Cladribine Tablets After Treatment With Natalizumab (CLADRINA)
Cladribine Tablets After Treatment With Natalizumab (CLADRINA)
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).
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.
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)

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