Browsing by Author "Brown, Kimberly"

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    Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest
    (Research Square, 2024-06-21) Meurer, William; Schmitzberger, Florian; Yeatts, Sharon; Ramakrishnan, Viswanathan; Abella, Benjamin; Aufderheide, Tom; Barsan, William; Benoit, Justin; Berry, Scott; Black, Joy; Bozeman, Nia; Broglio, Kristine; Brown, Jeremy; Brown, Kimberly; Carlozzi, Noelle; Caveney, Angela; Cho, Sung-Min; Chung-Esaki, Hangyul; Clevenger, Robert; Conwit, Robin; Cooper, Richelle; Crudo, Valentina; Daya, Mohamud; Harney, Deneil; Hsu, Cindy; Johnson, Nicholas J.; Khan, Imad; Khosla, Shaveta; Kline, Peyton; Kratz, Anna; Kudenchuk, Peter; Lewis, Roger J.; Madiyal, Chaitra; Meyer, Sara; Mosier, Jarrod; Mouammar, Marwan; Neth, Matthew; O'Neil, Brian; Paxton, James; Perez, Sofia; Perman, Sarah; Sozener, Cemal; Speers, Mickie; Spiteri, Aimee; Stevenson, Valerie; Sunthankar, Kavita; Tonna, Joseph; Youngquist, Scott; Geocadin, Romergryko; Silbergleit, Robert; Neurology, School of Medicine
    Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms.
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    Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease
    (Elsevier, 2015-09) Charlton, Michael; Everson, Gregory T.; Flamm, Steven L.; Kumar, Princy; Landis, Charles; Brown, Robert S., Jr.; Fried, Michael W.; Terrault, Norah A.; O'Leary, Jacqueline G.; Vargas, Hugo E.; Kuo, Alexander; Schiff, Eugene; Sulkowski, Mark S.; Gilroy, Richard; Watt, Kymberly D.; Brown, Kimberly; Kwo, Paul; Pungpapong, Surakit; Korenblat, Kevin M.; Muir, Andrew J.; Teperman, Lewis; Fontana, Robert J.; Denning, Jill; Arterburn, Sarah; Dvory-Sobol, Hadas; Brandt-Sarif, Theo; Pang, Phillip S.; McHutchison, John G.; Reddy, K. Rajender; Afdhal, Nezam; Department of Medicine, IU School of Medicine
    Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation.