CLICK-MS and MASTER-2 Phase IV Trial Design: Cladribine Tablets in Suboptimally Controlled Relapsing Multiple Sclerosis

Miravalle, Augusto; Katz, Jordan; Robertson, Derrick; Hayward, Brooke; Harlow, Danielle E.; Lebson, Lori; Bass, Ann D; Fox, Edward J.

doi:10.2217/nmt-2020-0059

Cited by 6 publications

(6 citation statements)

References 42 publications

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“…Subsequent clinical trials, clinical trials extensions, trial cohort follow-ups, and other studies have confirmed cladribine as a potent DMD for MS patients, with therapeutic efficiency lasting between 2-5 years or even up to 8 years in some individuals ( 29 , 42 , 44 – 49 ). Other ongoing clinical trials are aiming to further establish clear therapeutic indications for MS patients in various stages of the disease and clinical contexts ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

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BackgroundMultiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3−CCR6+IFNγ−IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17− phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients.MethodsAn experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology.ResultsEx vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro.ConclusionsCD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.

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Section: Discussionmentioning

confidence: 99%

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

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“…PROs on the effectiveness and safety of cladribine tablets, including fatigue (through the 5-item version of Modified Fatigue Impact Scale), physical functioning (36-Item Short Form Health Survey), TSQM v1.4, and WPAI-MS, are also being evaluated as part of the CLICK-MS and MASTER-2 trials [ 28 ] and will provide a useful comparison with the results described in our study.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Patient-Reported Outcomes in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets in the CLAWIR Study: 12-Month Interim Analysis

Rau,

Müller,

Übler

2023

Adv Ther

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Introduction Patient-reported outcomes (PROs) provide an insightful method of assessing the subjective impact of therapies for those affected by multiple sclerosis (MS), a chronic neurologic disease notable for symptoms of fatigue and reduced physical function. The ongoing CLAWIR study aims to assess the effect of cladribine tablets (3.5 mg/kg cumulative dose over 2 years) in patients with highly active relapsing MS focusing on PROs of fatigue, physical function, treatment satisfaction, and work productivity. Here, we report on a pre-planned analysis at 12 months after treatment initiation with cladribine tablets. Methods CLAWIR is a 2-year, multicenter, prospective, observational study of patients with relapsing MS newly initiating cladribine tablets. The following PROs were analyzed: PRO Measurement Information System (PROMIS ® ) Fatigue MS (v1.0) and Physical Function MS (v2.1), Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4), and Work Productivity and Activity Impairment MS Questionnaire (WPAI-MS). Data were analyzed descriptively. Results In total, 128 patients were eligible for analysis: 95 females (74.2%); median (range) age 34.5 (29, 44) years; 34 patients (26.6%) were treatment-naïve, and 89 (69.5%) were early switchers from platform therapies (the remaining 5 patients [3.9%] switched from a high-efficacy disease-modifying therapy). PROMIS ® Fatigue MS mean (± standard deviation [SD]) T-scores decreased from 54.6 (± 9.59) at baseline to 51.8 (± 10.30) at 12 months, indicating an alleviation of fatigue, whereas PROMIS ® Physical Function MS mean T-scores remained stable over time [baseline: 49.4 (± 10.69); 12 months: 50.3 (± 10.88)]. TSQM v1.4 mean scores indicated an improvement over time, increasing from 52.2 (± 27.79) at baseline to 81.4 (± 17.06) at 12 months for global satisfaction. WPAI-MS scores also showed an improvement across all four domains over 12 months. Conclusion This real-world study demonstrates the effect of cladribine tablets over 12 months on PROs of fatigue, physical function, treatment satisfaction, and work productivity. Trial Registration The CLAWIR study is registered at the German Federal Institute for Drugs and Medical Devices with the internal NIS number 7469.

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“…The primary endpoint is 24-month annualized relapse rate. Key secondary endpoints include patient-reported outcomes on quality of life measures, treatment adherence, and AEs [ 57 ].…”

Section: Emerging Data On the Efficacy Of Cladribine Tabletsmentioning

confidence: 99%

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

Giovannoni

Mathews

2022

Neurol Ther

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CLICK-MS and MASTER-2 Phase IV Trial Design: Cladribine Tablets in Suboptimally Controlled Relapsing Multiple Sclerosis

Cited by 6 publications

References 42 publications

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Evaluation of Patient-Reported Outcomes in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets in the CLAWIR Study: 12-Month Interim Analysis

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

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