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Cladribine Tablets After Treatment With Natalizumab (CLADRINA)

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ClinicalTrials.gov Identifier: NCT04178005
Recruitment Status : Recruiting
First Posted : November 26, 2019
Last Update Posted : February 23, 2021
Sponsor:
Collaborator:
EMD Serono
Information provided by (Responsible Party):
Olaf Stuve, University of Texas Southwestern Medical Center

Study Description
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Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Cladribine Phase 4

Detailed Description:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cladribine Tablets After Treatment With Natalizumab (CLADRINA)
Actual Study Start Date : February 19, 2020
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Cladribine

Arms and Interventions
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Arm Intervention/treatment
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.

 Drug: 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
Other Name: Mavenclad


Outcome Measures
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Primary Outcome Measures :
  1. Absolute and percent change of T cells, B cells, DC subset and NfL levels in blood. [ Time Frame: 24 months ]
    The absolute and percent change from baseline will be presented for each time point for CD3+ T lymphocytes, CD19+ B lymphocytes, CD11c+ DC subsets, NfL levels in blood, with a two-sided 95% CI and p value. As these data are not expected to be normally distributed, the nonparametric Wilcoxon signed rank test will be used to compare each biomarker at baseline and during treatment. Spearman rank correlations will be used to examine the relationship between biomarkers and clinical/safety endpoints.


Secondary Outcome Measures :
  1. Annualized Relapse Rate (ARR) [ Time Frame: 12 months ]
    The ARR over the 12- and 24-month periods will be presented, accompanied by the respective 95% CIs. The proportion (and 95% CI) of participants experiencing a relapse over the 12 month and 24-month periods will also be presented.


Other Outcome Measures:
  1. The Expanded Disability Status Scale : Neurological disability outcome [ Time Frame: 24 months ]

    The Expanded Disability Status Scale (EDSS) will be utilized to measure the accumulation of neurological disability.

    The change in EDSS from baseline will be reported at month 12 and month 24. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability.

    EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any aid and is based on measures of impairment in eight functional systems (FS):

    muscle weakness or difficulty moving limbs, ataxia, loss of balance, coordination or tremor, problems with speech, swallowing and nystagmus, numbness or loss of sensations, bowel and bladder function, problems with sight, problems with thinking and memory, other A functional system (FS) represents a network of neurons in the brain with responsibility for particular tasks. Each FS is scored on a scale of 0 (no disability) to 5 or 6 (more severe disability).

    EDSS steps 5.0 to 9.5 are defined by the impairment to walking.


  2. Magnetic Resonance imaging (MRI) outcomes [ Time Frame: 24 months ]
    The mean number of new or new/ enlarging T2 lesions, and the number of gadolinium (Gd)-enhancing lesions.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients who meet the following inclusion criteria will be eligible for enrollment in the study:

  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).

Exclusion Criteria:

Patients who meet any of the following exclusion criteria will not be eligible for enrollment in the study:

  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)

    -

Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04178005


Contacts
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Contact: Rehana Hussain 214-648-7244 Rehana.Hussain@utsouthwestern.edu

Locations
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United States, Texas
UT Southwestern Medical center Recruiting
Dallas, Texas, United States, 75390
Contact: Rehana Z Hussain, M.Sc    214-648-7244    Rehana.Hussain@utsouthwestern.edu   
Principal Investigator: Olaf Stuve, M.D., Ph.D         
Sponsors and Collaborators
University of Texas Southwestern Medical Center
EMD Serono
More Information
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Publications:

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Responsible Party: Olaf Stuve, Professor of Medicine, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT04178005    
Other Study ID Numbers: STU 2019-1618
First Posted: November 26, 2019    Key Record Dates
Last Update Posted: February 23, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: Yes
Additional relevant MeSH terms:
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Multiple Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
 Immune System Diseases
Cladribine
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs