Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets.
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ABSTRACT:
SUBMITTER: De Stefano N
PROVIDER: S-EPMC5818021 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets.
De Stefano Nicola N Giorgio Antonio A Battaglini Marco M De Leucio Alessandro A Hicking Christine C Dangond Fernando F Giovannoni Gavin G Sormani Maria Pia MP
Multiple sclerosis (Houndmills, Basingstoke, England) 20170131 2
<h4>Background</h4>Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage.<h4>Methods</h4>In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS).<h4>Results</h4>Compared with placebo (-0.70% ± 0.79), PBVC/y was reduce ...[more]
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Project description:Cladribine Tablets (MAVENCLAD®) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and maximum concentration (Cmax) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.
| S-EPMC6373393 | biostudies-literature
Project description:Cladribine is a deoxyadenosine analogue prodrug that preferentially depletes lymphocytes, key cells underlying multiple sclerosis (MS) pathogenesis. Cladribine tablets (Mavenclad®) represent the first short-course oral disease-modifying drug (DMD) for use in MS. The tablets, administered in two short courses 1 year apart, are indicated for the treatment of adults with highly active relapsing MS on the basis of data from pivotal clinical trials, including the phase 3 study CLARITY and its extension. A cumulative cladribine tablets dose of 3.5 mg/kg administered in this fashion in CLARITY reduced clinical relapse, disability progression and MRI-assessed disease activity and also improved some aspects of health-related quality of life (HR-QOL) versus placebo over 96 weeks in adults with relapsing-remitting MS (RRMS). Moreover, in the 96-week extension (plus 24 weeks' supplemental follow-up), no additional clinical benefit was gained from continuing versus discontinuing cladribine tablets after the first two annual courses of therapy, although MRI activity was more notable in a subset of cladribine tablet recipients who discontinued the drug. In post hoc analyses of CLARITY and/or a phase 2b trial, benefits of cladribine tablets were seen in patients with high disease activity (HDA) relapsing MS that were sometimes greater than in patients without HDA. Cladribine tablets have an acceptable tolerability profile and do not appear to be associated with an increased risk of overall infection or with an increased risk of malignancy (vs. matched reference populations). Active comparisons and longer-term follow-up would be beneficial, although current data indicate that for adults with highly active relapsing MS, cladribine tablets are an effective treatment option with the convenience of low-burden, short-course, oral administration.
| S-EPMC6353806 | biostudies-literature
Project description:BackgroundCladribine tablets have recently become available in The Netherlands for patients with relapsing-remitting multiple sclerosis (RRMS) as a disease-modifying agent that reduces the frequency and severity of relapses and delays disability progression.ObjectiveThe aim of this study was to evaluate the cost effectiveness of cladribine tablets, compared with alternative options, in the treatment of RRMS patients with high disease activity (HDA) and patients with rapidly evolving severe (RES) MS in The Netherlands.MethodsA Markov model was developed simulating the costs and effects of RRMS treatment. For HDA, alemtuzumab and fingolimod were used as comparators; natalizumab was used for the RES subpopulation. The analysis included a societal perspective and a value-of-information (VOI) analysis.ResultsFor the HDA subpopulation, treatment with cladribine tablets was the cost-effective (dominant) strategy compared with alemtuzumab and fingolimod, with 50.9% and 98.2%, respectively, probability of being cost effective at a threshold of €50,000/QALY gained and a net monetary benefit (NMB) of €10,866 and €151,115, respectively. For the RES subpopulation, treatment with cladribine tablets dominated treatment with natalizumab, with 94.1% probability of being cost effective at a threshold of €50,000/QALY gained and an NMB of €122,986. Note that these outcomes are driven by the lower costs of cladribine tablets. Efficacy differences were small, very uncertain, and likely not clinically meaningful. The probabilistic sensitivity analyses showed significant overlap in the credible intervals for total lifetime QALY outcomes and costs of cladribine tablets and all relevant comparators. The population-level VOI amounted to €19,295,441.ConclusionsThe base-case analysis shows that treatment of RRMS with cladribine tablets is cost effective versus alemtuzumab and fingolimod in HDA patients, and cost effective versus natalizumab in RES patients, at a threshold of €50,000. Driven by the lower costs, cladribine tablets were cost effective (dominant) in all base-case analyses. However, given that outcomes are based on indirect comparisons and post hoc subgroup analysis, as well as the uncertainty surrounding the outcomes, the results presented in this paper should be interpreted with caution.
| S-EPMC6885501 | biostudies-literature
Project description:Cladribine tablets (CladT) preferentially reduce B and T lymphocyte levels. As aging is associated with a decline in immune function, the effect of CladT on lymphocyte levels may differ by age. This post hoc analysis combined data from the Phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies to examine the effect of age (≤50 or >50 years) on lymphopenia following CladT 3.5 mg/kg (CladT3.5; cumulative dose over 2 years) treatment over 96 weeks. Both CladT3.5 and placebo were given over Weeks 1 and 5 (Year 1 treatment) and Weeks 48 and 52 (Year 2 treatment) from the start of the studies. Absolute lymphocyte count (ALC) and levels of lymphocyte subsets were examined in 1564 patients (Age ≤50 [placebo: N=566; CladT3.5: N=813]; Age >50 [placebo: N=75; CladT3.5: N=110]). In both age groups, following CladT3.5 treatment, nadir for ALC occurred at Week 9 (8 weeks following start of Year 1 treatment) and Week 55 (7 weeks following start of Year 2 treatment) of the 96-week period; for CD19+ B lymphocytes, nadir occurred at Week 9 (Year 1) and Week 52 (Year 2). For CD4+ T lymphocytes, nadir occurred at Week 16 (Year 1) in both age groups, and at Weeks 60 and 72 (Year 2) in the Age ≤50 and >50 groups, respectively. Nadir for CD8+ T lymphocytes occurred at Week 16 (Year 1) and Week 72 (Year 2) in the Age ≤50 group and levels remained in the normal range; nadir occurred at Week 9 (Year 1) and Week 96 (Year 2) in the Age >50 group. Lymphocyte recovery began soon after nadir following CladT3.5 treatment and median levels reached normal range by end of the treatment year in both age groups. By Week 96, ~25% of patients treated with CladT3.5 reported ≥1 episode of Grade ≥3 lymphopenia (Gr≥3L). The rate of certain infections was numerically higher in older versus younger patients who experienced Gr≥3L. In conclusion, CladT3.5 had a similar effect on ALC and lymphocyte subsets in both younger and older patient groups.
| S-EPMC8740297 | biostudies-literature
Project description:AimsCladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune-mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsCLARITY was a 96-week, double-blind, placebo-controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post-dose ECGs. ECG data were collected 15 minutes pre-dose and between 0.5 and 3 hours post-dose at pre-study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52.ResultsFor cladribine tablets 3.5 mg/kg, the maximum change in placebo-adjusted post-dose QTcF vs. visit-baseline (BL) was -0.42 ms (90% CI: -3.61-4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: -0.08-6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post-dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53-11.44) and 8.74 ms (90% CI: 3.18-14.31), respectively. No significant changes were observed in T-wave morphology in either treatment group.ConclusionsCladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization.
| S-EPMC6595470 | biostudies-literature
Project description:Cladribine is a purine nucleoside analogue that selectively depletes peripheral lymphocytes without a major impact on cells of the innate immune system. An oral formulation of cladribine has been developed to be given as short courses over two annual cycles. Oral cladribine results in the peripheral depletion of lymphocytes that is gradual, occurring over several weeks, and is not associated with a cell lysis syndrome, has a greater impact on B cells than T cells, and is followed by gradual reconstitution of the peripheral lymphocyte counts over several months. Oral cladribine is effective in relapsing forms of multiple sclerosis. As a selective immune reconstitution therapy (SIRT), cladribine acts as a short-term immunosuppressant, relative to other maintenance immunosuppressive therapies that result in long-term immunosuppression. The main safety signal that has emerge relates primarily to herpes zoster infection, which was more common in patients with higher grades of lymphopenia, in particular grade 3 and 4 lymphopenia. Data from the oral cladribine extension trial and safety register, and reanalysis of the pivotal phase III trial has indicated that oral cladribine is unlikely to be associated with an increased short- to intermediate-term risk of malignancy.
| S-EPMC5722776 | biostudies-literature
Project description:IntroductionIn the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, cladribine tablets significantly reduced relapse rates and improved findings on magnetic resonance imaging versus placebo in patients with relapsing multiple sclerosis. In the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by placebo for 2 years produced similar clinical benefits to 4 years of cladribine tablets. The objective of this exploratory post hoc analysis was to evaluate long-term disease stability (assessed by the Expanded Disability Status Scale [EDSS] score) after treatment with cladribine tablets.MethodsPatients enrolled into CLARITY Extension who were previously randomized to cladribine tablets 3.5 mg/kg in the CLARITY study were included in this post hoc analysis. Two treatment groups were investigated-patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and thereafter randomized to placebo in CLARITY Extension (the CP3.5 group) or to cladribine tablets 3.5 mg/kg in CLARITY Extension (the CC7 group). In each treatment group, EDSS scores at 6-month intervals, EDSS score improvement/worsening each year, and time to 3- and 6-month confirmed EDSS progression were assessed from CLARITY baseline over 5 years of follow-up (including a variable bridging interval between studies). All analyses are descriptive, and no statistical comparisons were performed for between-treatment group differences.ResultsThe median (95% confidence interval [CI]) EDSS score for patients in the CP3.5 group at 5 years was 2.5 (2.0-3.5) compared with 3.0 (2.5-3.5) at baseline. In the CC7 group, median EDSS score (95% CI) at 5 years was 2.0 (2.0-3.0) compared with 2.5 (2.5-3.0) at baseline. During year 5 for the CP3.5 group, and based on changes in minimum score each year, EDSS score stability was observed in 53.9% of patients, improvement in 21.3%, and worsening in 24.7%. In the CC7 group, EDSS score remained stable in 66.1%, improved in 18.1%, and worsened in 15.8% of patients. Over 70% of patients in both treatment groups did not show 3- or 6-month confirmed EDSS progression at 5 years from CLARITY baseline.ConclusionsThese findings confirm long-term beneficial effects on disability afforded by either the recommended dose of cladribine tablets over 4 years (cumulative dose, 3.5 mg/kg) or a higher cumulative dose.Trial registrationClinicalTrials.gov NCT00213135 (CLARITY); NCT00641537 (CLARITY Extension).
| S-EPMC8408069 | biostudies-literature
Project description:Background:The CLARITY and CLARITY Extension studies demonstrated that treatment of relapsing-remitting multiple sclerosis (RRMS) with cladribine tablets (CT) results in significant clinical improvements, compared with placebo. This paper presents the key magnetic resonance imaging (MRI) findings from the CLARITY Extension study. Methods:Patients who received a cumulative dose of either CT 3.5 or 5.25 mg/kg in CLARITY were rerandomized to either placebo or CT 3.5 mg/kg in CLARITY Extension. Patients from the arm that received placebo in CLARITY were assigned to CT 3.5 mg/kg. MRI assessments were carried out when patients entered CLARITY Extension and after Weeks 24, 48, 72 and 96, and in a supplemental follow-up period. Results:At CLARITY Extension baseline, patients who received placebo during CLARITY had more T1 gadolinium-enhanced (Gd+) lesions than patients who received CT during CLARITY. These patients, who were then exposed to cladribine 3.5 mg/kg during the extension, experienced a 90.4% relative reduction (median difference -0.33, 97.5% confidence interval -0.33-0.00; p < 0.001) in T1 Gd+ lesions at the end of the extension compared with the end of CLARITY. Overall, the majority of patients in each treatment group remained free from T1 Gd+ lesions throughout CLARITY Extension. However, a small proportion of patients who were treated with cladribine in CLARITY and received placebo in CLARITY Extension showed evidence of increased MRI activity, and this was associated with a prolonged treatment gap between CLARITY and CLARITY Extension. Conclusion:A 2-year treatment with CT 3.5 mg/kg has a durable effect on MRI outcomes in the majority of patients, an effect that was sustained in patients who were not retreated in the subsequent 2 years after initial treatment. ClinicalTrials.gov identifier: NCT00641537.
| S-EPMC5788142 | biostudies-literature
Project description:BACKGROUND:In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. OBJECTIVE:Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. METHODS:Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). RESULTS:In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. CONCLUSION:Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population.
| S-EPMC6460686 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system. The clinical course of MS varies among patients. Currently, interferon (IFN) products, including IFN ?-1a administered intramuscularly or subcutaneously and IFN ?-1b subcutaneously, glatiramer acetate, natalizumab, and mitoxantrone are approved disease-modifying therapies for the treatment of relapsing-remitting MS. Cladribine, also known as 2-chlorodeoxyadenosine, is a synthetic adenosine deaminase-resistant purine nucleoside analog that preferentially depletes lymphocyte subpopulations. This sustained effect on lymphocytes is advantageous for patients with MS. CLARITY (CLAdRIbine Tablets Treating MS OrallY), a Phase III trial, has demonstrated that short-term oral cladribine decreases relapse rates and risk of disability progression in comparison with placebo. Cladribine was well tolerated in the study, with the most common adverse effects being headache, nausea, upper respiratory tract infections, and lymphocytopenia. An ongoing study is evaluating the efficacy and safety of the combination of oral cladribine and IFN-? products. A further ongoing study is examining the use of oral cladribine in clinically isolated syndrome and time to conversion to MS. Although the results of CLARITY are promising, the exact role of oral cladribine may be better defined with the completion of ongoing studies.
| S-EPMC2951744 | biostudies-other