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- Goemans, N. M., et al.
(författare)
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Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Background Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations. This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73-80), followed by intermittent dosing (weeks 81-188). Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored "zero". When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking >= 330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary alpha(1)-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72. Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort.
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| 2. |
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| 3. |
- Vande Vyvere, Thijs, et al.
(författare)
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Central versus Local Radiological Reading of Acute Computed Tomography Characteristics in Multi-Center Traumatic Brain Injury Research
- 2019
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 36:7, s. 1080-1092
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Tidskriftsartikel (refereegranskat)abstract
- Observer variability in local radiological reading is a major concern in large-scale multi-center traumatic brain injury (TBI) studies. A central review process has been advocated to minimize this variability. The aim of this study is to compare central with local reading of TBI imaging datasets and to investigate the added value of central review. A total of 2050 admission computed tomography (CT) scans from subjects enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed for seven main CT characteristics. Kappa statistics were used to calculate agreement between central and local evaluations and a center-specific analysis was performed. The McNemar test was used to detect whether discordances were significant. Central interobserver and intra-observer agreement was calculated in a subset of patients. Good agreement was found between central and local assessment for the presence or absence of structural pathology (CT+, CT-, κ = 0.73) and most CT characteristics (κ = 0.62 to 0.71), except for traumatic axonal injury lesions (κ = 0.37). Despite good kappa values, discordances were significant in four of seven CT characteristics (i.e., midline shift, contusion, traumatic subarachnoid hemorrhage, and cisternal compression; p = 0.0005). Central reviewers showed substantial to excellent interobserver and intra-observer agreement (κ = 0.73 to κ = 0.96), contrasted by considerable variability in local radiological reading. Compared with local evaluation, a central review process offers a more consistent radiological reading of acute CT characteristics in TBI. It generates reliable, reproducible data and should be recommended for use in multi-center TBI studies.
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| 4. |
- Vande Vyvere, Thijs, et al.
(författare)
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Prognostic Validation of the NINDS Common Data Elements for the Radiologic Reporting of Acute Traumatic Brain Injuries : A CENTER-TBI Study.
- 2020
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 37:11, s. 1269-1282
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study is to investigate the prognostic value of using the National Institute of Neurological Disorders and Stroke (NINDS) standardized imaging-based pathoanatomic descriptors for the evaluation and reporting of acute traumatic brain injury (TBI) lesions. For a total of 3392 patients (2244 males and 1148 females, median age = 51 years) enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, we extracted 96 Common Data Elements (CDEs) from the structured reports, spanning all three levels of pathoanatomic information (i.e., 20 "basic," 60 "descriptive," and 16 "advanced" CDE variables per patient). Six-month clinical outcome scores were dichotomized into favorable (Glasgow Outcome Scale Extended [GOS-E] = 5-8) versus unfavorable (GOS-E = 1-4). Regularized logistic regression models were constructed and compared using the optimism-corrected area under the curve (AUC). An abnormality was reported for the majority of patients (64.51%). In 79.11% of those patients, there was at least one coexisting pathoanatomic lesion or associated finding. An increase in lesion severity, laterality, and volume was associated with more unfavorable outcomes. Compared with the full set of pathoanatomic descriptors (i.e., all three categories of information), reporting "basic" CDE information provides at least equal discrimination between patients with favorable versus unfavorable outcome (AUC = 0.8121 vs. 0.8155, respectively). Addition of a selected subset of "descriptive" detail to the basic CDEs could improve outcome prediction (AUC = 0.8248). Addition of "advanced" or "emerging/exploratory" information had minimal prognostic value. Our results show that the NINDS standardized-imaging based pathoanatomic descriptors can be used in large-scale studies and provide important insights into acute TBI lesion patterns. When used in clinical predictive models, they can provide excellent discrimination between patients with favorable and unfavorable 6-month outcomes. If further validated, our findings could support the development of structured and itemized templates in routine clinical radiology.
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| 5. |
- Vande Vyvere, Thijs, et al.
(författare)
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Prognostic Validation of the NINDS Standardized Pathoanatomic Terms and Definitions for the Reporting of Acute Traumatic Brain Injuries : A CENTER-TBI study
- 2020
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 37:11, s. 1269-1282
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To aim of this study is to investigate the prognostic value of using the NINDS standardized imaging-based pathoanatomic descriptors for the evaluation and reporting of acute TBI lesions.METHODS: For a total of 3,392 patients (2,244 males and 1,148 females, Median = 51 years) enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, we extracted 96 CDEs from the structured reports, spanning all three levels of pathoanatomic information (i.e. 20 "basic", 60 "descriptive" and 16 "advanced" CDE variables per patient). 6-month clinical outcome scores were dichotomized into favorable (GOS-E = 5-8) versus unfavorable (GOS-E = 1-4). Regularized logistic regression models were constructed and compared using the optimism-corrected AUC.RESULTS: An abnormality was reported for the majority of patients (64.51%). In 79.11% of those patients, there was at least one coexisting pathoanatomic lesion or associated finding. An increase in lesion severity, laterality and volume was associated with more unfavorable outcomes. Compared to the full set of pathoanatomic descriptors (i.e. all three categories of information), reporting "basic" CDE information provides at least equal discrimination between patients with favorable versus unfavorable outcome (AUC = 0.8121 vs. 0.8155, respectively). Addition of a selected subset of "descriptive" detail (i.e. location and volume) to specific basic CDEs could improve outcome prediction (AUC = 0.8248). Addition of "advanced" or "emerging" information had minimal prognostic value.CONCLUSION: Our results show that the NINDS standardized-imaging based pathoanatomic descriptors can be used in large-scale studies and provide important insights into acute TBI lesion patterns. When used in clinical predictive models, they can provide excellent discrimination between patients with favorable and unfavorable 6-month outcomes. If further validated, our findings could support the development of structured and itemized templates in routine clinical radiology. Key words: Traumatic Brain Injury, Computed Tomography, Common Data Elements, Structured Reporting.
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