Multiple Sclerosis
Conditions
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.
Interventions
DRUGCladribine
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
Sponsors
EMD Serono
University of Texas Southwestern Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute and percent change of T cells, B cells, DC subset and NfL levels in blood. | 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
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate (ARR) | 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
| Measure | Time frame | Description |
|---|---|---|
| The Expanded Disability Status Scale : Neurological disability outcome | 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. |
| Magnetic Resonance imaging (MRI) outcomes | 24 months | The mean number of new or new/ enlarging T2 lesions, and the number of gadolinium (Gd)-enhancing lesions. |
Countries
United States
Outcome results
None listed