Outcomes of natalizumab treatment within 3?years of relapsing-remitting multiple sclerosis diagnosis: a prespecified 2-year interim analysis of STRIVE.
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ABSTRACT:
SUBMITTER: Perumal J
PROVIDER: S-EPMC6555913 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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Outcomes of natalizumab treatment within 3 years of relapsing-remitting multiple sclerosis diagnosis: a prespecified 2-year interim analysis of STRIVE.
Perumal Jai J Fox Robert J RJ Balabanov Roumen R Balcer Laura J LJ Galetta Steven S Makh Shavy S Santra Sourav S Hotermans Christophe C Lee Lily L
BMC neurology 20190608 1
<h4>Background</h4>STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS.<h4>Methods</h4>Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Exp ...[more]
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Project description:IntroductionSTRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS.MethodsProportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events.ResultsIn years 1 and 2, 56.1% (95% confidence interval [CI] 48.7-63.4%) and 73.6% (95% CI 66.2-80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0-89.9%) and 91.9% (95% CI 86.4-95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54-9.63]; p = 0.004) and T2 lesion volume > 4 cc (OR = 0.39 [95% CI 0.15-0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05-0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients.ConclusionThese results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS.Trial registrationClinicalTrials.gov identifier NCT01485003.
| S-EPMC8279996 | biostudies-literature
Project description:IntroductionIn STRIVE, natalizumab treatment demonstrated effectiveness in clinical, magnetic resonance imaging (MRI), and patient-reported outcomes (PROs) in patients with early relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis examined the effectiveness and safety of natalizumab in patients who self-identified as either Black/African American (AA) or Hispanic/Latino.MethodsClinical, MRI, and PROs were assessed for the Black/AA subgroup (n = 40) and compared with the non-Hispanic White subgroup (n = 158). As a result of the very small sample size, outcomes for the Hispanic/Latino subgroup (n = 18) were assessed separately, including a sensitivity analysis with Hispanic/Latino patients who completed the 4-year study on natalizumab.ResultsClinical, MRI, and PROs were comparable between the Black/AA and non-Hispanic White subgroups except for MRI outcomes at year 1. A higher proportion of non-Hispanic White than Black/AA patients achieved MRI no evidence of disease activity (NEDA; 75.4% vs. 50.0%, p = 0.0121) and no new or newly enlarging T2 lesions (77.6% vs. 50.0%, p = 0.0031) at year 1; these differences were not observed in years 2-4 of the study. For the Hispanic/Latino subgroup in the intent-to-treat population, 46.2% and 55.6% achieved NEDA at years 1 and 2; 66.7% and 90.0% achieved clinical NEDA at years 3 and 4. Annualized relapse rate was reduced by 93.0% at year 1 versus the year before natalizumab initiation; this reduction was maintained throughout the study. Over 4 years, 37.5-50.0% of patients had a clinically meaningful improvement in their Symbol Digit Modalities Test score, and 81.8-100.0% and 90.9-100.0% had stable/improved Multiple Sclerosis Impact Scale-29 physical and psychological scores, respectively. Similar results were observed in the sensitivity analysis with Hispanic/Latino subgroup of the 4-year natalizumab completers.ConclusionThese results highlight the effectiveness and safety of natalizumab in patients with early RRMS who self-identified as Black/AA or Hispanic/Latino.ClinicaltrialsGOV: NCT01485003.
| S-EPMC10195921 | biostudies-literature
Project description:Background and purposeThe considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging.Materials and methodsIn this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-β or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter.ResultsAt baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-β/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased.ConclusionsPatients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism.
| S-EPMC8013024 | biostudies-literature
Project description:BackgroundREFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing-remitting multiple sclerosis (RRMS) patients.ObjectiveTo examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients.MethodsClinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60.ResultsIn total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable.ConclusionNatalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.
| S-EPMC8597184 | biostudies-literature
Project description:Ocrelizumab is often used as an alternative therapy in natalizumab-treated MS patients at risk for progressive multifocal leukoencephalopathy (PML). Our objective was to assess efficacy and safety of JC-virus positive patients switching (either directly or indirectly) from natalizumab to ocrelizumab. Forty-two patients were included from an observational cohort (median follow-up 21 months). No evidence of disease activity was found in 83% of direct switchers and 50% of indirect switchers. Two direct switchers were diagnosed with carry-over PML. Our data support a direct switch for adequate disease suppression, although carry-over PML illustrates the dilemma when choosing between a direct or indirect switch.
| S-EPMC8175839 | biostudies-literature
Project description:BackgroundThere is an unmet need for disease-modifying therapies to improve ambulatory function in disabled subjects with multiple sclerosis.ObjectivesAssess the effects of natalizumab on ambulatory function in disabled subjects with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS).MethodsWe retrospectively reviewed ambulatory function as measured by timed 25-foot walk (T25FW) in clinical trial subjects with an Expanded Disability Status Scale score ≥3.5, including RRMS subjects from the phase 3 AFFIRM and SENTINEL trials, relapsing SPMS subjects from the phase 2 MS231 study, and nonrelapsing SPMS subjects from the phase 1b DELIVER study. For comparison, SPMS subjects from the intramuscular interferon beta-1a (IM IFNβ-1a) IMPACT study were also analyzed. Improvement in ambulation was measured using T25FW responder status; response was defined as faster walking times over shorter (6-9-month) or longer (24-30-month) treatment periods relative to subjects' best predose walking times.ResultsThere were two to four times more T25FW responders among disabled MS subjects in the natalizumab arms than in the placebo or IM IFNβ-1a arms. Responders walked 25 feet an average of 24%-45% faster than nonresponders.ConclusionNatalizumab improves ambulatory function in disabled RRMS subjects and may have efficacy in disabled SPMS subjects. Confirmation of the latter finding in a prospective SPMS study is warranted.
| S-EPMC3537666 | biostudies-literature
Project description:ImportanceMost patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.ObjectiveTo evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT.Design, setting, and participantsHematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.InterventionsAutologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.Main outcomes and measuresThe primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.ResultsGrafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.Conclusions and relevanceAt 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.
| S-EPMC5261862 | biostudies-literature
Project description:Fingolimod and natalizumab are approved disease-modifying drugs in relapsing-remitting multiple sclerosis (RRMS). The two drugs have different modes of action and may therefore influence different aspects of MS-related tissue damage. In this retrospective cohort study, we longitudinally compared patients treated with fingolimod and patients treated with natalizumab by measures based on structural magnetic resonance imaging (MRI). We included patients with RRMS given that two standardized MRI scans under the same drug were available with an interval of at least 6 months both from therapy start to baseline scan and from baseline scan to follow-up scan. After matching for age, baseline and follow-up scans from 93 patients (fingolimod, 48; natalizumab, 45) were investigated. Mean follow-up time was 1.9 years. We determined the number of new white matter lesions as well as thalamic, cortical, and whole-brain atrophy. After scaling for time of the interscan interval, measures were analyzed by group comparisons and, to account for demographic and clinical characteristics, by multiple regression models and a binary logistic regression model. Compared to natalizumab, fingolimod treatment went along with more new white matter lesions (median [interquartile range, IQR] 0.0 [0.0; 0.7] vs. 0.0 [0.0; 0.0] /year; p < 0.01) whereas whole-brain atrophy was lower (median [IQR] 0.2 [0.0; 0.5] vs. 0.5 [0.2; 1.0] %/year; p = 0.01). These significant differences were confirmed by multiple regression models and the binary logistic regression model. In conclusion, our observation is compatible with stronger neuroprotective properties of fingolimod compared to natalizumab.
| S-EPMC8804113 | biostudies-literature
Project description:BACKGROUND:Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. METHODS:The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumab-naive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. RESULTS:Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. CONCLUSIONS:Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment.
| S-EPMC3967702 | biostudies-literature
Project description:BackgroundThere is a need in Relapsing-Remitting Multiple Sclerosis (RRMS) treatment for biomarkers that monitor neuroinflammation, neurodegeneration, treatment response, and disease progression despite treatment.ObjectiveTo assess the value of serum glial fibrillary acidic protein (sGFAP) as a biomarker for clinical disease progression and brain volume measurements in natalizumab-treated RRMS patients.MethodssGFAP and neurofilament light (sNfL) were measured in an observational cohort of natalizumab-treated RRMS patients at baseline, +3, +12, and +24 months and at the last sample follow-up (median 5.17 years). sGFAP was compared between significant clinical progressors and non-progressors and related to magnetic resonance imaging (MRI)-derived volumes of the whole brain, ventricle, thalamus, and lesion. The relationship between sGFAP and sNfL was assessed.ResultsA total of 88 patients were included, and 47.7% progressed. sGFAP levels at baseline were higher in patients with gadolinium enhancement (1.3-fold difference, p = 0.04) and decreased in 3 months of treatment (adj. p < 0.001). No association was found between longitudinal sGFAP levels and progressor status. sGFAP at baseline and 12 months was significantly associated with normalized ventricular (positively), thalamic (negatively), and lesion volumes (positively). Baseline and 12-month sGFAP predicted annualized ventricle volume change rate after 1 year of treatment. sGFAP correlated with sNfL at baseline (p < 0.001) and last sample follow-up (p < 0.001) but stabilized earlier.DiscussionsGFAP levels related to MRI markers of neuroinflammation and neurodegeneration.
| S-EPMC10503252 | biostudies-literature