Research Spotlight

Spinowitz, B. S., S. Fishbane, P. E. Pergola, S. D. Roger, E. V. Lerma, J. Butler, S. von Haehling, S. H. Adler, J. Zhao, B. Singh, P. T. Lavin, P. A. McCullough, M. Kosiborod and D. K. Packham (2019). “Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study.” Clin J Am Soc Nephrol Jun 7; 14(6):798-809. May 20. [Epub ahead of print].

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BACKGROUND AND OBJECTIVES: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the correction phase, adult outpatients with plasma potassium >/=5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the /=65 years old; 74% had an eGFR<60 ml/min per 1.73 m(2), and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values less-than-or-equal-to 5.1 and less-than-or-equal-to 5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naive participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively. CONCLUSIONS: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for less-than-or-equal-to 12 months.

Scott, F. I., D. T. Rubin, S. Kugathasan, A. Bousvaros, C. O. Elson, R. D. Newberry, G. Y. Melmed, J. Pekow, J. W. Fleshman, B. M. Boyle, U. Mahadevan, L. M. Cannon, M. D. Long, R. K. Cross, C. Y. Ha, K. L. Lasch, A. M. Robinson, J. F. Rafferty, J. J. Lee, K. D. C. Dahl, A. Weaver, N. Shtraizent, G. Honig, A. Hurtado-Lorenzo and C. A. Heller (2019). “Challenges in IBD Research: Pragmatic Clinical Research.” Inflamm Bowel Dis 25(Supplement_2): S40-s47.

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Pragmatic clinical research is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and precision medicine. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the pragmatic clinical research section is focused on highlighting gaps that need to be addressed in order to optimize and standardize IBD care. Identified gaps include: 1) understanding the incidence and prevalence of IBD; 2) evaluating medication positioning to increase therapeutic effectiveness; 3) understanding the utility of therapeutic drug monitoring (TDM); 4) studying pain management; and 5) understanding healthcare economics and resources utilization. To address these gaps, there is a need to emphasize the use of emerging data sources and real-world evidence to better understand epidemiologic and therapeutic trends in IBD, expanding on existing data to better understand how and where we should improve care. Proposed approaches include epidemiological studies in ethnically and geographically diverse cohorts to estimate incidence and prevalence of IBD and impact of diversity on treatment patterns and outcomes. The implementation of new clinical trial design and methodologies will be essential to evaluate optimal medication positioning, appropriate use of TDM in adults and children, and multidisciplinary approaches to IBD pain management and its impact on healthcare resources.

Saif, M. W., L. Rosen, M. A. Rudek, W. Sun, D. R. Shepard, C. Becerra, F. Yamashita, P. Bebeau and R. Winkler (2019). “Open-label study to evaluate trifluridine/tipiracil safety, tolerability and pharmacokinetics in patients with advanced solid tumours and hepatic impairment.” Br J Clin Pharmacol 85(6): 1239-1246.

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AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged >/=18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m(2) orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade >/= 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.

Ryan-Gonzalez, C., N. A. Kimbrel, E. C. Meyer, E. M. Gordon, B. B. DeBeer, S. B. Gulliver, T. R. Elliott and S. B. Morissette (2019). “Differences in Post-Traumatic Stress Disorder Symptoms among Post-9/11 Veterans with Blast- and Non-Blast Mild Traumatic Brain Injury.” J Neurotrauma 36(10): 1584-1590.

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The relationship between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) has been difficult to disentangle, in part due to the commonality of incidents that can cause both conditions, as well as high rates of comorbidity between the two conditions. Inconsistent findings may be related to different study characteristics and types of mild TBI (mTBI) sustained (e.g., blast, non-blast). The objective of this study was to determine the association of blast- versus non-blast-related TBIs with long-term PTSD symptoms after controlling for demographic variables and trauma exposure. The sample included 230 post-9/11 veterans who experienced a blast-related mTBI (n = 29), non-blast mTBI (n = 74), combined blast and non-blast mTBI (n = 40), or no TBI (n = 87). As hypothesized, a between-groups analysis of covariance (ANCOVA) revealed that, after controlling for demographics, combat exposure, and prior trauma, PTSD symptoms among individuals with blast-related mTBI and combined blast and non-blast mTBI were significantly higher compared with non-blast-related mTBI and no TBI. These data suggest that blast-related mTBI is associated with more severe long-term PTSD symptoms.

Roberts, W. C., L. C. Jameson, A. Bahmani, C. S. Roberts, A. E. Rafael and S. A. Hall (2019). “Morphological and Functional Characteristics of the Right Ventricle Functioning as a Systemic Ventricle for Decades After an Atrial Switch Procedure for Complete Transposition of the Great Arteries.” Am J Cardiol 123(11): 1863-1867.

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Described herein are certain clinical and cardiac morphologic findings in 4 adults with complete transposition of the great arteries who underwent the Mustard procedure in the newborn period or in childhood and each lived >30 years thereafter before either having orthotopic heart transplantation (3 patients) or dying while awaiting orthotopic heart transplantation. Compared with the wall of the left ventricle, the wall of the right ventricle (the systemic one) was much thicker, the myofibers much larger, and either grossly-visible or microscopic-sized scars were present in its wall. Additionally, some intramural coronary arteries in the right ventricular wall were numerous, large, had thick walls, and often narrowed lumens. That the Mustard operation provided the necessary time for the right ventricle (the systemic one) to develop to its fullest is a tribute to this procedure.