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

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03963375
• Collaborator: EMD Serono (Industry)
• Enrollment: 50
• Location: 1
• Arms: 4
• Anticipated Duration (Months): 43.1
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting	Drug: Cladribine	Phase 4

Detailed Description

This will be 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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.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.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Cladribine Tablets: Collaborative Study to Evaluate the Impact On Central Nervous System Biomarkers in Multiple Sclerosis
• Actual Study Start Date: Oct 28, 2019
• Anticipated Primary Completion Date: Jun 1, 2023
• Anticipated Study Completion Date: Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Other: 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	Drug: Cladribine; 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.
Other: Group 2: LP at Baseline and Week 10 Group 2: LP at Baseline and end of Week 10. Week 10 is the expected "nadir" time for lymphocyte and monocyte levels in CSF	Drug: Cladribine; 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.
Other: 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	Drug: Cladribine; 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.
Other: 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	Drug: Cladribine; 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.

Outcome Measures

Primary Outcome Measures

1. Changes in the CSF levels of lymphocyte subtypes and markers of neuronal injury during treatment with cladribine tablets in patients with RMS [5 weeks, 10 weeks, 1 year, or 2 years]

   Change in CSF levels of CD3+ T lymphocytes, CD19+ B lymphocytes, and NfL in the CSF from baseline to second LP using quality-controlled flow cytometry and assays

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• EMD Serono

Investigators

• Principal Investigator: Gregory Wu, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03963375
• Other Study ID Numbers: MS700568_0049-201906092
• First Posted: May 24, 2019
• Last Update Posted: Oct 4, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Cladribine

Study Results

No Results Posted as of Oct 4, 2021