Year 1 (45 weeks after first cladribine dose) | Change in CSF level of CD19+ B cells absolute numbers from Baseline to second LP at Year 1, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 1 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cells absolute numbers and a negative number indicates decrease in CD19+ B cells absolute numbers. |
| Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Year 2 | Baseline to Year 2 (45 weeks after last cladribine dose) | Change in CSF level of CD19+ B cells absolute numbers from Baseline to second LP at Year 2, using quality-controlled flow cytometry and assays. Within-group differences from Baseline to Year 2 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in CD19+ B cells absolute numbers and a negative number indicates decrease in CD19+ B cells absolute numbers. |
| Change in the Neurofilament Light Chain (NfL) Level From Baseline to Week 5 | Baseline to Week 5 (5 weeks after first cladribine dose) | Change in CSF level NfL (measured in pg/mL) from baseline to week 5 using the highly sensitive Neurology 4-Plex D Advantage Plus (N4PD+) single molecule array (SIMOA) technology. A single batch of samples with duplicates were run at the conclusion of the study. Within-group differences from baseline to Week 5 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in NfL value and a negative number indicates decrease in NfL value. |
| Change in the Neurofilament Light Chain (NfL) Level From Baseline to Week 10 | Baseline to Week 10 (10 weeks after first cladribine dose) | Change in CSF level NfL (measured in pg/mL) from baseline to Week 10 using the highly sensitive Neurology 4-Plex D Advantage Plus (N4PD+) single molecule array (SIMOA) technology. A single batch of samples with duplicates were run at the conclusion of the study. Within-group differences from baseline to Week 10 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in NfL value and a negative number indicates decrease in NfL value. |
| Change in the Neurofilament Light Chain (NfL) Level From Baseline to Year 1 | Baseline to Year 1 (45 weeks after first cladribine dose) | Change in CSF level NfL (measured in pg/mL) from baseline to Year 1 using the highly sensitive Neurology 4-Plex D Advantage Plus (N4PD+) single molecule array (SIMOA) technology. A single batch of samples with duplicates were run at the conclusion of the study. Within-group differences from baseline to Year 1 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in NfL value and a negative number indicates decrease in NfL value. |
| Change in the Neurofilament Light Chain (NfL) Level From Baseline to Year 2 | Baseline to Year 2 (45 weeks after last cladribine dose) | Change in CSF level NfL (measured in pg/mL) from baseline to year 2 using the highly sensitive Neurology 4-Plex D Advantage Plus (N4PD+) single molecule array (SIMOA) technology. A single batch of samples with duplicates were run at the conclusion of the study. Within-group differences from baseline to year 2 were analyzed using the Wilcoxon signed-rank test because outcome differences were non-normally distributed. Positive number indicates increase in NfL value and a negative number indicates decrease in NfL value. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORGregory Wu, MD, PhD
Washington University School of Medicine
Participant flow
Recruitment details
Potential study participants were identified by the PI and/or collaborators in their clinics or through medical records. A study team member discussed the study and reviewed the consent with prospective participants over the telephone or during a routine office visit. Recruitment began in October of 2019 and ended in June of 2023. Sites were unable to recruit during the height of the COVID pandemic (April & May, 2020).
Pre-assignment details
All 47 eligible participants were randomized to a study arm.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 44.7 years STANDARD_DEVIATION 11.6 |
| Disease (MS) duration | 8.0 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Expanded Disability Status Scale (EDSS) | 2.0 Scores on a scale |
| Multiple Sclerosis (MS) Type Relapsing-remitting multiple sclerosis (RRMS) | 9 Participants |
| Multiple Sclerosis (MS) Type Secondary progressive multiple sclerosis (SPMS) | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 39 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 15 | 0 / 16 | 0 / 7 |
| other Total, other adverse events | 8 / 9 | 12 / 15 | 13 / 16 | 4 / 7 |
| serious Total, serious adverse events | 0 / 9 | 1 / 15 | 0 / 16 | 0 / 7 |
Outcome results
None listed