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1. Impact of long‐term administration of maralixibat on children with cholestasis secondary to Alagille syndrome

Author

Benjamin L. Shneider, Catherine A. Spino, Binita M. Kamath, John C. Magee, Rosalinda V. Ignacio, Suiyuan Huang, Simon P. Horslen, Jean P. Molleston, Alexander G. Miethke, Rohit Kohli, Daniel H. Leung, M. Kyle Jensen, Kathleen M. Loomes, Saul J. Karpen, Cara Mack, Philip Rosenthal, Robert H. Squires, Alastair Baker, Sanjay Rajwal, Deirdre Kelly, Ronald J. Sokol, Richard J. Thompson, and for ChiLDReN and UK IMAGO/IMAGINE Investigators

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo‐controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0–100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo‐controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] −1.59 [−1.81, −1.36], CSS −1.36 [−1.67, −1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment‐emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.

Published
2022
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2. Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome

Author

Benjamin L. Shneider, Binita M. Kamath, John C. Magee, Nathan P. Goodrich, Kathleen M. Loomes, Wen Ye, Cathie Spino, Estella M. Alonso, Jean P. Molleston, Jorge A. Bezerra, Kasper S. Wang, Saul J. Karpen, Simon P. Horslen, Stephen L. Guthery, Philip Rosenthal, Robert H. Squires, Ronald J. Sokol, and for the Childhood Liver Disease Research Network (ChiLDReN)

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract The conduct of long‐term conventional randomized clinical trials in rare diseases is very difficult, making evidenced‐based drug development problematic. As a result, real‐world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2‐year prospective follow‐up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (−1.43 [0.28] −1.99, −0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (−65.2 [16.2] −98.3, −32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real‐world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.

Published
2022
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4. Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease

Author

Daniel H, Leung, Sridevi, Devaraj, Nathan P, Goodrich, Xinpu, Chen, Deepthi, Rajapakshe, Wen, Ye, Victor, Andreev, Charles G, Minard, Danielle, Guffey, Jean P, Molleston, Lee M, Bass, Saul J, Karpen, Binita M, Kamath, Kasper S, Wang, Shikha S, Sundaram, Philip, Rosenthal, Patrick, McKiernan, Kathleen M, Loomes, M Kyle, Jensen, Simon P, Horslen, Jorge A, Bezerra, John C, Magee, Robert M, Merion, Ronald J, Sokol, and Benjamin L, Shneider

Subjects
Article
Abstract

BACKGROUND & AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH & RESULTS: A targeted ELISA-based panel of 9 biomarkers (lysyl oxidase (LOX), tissue inhibitor matrix metalloproteinase 1 (TIMP1), connective tissue growth factor (CTGF), interleukin-8 (IL-8), endoglin, periostin, mac-2-binding protein (mac2-BP), matrix metalloproteinase-3 and −7 (MMP-3, MMP-7) was examined in children with biliary atresia (BA, n=187), alpha-1 antitrypsin deficiency (A1AT, n=78) and Alagille syndrome (ALGS, n=65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations between LSM and endoglin (p=0.04), IL-8 (p

Published
2022

5. Society of pediatric liver transplantation: Current registry status 2011-2018

Author

Scott A, Elisofon, John C, Magee, Vicky L, Ng, Simon P, Horslen, Vicki, Fioravanti, Julie, Economides, Jinson, Erinjeri, Ravinder, Anand, George V, Mazariegos, and R, Tomlin

Subjects
Male, medicine.medical_specialty, Adolescent, Acute cellular rejection, medicine.medical_treatment, 030232 urology & nephrology, 030230 surgery, Liver transplantation, Pediatrics, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Biliary atresia, medicine, Humans, Registries, Metabolic disease, Child, Societies, Medical, Transplantation, business.industry, Liver Diseases, Infant, Newborn, Infant, medicine.disease, Survival Analysis, Tacrolimus, Surgery, Portal vein thrombosis, Liver Transplantation, Cross-Sectional Studies, Treatment Outcome, Biliary tract, Sirolimus, Child, Preschool, Pediatrics, Perinatology and Child Health, North America, Female, business, medicine.drug
Abstract

BACKGROUND SPLIT was founded in 1995 in order to collect comprehensive prospective data on pediatric liver transplantation, including waiting list data, transplant, and early and late outcomes. Since 2011, data collection of the current registry has been refined to focus on prospective data and outcomes only after transplant to serve as a foundation for the future development of targeted clinical studies. OBJECTIVE To report the outcomes of the SPLIT registry from 2011 to 2018. METHODS This is a multicenter, cross-sectional analysis characterizing patients transplanted and enrolled in the SPLIT registry between 2011 and 2018. All patients

Published
2019

6. A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients

Author

Michael R. Narkewicz, Simon Horslen, Regina M. Hardison, Benjamin L. Shneider, Norberto Rodriguez-Baez, Estella M. Alonso, Vicky L. Ng, Mike A. Leonis, Kathleen M. Loomes, David A. Rudnick, Philip Rosenthal, Rene Romero, Girish C. Subbarao, Ruosha Li, Steven H. Belle, Robert H. Squires, Kathryn Bukauskas, Madeline Schulte, Michelle Hite, Elizabeth B. Rand, David Piccoli, Deborah Kawchak, Christa Seidman, Saul Karpen, Liezl de la Cruz-Tracy, Vicky Ng, Kelsey Hunt, Ann Klipsch, Sarah Munson, Lisa Sorenson, Susan Kelly, Katie Neighbors, Shannon Fleck, John Bucuvalas, Tracie Horning, Norberto Rodriguez Baez, Shirley Montanye, Margaret Cowie, Simon P. Horslen, Karen Murray, Melissa Young, Heather Nielson, Jani Klein, Ross W. Shepherd, Kathy Harris, Saul J. Karpen, Alejandro De La Torre, Dominic Dell Olio, Deirdre Kelly, Carla Lloyd, Steven J. Lobritto, Sumerah Bakhsh, Maureen Jonas, Scott A. Elifoson, Roshan Raza, Kathleen B. Schwarz, Wikrom W. Karnsakul, Mary Kay Alford, Anil Dhawan, Emer Fitzpatrick, Nanda N. Kerkar, Brandy Haydel, Sreevidya Narayanappa, M. James Lopez, Victoria Shieck, Edward Doo, and Averell H. Sherker

Subjects
Male, medicine.medical_specialty, Canada, Adolescent, medicine.medical_treatment, Encephalopathy, Disease, Liver transplantation, Sensitivity and Specificity, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Electronic Health Records, Humans, Cumulative incidence, 030212 general & internal medicine, Child, Hepatology, business.industry, Diagnostic Tests, Routine, Gastroenterology, Electronic medical record, Liver failure, Infant, Newborn, Disease Management, Infant, Liver Failure, Acute, medicine.disease, United States, Child, Preschool, 030211 gastroenterology & hepatology, Female, business, Indeterminate, Cohort study
Abstract

Background & Aims Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)—they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. Methods We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. Results The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1–2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). Conclusions In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Published
2018

7. Health Related Quality of Life and Neurocognitive Outcomes in the First Year after Pediatric Acute Liver Failure

Author

Lisa G. Sorensen, Katie Neighbors, Regina M. Hardison, Kathleen M. Loomes, James W. Varni, Vicky L. Ng, Robert H. Squires, Estella M. Alonso, Kathryn Bukauskas, Madeline Schulte, Michael R. Narkewicz, Michelle Hite, Elizabeth B. Rand, David Piccoli, Deborah Kawchak, Christa Seidman, Rene Romero, Saul Karpen, Liezl de la Cruz-Tracy, Kelsey Hunt, Girish C. Subbarao, Ann Klipsch, Sarah Munson, Susan Kelly, Philip J. Rosenthal, Shannon Fleck, Mike A. Leonis, John Bucuvalas, Tracie Horning, Norberto Rodriguez Baez, Shirley Montanye, Margaret Cowie, Simon P. Horslen, Karen Murray, Melissa Young, Heather Nielson, Jani Klein, David A. Rudnick, Ross W. Shepherd, Kathy Harris, Saul J. Karpen, Alejandro De La Torre, Dominic Dell Olio, Deirdre Kelly, Carla Lloyd, Steven J. Lobritto, Sumerah Bakhsh, Maureen Jonas, Scott A. Elifoson, Roshan Raza, Kathleen B. Schwarz, Wikrom W. Karnsakul, Mary Kay Alford, Anil Dhawan, Emer Fitzpatrick, Nanda N. Kerkar, Brandy Haydel, Sreevidya Narayanappa, M. James Lopez, and Victoria Shieck

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Article, Stress Disorders, Post-Traumatic, 03 medical and health sciences, Executive Function, Young Adult, 0302 clinical medicine, Cognition, Quality of life, 030225 pediatrics, Medicine, Humans, Matched sample, Attention, Cognitive Dysfunction, Longitudinal Studies, Prospective Studies, Prospective cohort study, Child, Motor skill, Fatigue, Health related quality of life, Intelligence Tests, business.industry, Depression, Liver failure, Infant, Newborn, Infant, Liver Failure, Acute, Mental Status and Dementia Tests, humanities, Cross-Sectional Studies, Treatment Outcome, Motor Skills, Child, Preschool, Pediatrics, Perinatology and Child Health, Quality of Life, 030211 gastroenterology & hepatology, Female, business, Neurocognitive
Abstract

To determine health-related quality of life (HRQoL) and neurocognitive impairment in survivors of pediatric acute liver failure (PALF).A longitudinal prospective study was conducted. At 6 and 12 months after PALF presentation, surveys of HRQoL were completed for 2- to 19-year-olds and executive functioning for ages 2-16 years. At 12 months, patients 3-16 years of age completed neurocognitive testing. HRQoL scores were compared with a healthy, matched sample. Neurocognitive scores were compared with norms; executive functioning scores were examined categorically.A total of 52 parent-report HRQoL surveys were completed at 6 months, 48 at 12 months; 25 patients completed neurocognitive testing. The median age at 6 months was 7.9 years (range 3.5-15.0), and final diagnosis was indeterminate for 46.2% (n = 24). Self and parent-report on Pediatric Quality of Life Inventory Generic and Multidimensional Fatigue scales fell below the healthy sample at 6 months and 12 months (almost all P .001). Children reported lower mean scores on cognitive fatigue at 12 months (60.91 ± 22.99) compared with 6 months (73.61 ± 27.49, P = .006) . The distribution of Behavior Rating Inventory of Executive Function scores was shifted downward on parent-report (preschool) for all indices at 6 months (n = 14, P ≤ .003); Global Executive Composite and Emergent Metacognition at 12 months (n = 10, P = .03). Visual Motor Integration (VMI-6) Copying (mean = 90.3 ± 13.8, P = .0002) and VMI-6 Motor Coordination (mean = 85.1 ± 15.2 P = .0002) fell below norms, but full scale IQ (Wechsler Scales) and Attention (Conners' Continuous Performance Test) did not.Survivors of PALF appear to show deficits in motor skills, executive functioning, HRQoL, and evidence for worsening cognitive fatigue from 6 to 12 months following PALF presentation.

Published
2017

8. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study

Author

Faraz A. Khan, Robert H. Squires, Heather J. Litman, Jane Balint, Beth A. Carter, Jeremy G. Fisher, Simon P. Horslen, Tom Jaksic, Samuel Kocoshis, J. Andres Martinez, David Mercer, Susan Rhee, Jeffrey A. Rudolph, Jason Soden, Debra Sudan, Riccardo A. Superina, Daniel H. Teitelbaum, Robert Venick, Paul W. Wales, Christopher Duggan, Cartland Burns, George Mazariegos, Sharon Lawlor, Tamara Haller, Marcia Kurs-Lasky, Steven H. Belle, Anita Nucci, Jane Anne Yawarski, Danielle Sebbens, Rhonda Cunningham, Daniel Kamin, Heung Bae Kim, Sharon Collier, Melanie Connolly, Pamela Brown, Michele Johnson, Robert Drongowski, Christina Valentine, Steven Teich, Beth Skaggs, Martin G. Martin, Patty Beckwith, James Dunn, Douglas G. Farmer, Laurie Reyen, Diana Farmer, Sang-Mo Kang, Lane Bower, Dean L. Antonson, Steve C. Raynor, Brandy Sunderman, Kris Seipel, Brent Polk, Martha Ballew, Mary Brandt, Saul Karpen, Sara Philips, Kristin Brown, Alejandro De La Torre, Sara Fidanza, Frances Malone, Patrick Healey, Jorge Reyes, Cheryl Davis, Greg Tiao, Jacqueline Wessel, Valeria Cohran, Kimberley Kazmerski, Lisa Keys, Margaret 'Peggy' Richard, David Sigalet, and Conrad Cole

Subjects
Male, Pediatrics, Parenteral Nutrition, Bacteremia, Enteral administration, Oral and gastrointestinal, Cohort Studies, Risk Factors, Cumulative incidence, Child, Growth Disorders, Pediatric, Pediatric Intestinal Failure Consortium, Ileocecal Valve, Intestines, medicine.anatomical_structure, Child, Preschool, 6.1 Pharmaceuticals, Necrotizing enterocolitis, Female, Cohort study, Short Bowel Syndrome, medicine.medical_specialty, Catheterization, Central Venous, Canada, Article, Paediatrics and Reproductive Medicine, Ileocecal valve, Enterocolitis, Necrotizing, Clinical Research, medicine, Humans, Preschool, Retrospective Studies, Nutrition, Transplantation, business.industry, Enterocolitis, Infant, Newborn, Infant, Evaluation of treatments and therapeutic interventions, Retrospective cohort study, Human Movement and Sports Sciences, medicine.disease, Newborn, United States, Intestinal Diseases, Parenteral nutrition, Catheter-Related Infections, Pediatrics, Perinatology and Child Health, Multivariate Analysis, business, Necrotizing, Digestive Diseases, Follow-Up Studies
Abstract

Objectives In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. Study design A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. Results A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. Conclusions A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

Published
2015

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