Baylor Research Institute

Schiffmann, R. and B. Banwell (2016). “Brain mri and motor function in leukodystrophies.” Neurology: 2016 Jul [Epub ahead of print].

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There is a need to develop clinical outcome measures for future treatment trials, particularly for pediatric studies and for studies of rare disorders for which such outcome metrics are neither currently well-defined nor validated.1 Patient-reported outcome measures should reflect outcomes that are meaningful to patient-perceived quality of life and sensitive to patient-identified change over time. Physician-reported outcome measures are typically quantifiable and consistently applied across multiple study sites by different investigators, which requires that the metrics be well-defined and that investigator training be rigorous. While clinically relevant outcomes are considered the “gold standard,” and are often the mandated primary outcome of federally funded research, many slowly progressive disorders do not demonstrate clinically apparent change over the time course of a clinical trial. Thus, there is a need for biomarkers, such as neuroimaging measures, that may be more sensitive to change over the typical 2- to 5-year period of a trial. Key to the applicability of such surrogate measures, however, is that they ultimately correlate with changes in neurologic function.

Schmitt, N., Y. Liu, S. E. Bentebibel and H. Ueno (2016). “Molecular mechanisms regulating t helper 1 versus t follicular helper cell differentiation in humans.” Cell Rep 16(4): 1082-1095.

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IL-12 is important for the differentiation of T follicular helper (Tfh) cells, as well as Th1 cells in humans. Still, how IL-12 signals regulate Tfh versus Th1 cell differentiation remains poorly characterized. Here we aimed to determine the molecular mechanisms that regulate the differentiation and the function of IL-12-stimulated human naive CD4(+) T cells. We found that T-bet promoted the expression of CXCR5 in human CD4(+) T cells. We provide evidence that T-bet does not strongly inhibit the Tfh cell differentiation program per se but diminishes the functions to provide help to B cells. This study also suggests that IRF4 plays an important role in driving the early differentiation of IL-12-stimulated CD4(+) T cells toward Tfh and away from Th1 by inhibiting the expression of Eomesodermin. Thus, the fate of IL-12-stimulated CD4(+) T cells is determined through interplay of multiple transcription factors at early stages.

Zaman, A., R. Dubiel, S. Driver, M. Bennett, V. Diggs and L. Callender (2016). “Seizure prophylaxis guidelines following traumatic brain injury: An evaluation of compliance.” J Head Trauma Rehabil: 2016 June [Epub ahead of print].

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OBJECTIVE: To determine degree of adherence to guidelines for seizure prophylaxis following traumatic brain injury (TBI). SETTING: Tertiary care level 1 trauma center and affiliated inpatient rehabilitation facility. PARTICIPANTS: A total of 173 individuals with TBI who required inpatient rehabilitation from January 1, 2007, to December 31, 2013. DESIGN: Retrospective medical record review. MAIN MEASURES: Overutilization rate of prophylactic antiepileptic drugs (AEDs); failure to stop rate of AED utilization upon admission to and during inpatient rehabilitation; and duration of overutilization. RESULTS: Of the 173 participants included, 77 were started on seizure prophylaxis at hospital presentation and 96 were not. Of the 77 participants, 11 had a posttraumatic seizure. Of the 66 remaining, 18 participants (10.4%) were continued on AEDs for more than 7 days after injury. Of these 18 participants, 12 were continued on AEDs without indication upon admission to inpatient rehabilitation. Finally, 8 of the 12 were continued on AEDs at discharge from rehabilitation, resulting in a failure to stop rate of 66.67%. CONCLUSION: Despite existing guidelines for stopping seizure prophylaxis after TBI, some patients remain on AEDs and may be inappropriately exposed to possible medication side effects. These findings highlight the importance of communication at the time of rehabilitation transfer and the need for ongoing education about AED guidelines.

Goker-Alpan, O., N. Longo, M. McDonald, S. P. Shankar, R. Schiffmann, P. Chang, Y. Shen and A. Pano (2016). “An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with fabry disease who are naive to enzyme replacement therapy.” Drug Des Devel Ther 10: 1771-1781.

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BACKGROUND: Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naive children with Fabry disease. METHODS: In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged >/=7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life. RESULTS: Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes. CONCLUSION: Fifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.

Gold, R., D. L. Arnold, A. Bar-Or, M. Hutchinson, L. Kappos, E. Havrdova, D. G. MacManus, T. A. Yousry, C. Pozzilli, K. Selmaj, M. T. Sweetser, R. Zhang, M. Yang, J. Potts, M. Novas, D. H. Miller, N. C. Kurukulasuriya, R. J. Fox and T. J. Phillips (2016). “Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of endorse, a randomized extension study.” Mult Scler: May 2016 [Epub ahead of print].

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BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. OBJECTIVE: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). METHODS: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. RESULTS: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. CONCLUSION: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.