Cladribine Tablets: Collaborative Study to Evaluate the Impact On Central Nervous System Biomarkers in Multiple Sclerosis
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- Gregory Wu
- 入组人数
- 47
- 试验地点
- 5
- 主要终点
- Change in CD3+ T Cells % From Baseline to Week 5
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
- •Have moderate or severe renal impairment (creatinine clearance <60 mL per minute)
- •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
- •Are intending to breastfeed on a cladribine tablet treatment day and/or during the 10 days after the last cladribine tablet dose.
研究组 & 干预措施
Group 3: LP at Baseline and End of Year 1
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
干预措施: Cladribine (Drug)
Group 1: LP at Baseline and Week 5
Group 1: LP at Baseline and end of Week 5. Week 5 is the optimal time point for assessing cladribine concentrations in CSF
干预措施: Cladribine (Drug)
Group 2: LP at Baseline and Week 10
Group 2: LP at Baseline and end of Week 10. Week 10 is the hypothesized "nadir" time for lymphocyte and monocyte levels in CSF
干预措施: Cladribine (Drug)
Group 4: LP at Baseline and End of Year 2
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
干预措施: Cladribine (Drug)
结局指标
主要结局
Change in CD3+ T Cells % From Baseline to Week 5
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
未报告次要终点
研究者
Gregory Wu
Principal Investigator
Washington University School of Medicine