Cladribine Tablets: Collaborative Study to Evaluate Impact On Central Nervous System Biomarkers in Multiple Sclerosis

NCT03963375 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: MS700568_0049-201906092
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 5

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).

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Outcome Measures

Primary Outcomes (20)

• Change in CD3+ T Cells % From Baseline to Week 5

  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.

  Baseline to Week 5 (5 weeks after first cladribine dose)

• Change in CD3+ T Cells % From Baseline to Week 10

  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.

  Baseline to Week 10 (10 weeks after first cladribine dose)

• Change in CD3+ T Cells % From Baseline to Year 1

  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.

  Baseline to Year 1 (45 weeks after first cladribine dose)

• Change in CD3+ T Cells % From Baseline to Year 2

  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.

  Baseline to Year 2 (45 weeks after last cladribine dose)

• Change in CD3+ T Cells Absolute Numbers (Cells/mL) From 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.

  Baseline to Week 5

• Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Week 10

  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.

  Baseline to Week 10 (10 weeks after first cladribine dose)

• Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Year 1

  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.

  Baseline to Year 1 (45 weeks after first cladribine dose)

• Change in CD3+ T Cells Absolute Numbers (Cells/mL) From Baseline to Year 2

  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.

  Baseline to Year 2 (45 weeks after last cladribine dose)

• Change in CD19+ B Cells % From Baseline to Week 5

  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.

  Baseline to Week 5 (5 weeks after first cladribine dose)

• Change in CD19+ B Cells % From Baseline to Week 10

  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.

  Baseline to Week 10 (10 weeks after first cladribine dose)

• Change in CD19+ B Cells % From Baseline to Year 1

  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.

  Baseline to Year 1 (45 weeks after first cladribine dose)

• Change in CD19+ B Cells % From Baseline to Year 2

  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.

  Baseline to Year 2 (45 weeks after last cladribine dose)

• Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Week 5

  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.

  Baseline to Week 5 (5 weeks after first cladribine dose)

• Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Week 10

  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.

  Baseline to Week 10 (10 weeks after first cladribine dose)

• Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Year 1

  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.

  Baseline to Year 1 (45 weeks after first cladribine dose)

• Change in CD19+ B Cells Absolute Numbers (Cells/mL) From Baseline to Year 2

  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.

  Baseline to Year 2 (45 weeks after last cladribine dose)

• Change in the Neurofilament Light Chain (NfL) Level From Baseline to Week 5

  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.

  Baseline to Week 5 (5 weeks after first cladribine dose)

• Change in the Neurofilament Light Chain (NfL) Level From Baseline to Week 10

  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.

  Baseline to Week 10 (10 weeks after first cladribine dose)

• Change in the Neurofilament Light Chain (NfL) Level From Baseline to Year 1

  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.

  Baseline to Year 1 (45 weeks after first cladribine dose)

• Change in the Neurofilament Light Chain (NfL) Level From Baseline to Year 2

  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.

  Baseline to Year 2 (45 weeks after last cladribine dose)

Study Arms (4)

Group 1: LP at Baseline and Week 5

OTHER

Group 1: LP at Baseline and end of Week 5. Week 5 is the optimal time point for assessing cladribine concentrations in CSF

Drug: Cladribine

Group 2: LP at Baseline and Week 10

OTHER

Group 2: LP at Baseline and end of Week 10. Week 10 is the hypothesized "nadir" time for lymphocyte and monocyte levels in CSF

Drug: Cladribine

Group 3: LP at Baseline and End of Year 1

OTHER

Group 3: LP at Baseline and end of Year 1. To assess if cladribine effects on CSF markers are maintained at the end of the first treatment cycle

Drug: Cladribine

Group 4: LP at Baseline and End of Year 2

OTHER

Group 4: LP at Baseline and end of Year 2. To assess if cladribine effects on CSF markers are maintained at the end of the last treatment cycle

Drug: Cladribine

Interventions

Cladribine DRUG

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.

Group 1: LP at Baseline and Week 5; Group 2: LP at Baseline and Week 10; Group 3: LP at Baseline and End of Year 1; Group 4: LP at Baseline and End of Year 2

Eligibility Criteria

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

You may qualify if:

• Have a relapsing form of multiple sclerosis (RMS; to include RRMS or active secondary progressive MS)
• Are willing and able to receive at least 2 lumbar punctures
• Have an EDSS of 0 to ≤ 5.5 during the screening period
• Had at least 1 relapse or 1 gadolinium-enhancing or 1 new or enlarged T2 lesion in the last 12 months
• 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
• Capable of giving signed informed consent

You may not qualify if:

• Have any contraindication for lumbar puncture
• Have current malignancy
• Are infected with human immunodeficiency virus (HIV)
• Have active chronic infections (e.g. hepatitis or tuberculosis)
• Have signs or symptoms suggestive of progressive multifocal leukoencephalopathy (PML) in MRI
• Have history of hypersensitivity to cladribine or any of the excipients listed in the cladribine tablets US Prescribing Information
• Allergy or hypersensitivity to gadolinium and/or any other contraindication to perform a MRI
• Have any other comorbid conditions that preclude participation
• Have been previously treated with cladribine
• Have previously been treated with ocrelizumab, alemtuzumab, rituximab, or daclizumab
• Have received treatment with natalizumab during the last 6 months
• Are currently receiving immunosuppressive or myelosuppressive therapy, e.g., methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic treatment with systemic corticosteroids
• Have received treatment with immunosuppressive or myelosuppressive therapy during the last 6 months
• Have received chronic treatment with systemic corticosteroids during the last 4 weeks
• Have moderate or severe hepatic impairment (Child-Pugh score \>6)

Sponsors & Collaborators

• EMD Serono: collaborator
• Gregory Wu: lead

Study Sites (5)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, 73104, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Interventions

Cladribine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Gregory Wu, MD, PhD, FAAN and Study PI
• Organization: Washington University in St. Louis

gfwu@wustl.edu

(314) 362-3293

Study Officials

• Gregory Wu, MD, PhD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: May 23, 2019
• First Posted: May 24, 2019
• Study Start: October 28, 2019
• Primary Completion: May 27, 2025
• Study Completion: May 27, 2025
• Last Updated: July 28, 2026
• Results First Posted: July 28, 2026

Record last verified: 2026-07

Locations

US (5)