Clinical trial NCT04178005: Cladribine Tablets After Treatment With Natalizumab (CLADRINA)
Official title: Cladribine Tablets After Treatment With Natalizumab (CLADRINA)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Multiple Sclerosis
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: EMD Serono
First posted: 2019-11-26
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

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.

Eligibility 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)

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Primary outcomes:
measure: Absolute and percent change of T cells, B cells, DC subset and NfL levels in blood.
timeFrame: 24 months
Secondary outcomes:
measure: Annualized Relapse Rate (ARR)
timeFrame: 12 months
Other outcomes:
measure: The Expanded Disability Status Scale : Neurological disability outcome
timeFrame: 24 months
measure: Magnetic Resonance imaging (MRI) outcomes
timeFrame: 24 months
Locations:
city: Overland Park
country: United States
facility: College Park Family Care Center Physicians Group
state: Kansas
city: Dallas
country: United States
facility: UT Southwestern Medical center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Olaf Stuve, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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