Cladribine Tablets After Treatment With Natalizumab (CLADRINA)
NCT ID: NCT04178005
Last Updated: 2025-12-08
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
ACTIVE_NOT_RECRUITING
Clinical Phase
PHASE4
Total Enrollment
40 participants
Study Classification
INTERVENTIONAL
Study Start Date
2020-02-19
Study Completion Date
2026-12-31
Brief Summary
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The purpose of this study is to generate hypotheses regarding the safety, efficacy, and immunological impact of cladribine tablets after treatment with natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (active SPMS).
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Detailed Description
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This will be an open label, single arm, multicenter, collaborative phase 4 research study, designed to generate hypotheses regarding the transition to cladribine tablets after treatment with natalizumab in patients with relapsing forms of multiple sclerosis MS, to include relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).
The total duration of this interventional study will be 2 years, but patients who require additional time (up to 6 months) for recovery of Absolute lymphocyte count (ALC) to 800 cells/ul prior to the second treatment course will be followed for up to 6 additional months in order to have a full second year of follow up after initiation of the second year's treatment course (for a total study duration of up to 30 months in some patients). A total of 40 study participants with relapsing forms of MS, to include RRMS and active SPMS, who meet the criteria for treatment with cladribine tablets as per the approved United States Prescribing Information (USPI) are planned to be enrolled at up to three centers in the United States. All study participants will receive treatment with cladribine 10 mg tablets during year 1 and year 2 according to the approved USPI (EMD Serono, 2019). Cladribine 10 mg tablets will be provided as commercial material. Treatment with cladribine tablets is intended to be initiated approximately 14 days after the last infusion of natalizumab (e.g., a 14-day "washout"), with a maximum permissible washout period of no more than four weeks.
After successful completion of the study, all participants in CLADRINA will be offered to participate in the CLADRINA 2-Year Extension study. During this extension trial, there will be no intervention. Patient will be followed for an additional 24 months, and their clinical and paraclinical disease activity will be assessed through neurological examinations, EDSS scores, brain MRI, and biological markers.
The total duration of this interventional study will be 2 years, but patients who require additional time (up to 6 months) for recovery of Absolute lymphocyte count (ALC) to 800 cells/ul prior to the second treatment course will be followed for up to 6 additional months in order to have a full second year of follow up after initiation of the second year's treatment course (for a total study duration of up to 30 months in some patients). A total of 40 study participants with relapsing forms of MS, to include RRMS and active SPMS, who meet the criteria for treatment with cladribine tablets as per the approved United States Prescribing Information (USPI) are planned to be enrolled at up to three centers in the United States. All study participants will receive treatment with cladribine 10 mg tablets during year 1 and year 2 according to the approved USPI (EMD Serono, 2019). Cladribine 10 mg tablets will be provided as commercial material. Treatment with cladribine tablets is intended to be initiated approximately 14 days after the last infusion of natalizumab (e.g., a 14-day "washout"), with a maximum permissible washout period of no more than four weeks.
After successful completion of the study, all participants in CLADRINA will be offered to participate in the CLADRINA 2-Year Extension study. During this extension trial, there will be no intervention. Patient will be followed for an additional 24 months, and their clinical and paraclinical disease activity will be assessed through neurological examinations, EDSS scores, brain MRI, and biological markers.
Conditions
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Multiple Sclerosis
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Cladribine
All study participants will receive treatment with cladribine 10 mg tablets at the recommended cumulative dose of 3.5 mg/kg, divided into 2 yearly treatment courses (1.75 mg/kg per treatment course). This regimen corresponds to the recommended dosage as per the USPI.
Each treatment course is divided into 2 treatment cycles:
* Administration of first treatment course (year 1 treatment):
* First cycle: Starts on Day 1 of the study
* Second cycle: Administered 23 to 27 days after the last dose of first cycle.
* Administration of second treatment course (year 2 treatment):
* First cycle: Administered at least 43 weeks after the last dose of year 1 treatment
* Second cycle: Administered 23 to 27 days after the last dose of first cycle of year 2 treatment.
The cycle dosage will be administered as 1 or 2 cladribine 10 mg tablets daily over 4 or 5 consecutive days.
Group Type
OTHER
Cladribine
Intervention Type
DRUG
All study participants will receive treatment with cladribine 10 mg tablets at the recommended cumulative dose of 3.5 mg/kg, divided into 2 yearly treatment courses (1.75 mg/kg per treatment course). This regimen corresponds to the recommended dosage as per the USPI
Interventions
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Cladribine
All study participants will receive treatment with cladribine 10 mg tablets at the recommended cumulative dose of 3.5 mg/kg, divided into 2 yearly treatment courses (1.75 mg/kg per treatment course). This regimen corresponds to the recommended dosage as per the USPI
Intervention Type
DRUG
Other Intervention Names
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Mavenclad
Eligibility Criteria
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Inclusion Criteria
1. Age between 18 and 60 years, inclusive.
2. Diagnosis of relapsing forms of MS, to include RRMS and active SPMS, diagnosed with McDonald Criteria 2005, 2010, and/or 2017 (1-3)
3. EDSS 0 - 5.5 (Functional system changes in cerebral (or mental) functions and in bowel and bladder functions not used in determining EDSS for protocol eligibility).
4. Has had a minimum of 12 months of continuous natalizumab therapy (300 mg/d), including patients receiving extended interval dosing of natalizumab (e.g., less frequently than every-4-week infusion).
5. Negative history for any relapses at least 28 days prior to enrollment.
6. Weighing between 40 kilograms or more.
7. Female subjects of childbearing potential must use effective methods of contraception to prevent pregnancy for 4 weeks before initiation of cladribine tablets and must agree to continue to practice adequate contraception for at least 6 months after the last dose. Women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year.
8. Female subjects must not be pregnant; female subjects must not be lactating or breast-feeding at least 10 days after the last dose.
9. Male subjects must be willing to use a condom during dosing and for six months after the last dose. Alternatively, their female partner must use another form of contraception (such as an intra-uterine device \[IUD\], barrier method with spermicide, or hormonal contraceptive \[e.g., implant, injectable, patch or oral\]) during dosing and for six months after last dose.
10. Understands and is capable of following through with study protocol requirements and assessments.
11. Willing to provide voluntary and informed consent based on the Health Insurance Portability and Accountability Act (HIPPA).
2. Diagnosis of relapsing forms of MS, to include RRMS and active SPMS, diagnosed with McDonald Criteria 2005, 2010, and/or 2017 (1-3)
3. EDSS 0 - 5.5 (Functional system changes in cerebral (or mental) functions and in bowel and bladder functions not used in determining EDSS for protocol eligibility).
4. Has had a minimum of 12 months of continuous natalizumab therapy (300 mg/d), including patients receiving extended interval dosing of natalizumab (e.g., less frequently than every-4-week infusion).
5. Negative history for any relapses at least 28 days prior to enrollment.
6. Weighing between 40 kilograms or more.
7. Female subjects of childbearing potential must use effective methods of contraception to prevent pregnancy for 4 weeks before initiation of cladribine tablets and must agree to continue to practice adequate contraception for at least 6 months after the last dose. Women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year.
8. Female subjects must not be pregnant; female subjects must not be lactating or breast-feeding at least 10 days after the last dose.
9. Male subjects must be willing to use a condom during dosing and for six months after the last dose. Alternatively, their female partner must use another form of contraception (such as an intra-uterine device \[IUD\], barrier method with spermicide, or hormonal contraceptive \[e.g., implant, injectable, patch or oral\]) during dosing and for six months after last dose.
10. Understands and is capable of following through with study protocol requirements and assessments.
11. Willing to provide voluntary and informed consent based on the Health Insurance Portability and Accountability Act (HIPPA).
Exclusion Criteria
1. Natalizumab failure based on clinician's discretion.
2. Not active progressive MS (4).
3. A diagnosis of PML or any suspicion of PML.
4. A diagnosis of Clinically Isolated Syndrome
5. Known hypersensitivity to cladribine.
6. Any prior exposure to cladribine.
7. Lymphocyte count not within normal limits of the local, hospital laboratory.
8. Previous or current exposure to mitoxantrone, azathioprine, methotrexate, cyclophosphamide, myelosuppressive treatments, total lymphoid irradiation.
9. Receiving oral or systemic corticosteroid treatments within the 28 days prior to enrollment.
10. Receiving cytokine base treatment, Intra Venous Immuno Globulin (IVIG) or Plasma pheresis, 3 months prior to enrollment in the study.
11. Having platelet count or neutrophil count below the lower limit of the normal range within the 28 days prior to enrollment in the study.
12. Positive for HIV, or positive hepatitis C antibody test or hepatitis B surface antigen test and/or core antibody test for IgG and/or IgM.
13. History of tuberculosis (TB), presence of active tuberculosis, or latent tuberculosis as detected by local standard of practice like imaging (e.g., chest X-ray, chest CT scan, MRI) and/or positive QuantiFERON-TB Gold test and/or skin test and/or clinical examination or has had latent TB disease at any time in the past.
14. Immunocompromised subjects, including subjects currently receiving immunosuppressive or myelosuppressive therapy with, e.g., monoclonal antibodies, methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids.
15. Active malignancy or history of malignancy.
16. Received a live vaccine within 6 weeks prior to cladribine tablet administration or intends to receive a live vaccination during the trial. After the last dose of cladribine tablets, the subject should avoid live vaccine as long as the subject's white blood cell counts are not within normal limits.
17. Allergy or hypersensitivity to gadolinium and/or any other contraindication to perform an MRI.
18. Has any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR \< 30 mL/min/1.73m2)
\-
2. Not active progressive MS (4).
3. A diagnosis of PML or any suspicion of PML.
4. A diagnosis of Clinically Isolated Syndrome
5. Known hypersensitivity to cladribine.
6. Any prior exposure to cladribine.
7. Lymphocyte count not within normal limits of the local, hospital laboratory.
8. Previous or current exposure to mitoxantrone, azathioprine, methotrexate, cyclophosphamide, myelosuppressive treatments, total lymphoid irradiation.
9. Receiving oral or systemic corticosteroid treatments within the 28 days prior to enrollment.
10. Receiving cytokine base treatment, Intra Venous Immuno Globulin (IVIG) or Plasma pheresis, 3 months prior to enrollment in the study.
11. Having platelet count or neutrophil count below the lower limit of the normal range within the 28 days prior to enrollment in the study.
12. Positive for HIV, or positive hepatitis C antibody test or hepatitis B surface antigen test and/or core antibody test for IgG and/or IgM.
13. History of tuberculosis (TB), presence of active tuberculosis, or latent tuberculosis as detected by local standard of practice like imaging (e.g., chest X-ray, chest CT scan, MRI) and/or positive QuantiFERON-TB Gold test and/or skin test and/or clinical examination or has had latent TB disease at any time in the past.
14. Immunocompromised subjects, including subjects currently receiving immunosuppressive or myelosuppressive therapy with, e.g., monoclonal antibodies, methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids.
15. Active malignancy or history of malignancy.
16. Received a live vaccine within 6 weeks prior to cladribine tablet administration or intends to receive a live vaccination during the trial. After the last dose of cladribine tablets, the subject should avoid live vaccine as long as the subject's white blood cell counts are not within normal limits.
17. Allergy or hypersensitivity to gadolinium and/or any other contraindication to perform an MRI.
18. Has any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR \< 30 mL/min/1.73m2)
\-
Minimum Eligible Age
18 Years
Maximum Eligible Age
60 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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EMD Serono
INDUSTRY
Sponsor Role
collaborator
University of Texas Southwestern Medical Center
OTHER
Sponsor Role
lead
Responsible Party
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Olaf Stuve
Professor of Medicine
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Olaf Stuve, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
UT Southwestern Medical Center
Locations
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College Park Family Care Center Physicians Group
Overland Park, Kansas, United States
Site Status
UT Southwestern Medical center
Dallas, Texas, United States
Site Status
Countries
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United States
References
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Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC. Identification of targets and new developments in the treatment of multiple sclerosis--focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. doi: 10.2147/dddt.s6627.
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Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stuve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86. doi: 10.1212/WNL.0000000000000560. Epub 2014 May 28.
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Shirani A, Stuve O. Natalizumab for Multiple Sclerosis: A Case in Point for the Impact of Translational Neuroimmunology. J Immunol. 2017 Feb 15;198(4):1381-1386. doi: 10.4049/jimmunol.1601358.
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Shirani A, Stuve O. Natalizumab: Perspectives from the Bench to Bedside. Cold Spring Harb Perspect Med. 2018 Dec 3;8(12):a029066. doi: 10.1101/cshperspect.a029066.
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BACKGROUND
Stuve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Hemmer B, Monson NL, Racke MK. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2006 May;59(5):743-7. doi: 10.1002/ana.20858.
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BACKGROUND
Stuve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von Geldern G, Cepok S, Singh MP, Tervaert JW, De Baets M, MacManus D, Miller DH, Radu EW, Cameron EM, Monson NL, Zhang S, Kim R, Hemmer B, Racke MK. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009 Feb 3;72(5):396-401. doi: 10.1212/01.wnl.0000327341.89587.76. Epub 2008 Nov 5.
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BACKGROUND
del Pilar Martin M, Cravens PD, Winger R, Frohman EM, Racke MK, Eagar TN, Zamvil SS, Weber MS, Hemmer B, Karandikar NJ, Kleinschmidt-DeMasters BK, Stuve O. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol. 2008 Dec;65(12):1596-603. doi: 10.1001/archneur.65.12.noc80051. Epub 2008 Oct 13.
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BACKGROUND
Yao K, Gagnon S, Akhyani N, Williams E, Fotheringham J, Frohman E, Stuve O, Monson N, Racke MK, Jacobson S. Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS One. 2008 Apr 30;3(4):e2028. doi: 10.1371/journal.pone.0002028.
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BACKGROUND
Stuve O, Bennett JL. Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev. 2007 Spring;13(1):79-95. doi: 10.1111/j.1527-3458.2007.00003.x.
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Cutter GR, Stuve O. Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? Mult Scler. 2014 Sep;20(10):1304-5. doi: 10.1177/1352458514531843. Epub 2014 May 8.
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De Stefano N, Giorgio A, Battaglini M, De Leucio A, Hicking C, Dangond F, Giovannoni G, Sormani MP. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets. Mult Scler. 2018 Feb;24(2):222-226. doi: 10.1177/1352458517690269. Epub 2017 Jan 31.
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Comi G, Cook S, Rammohan K, Soelberg Sorensen P, Vermersch P, Adeniji AK, Dangond F, Giovannoni G. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. Ther Adv Neurol Disord. 2018 Jan 23;11:1756285617753365. doi: 10.1177/1756285617753365. eCollection 2018.
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Freedman MS, Leist TP, Comi G, Cree BA, Coyle PK, Hartung HP, Vermersch P, Damian D, Dangond F. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802. doi: 10.1177/2055217317732802. eCollection 2017 Oct-Dec.
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BACKGROUND
Other Identifiers
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STU 2019-1618
Identifier Type: -
Identifier Source: org_study_id
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Natalizumab in Combination With Glatiramer Acetate (GA) in Patients With Relapsing-Remitting Multiple Sclerosis
NCT00097760
COMPLETED
PHASE2
Oral Cladribine in Early Multiple Sclerosis (MS)
NCT00725985
COMPLETED
PHASE3
Consolidation Therapy with Cladribine in Relapsing Multiple Sclerosis Patients
NCT06854094
RECRUITING
Exploratory Study of the Safety, Tolerability and Efficacy of Multiple Regimens of Natalizumab in Adult Participants With Relapsing Multiple Sclerosis (MS)
NCT01405820
COMPLETED
PHASE2
Role of Simvastatin in Relapsing-Remitting Multiple Sclerosis
NCT04178980
UNKNOWN
PHASE1
Safety Study of Natalizumab to Treat Multiple Sclerosis (MS)
NCT00559702
COMPLETED
PHASE1
Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
NCT03109288
RECRUITING
PHASE1/PHASE2
A Prospective Biomarker Study in Active SPMS Subjects Treated With Cladribine Tablets
NCT04550455
RECRUITING
PHASE4
Prospective Observational Long-term Safety Registry of Multiple Sclerosis Participants Who Have Participated in Cladribine Clinical Trials
NCT01013350
COMPLETED
Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis
NCT02040298
COMPLETED
PHASE2
Assessing Changes in Multi-parametric MRI in MS Patients Taking Clemastine Fumarate as a Myelin Repair Therapy
NCT05359653
RECRUITING
PHASE1/PHASE2
A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)
NCT00436826
COMPLETED
PHASE2
Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis
NCT00027300
COMPLETED
PHASE3
Phase II Study of Teriflunomide as Adjunctive Therapy to Glatiramer Acetate in Subjects With Multiple Sclerosis
NCT00475865
COMPLETED
PHASE2
Study of the Mechanisms of Action of Cladribine in Multiple Sclerosis
NCT04821596
UNKNOWN
NA
Long-Term Outcomes and Durability of Effect Following Treatment With Cladribine Tablets for MS (CLASSIC-MS)
NCT03961204
COMPLETED
PHASE4
A Safety and Efficacy Study of ELND002 in Patients With Relapsing Forms of Multiple Sclerosis
NCT01144351
TERMINATED
PHASE1
A Study to Test the Use of Duloxetine for Pain in MS
NCT00457730
COMPLETED
PHASE2/PHASE3
Cladribine Tablets as an Exit Therapy Strategy
NCT06887426
NOT_YET_RECRUITING
ChariotMS - Cladribine to Halt Deterioration in People With Advanced Multiple Sclerosis
NCT04695080
ACTIVE_NOT_RECRUITING
PHASE2/PHASE3
Safety and Efficacy of Intrathecal Rituximab in Patients With Multiple Sclerosis
NCT05078177
UNKNOWN
PHASE1