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Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Miethke, Alexander G; Moukarzel, Adib; Porta, Gilda; Covarrubias Esquer, Joshue; Czubkowski, Piotr; Ordonez, Felipe; Mosca, Antonella; Aqul, Amal A; Squires, Robert H; Sokal, Etienne; D'Agostino, Daniel; Baumann, Ulrich; D'Antiga, Lorenzo; Kasi, Nagraj; Laborde, Nolwenn; Arikan, Cigdem; Lin, Chuan-Hao; Gilmour, Susan; Mittal, Naveen; Chiou, Fang Kuan; Horslen, Simon P; Huber, Wolf-Dietrich; Jaecklin, Thomas; Nunes, Tiago; Lascau, Anamaria; Longpre, Lara; Mogul, Douglas B; Garner, Will; Vig, Pamela; Hupertz, Vera F; Gonzalez-Peralta, Regino P; Ekong, Udeme; Hartley, Jane; Laverdure, Noemie; Ovchinsky, Nadia; Thompson, Richard J
BACKGROUND:Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS:MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS/RESULTS:Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION/CONCLUSIONS:Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING/BACKGROUND:Mirum Pharmaceuticals.
PMID: 38723644
ISSN: 2468-1253
CID: 5658462

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

Ovchinsky, Nadia; Aumar, Madeleine; Baker, Alastair; Baumann, Ulrich; Bufler, Philip; Cananzi, Mara; Czubkowski, Piotr; Durmaz, Özlem; Fischer, Ryan; Indolfi, Giuseppe; Karnsakul, Wikrom W; Lacaille, Florence; Lee, Way S; Maggiore, Giuseppe; Rosenthal, Philip; Ruiz, Mathias; Sokal, Etienne; Sturm, Ekkehard; van der Woerd, Wendy; Verkade, Henkjan J; Wehrman, Andrew; Clemson, Christine; Yu, Qifeng; Ni, Quanhong; Ruvido, Jessica; Manganaro, Susan; Mattsson, Jan P
BACKGROUND:In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. METHODS:The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS/RESULTS:Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. INTERPRETATION/CONCLUSIONS:Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. FUNDING/BACKGROUND:Albireo Pharma, an Ipsen company.
PMID: 38670135
ISSN: 2468-1253
CID: 5657852

Molecular Adsorbent Recirculating System for Acute Liver Failure in a New Pediatric-Based Extracorporeal Liver Support Program

Baker, David R; Mac, Helen; Steinman, Benjamin; Soshnick, Sara H; Frager, Shalom Z; Goilav, Beatrice; Kogan-Liberman, Debora; Ovchinsky, Nadia; Shlomovich, Mark
IMPORTANCE/OBJECTIVE:Acute liver failure (ALF) carries significant morbidity and mortality, for both pediatric and adult patients. Albumin dialysis via the molecular adsorbent recirculating system (MARS) is a form of extracorporeal liver support (ELS) that can reduce hepatic encephalopathy (HE), a main driver of mortality in ALF. However, data on MARS and its benefit on mortality have been inconsistent. OBJECTIVES/OBJECTIVE:We sought to report our experiences and patient outcomes from the first 2 years of operation of a new ELS program, within an established pediatric liver transplantation center. DESIGN SETTING AND PARTICIPANTS/METHODS:Retrospective review of outcomes in pediatric and adult patients treated with MARS therapy for ALF, from 2021 to 2022. MAIN OUTCOMES AND MEASURES/METHODS:Outcomes included reduction in HE and biochemical markers of ALF after MARS therapy, survival, and transplant-free survival. Comparisons were made via Wilcoxon signed-rank test. RESULTS:= 0.02). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:MARS therapy for ALF was well tolerated by both pediatric and adult patients, and resulted in significant improvement in clinical and biochemical parameters. We demonstrated encouraging overall and transplant-free survival, suggesting that early initiation of MARS with relatively long and frequent cycle times may be of significant benefit to ALF patients, and is worthy of additional study in larger cohorts.
PMID: 37954902
ISSN: 2639-8028
CID: 5610992

Safety and Immunogenicity of Live Viral Vaccines in a Multicenter Cohort of Pediatric Transplant Recipients

Feldman, Amy G; Beaty, Brenda L; Ferrolino, Jose A; Maron, Gabriela; Weidner, Hillary K; Ali, Saira A; Bitterfeld, Leandra; Boulware, Mary Alice; Campbell, Kathleen M; Carr, Emily; Chapman, Shelley; Chang, Yeh-Chung; Cunningham, Ryan; Dallas, Ronald H; Dantuluri, Keerti L; Domenick, Bryanna N; Ebel, Noelle H; Elisofon, Scott; Fawaz, Rima; Foca, Marc; Gans, Hayley A; Gopalareddy, Vani V; Gu, Cindy; Gupta, Nitika A; Harmann, Katherine; Hollenbeck, Jessica; Huppler, Anna R; Jaramillo, Catalina; Kasi, Nagraj; Kerkar, Nanda; Lerret, Stacee; Lobritto, Steven J; Lopez, Maclovio J; Marini, Elizabeth; Mavis, Alisha; Mehra, Sonia; Moats, Lynnette; Mohandas, Sindhu; Munoz, Flor M; Mysore, Krupa R; Onsan, Ceren; Ovchinsky, Nadia; Perkins, Kerrigan; Postma, Stacy; Pratscher, Lauren; Rand, Elizabeth B; Rowe, Regina K; Schultz, Danielle; Sear, Katherine; Sell, Megan L; Sharma, Tanvi; Stoll, Janis; Vang, Mychoua; Villarin, Dominique; Weaver, Carly; Wood, Phoebe; Woodford-Berry, Olivia; Yanni, George; Danziger-Isakov, Lara A
IMPORTANCE:Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions. OBJECTIVE:To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS:This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols. EXPOSURES:Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine. MAIN OUTCOME AND MEASURE:Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis. RESULTS:The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination. CONCLUSIONS AND RELEVANCE:The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.
PMID: 37824141
ISSN: 2574-3805
CID: 5604492

Caring for a child after a liver transplant: Challenges beyond medical complexity [Comment]

Perez, Adriana; Ovchinsky, Nadia
PMID: 35779249
ISSN: 1527-6473
CID: 5416622

Patient-reported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases

Serper, Marina; Parikh, Neehar D; Thiele, Grace; Ovchinsky, Nadia; Mehta, Shivang; Kuo, Alexander; Ho, Chanda; Kanwal, Fasiha; Volk, Michael; Asrani, Sumeet K; Ghabril, Marwan S; Lake, John R; Merriman, Raphael B; Morgan, Timothy R; Tapper, Elliot B
BACKGROUND AND AIMS:HCC is a leading cause of mortality in patients with advanced liver disease and is associated with significant morbidity. Despite multiple available curative and palliative treatments, there is a lack of systematic evaluation of patient-reported outcomes (PROs) in HCC. APPROACH AND RESULTS:The American Association for the Study of Liver Diseases Practice Metrics Committee conducted a scoping review of PROs in HCC from 1990 to 2021 to (1) synthesize the evidence on PROs in HCC and (2) provide recommendations on incorporating PROs into clinical practice and quality improvement efforts. A total of 63 studies met inclusion criteria investigating factors associated with PROs, the relationship between PROs and survival, and associations between HCC therapy and PROs. Studies recruited heterogeneous populations, and most were cross-sectional. Poor PROs were associated with worse prognosis after adjusting for clinical factors and with more advanced disease stage, although some studies showed better PROs in patients with HCC compared to those with cirrhosis. Locoregional and systemic therapies were generally associated with a high symptom burden; however, some studies showed lower symptom burden for transarterial radiotherapy and radiation therapy. Qualitative studies identified additional symptoms not routinely assessed with structured questionnaires. Gaps in the literature include lack of integration of PROs into clinical care to guide HCC treatment decisions, unknown impact of HCC on caregivers, and the effect of palliative or supportive care quality of life and health outcomes. CONCLUSION:Evidence supports assessment of PROs in HCC; however, clinical implementation and the impact of PRO measurement on quality of care and longitudinal outcomes need future investigation.
PMID: 34990516
ISSN: 1527-3350
CID: 5416602

50 Years Ago in TheJournalofPediatrics: Hepatic Encephalopathy: Progress Made, but Mystery Remains

Shlomovich, Mark; Ovchinsky, Nadia
PMID: 35534154
ISSN: 1097-6833
CID: 5416612

Quality measures in HCC care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases

Asrani, Sumeet K; Ghabril, Marwan S; Kuo, Alexander; Merriman, Raphael B; Morgan, Timothy; Parikh, Neehar D; Ovchinsky, Nadia; Kanwal, Fasiha; Volk, Michael L; Ho, Chanda; Serper, Marina; Mehta, Shivang; Agopian, Vatche; Cabrera, Roniel; Chernyak, Victoria; El-Serag, Hashem B; Heimbach, Julie; Ioannou, George N; Kaplan, David; Marrero, Jorge; Mehta, Neil; Singal, Amit; Salem, Riad; Taddei, Tamar; Walling, Anne M; Tapper, Elliot B
The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.
PMID: 34778999
ISSN: 1527-3350
CID: 5416582

50 Years Ago in TheJournalofPediatrics: Disappearance of Reye Syndrome Outbreaks: One of the Greatest Public Health Victories

Ovchinsky, Nadia; Litman, Nathan
PMID: 34971652
ISSN: 1097-6833
CID: 5416592

COVID-19 infection in pediatric solid organ transplant patients

Bansal, Neha; Ovchinsky, Nadia; Foca, Marc; Lamour, Jacqueline M; Kogan-Liberman, Debora; Hsu, Daphne T; Beddows, Kimberly; Abraham, Lincy; Coburn, Maura; Cunningham, Ryan; Nguyen, Trang; Hayde, Nicole
BACKGROUND:Adult SOT recipients with COVID-19 have higher mortality rates when compared to general population. There is paucity of data on outcomes in pediatric SOT recipients. METHODS:This is a cross-sectional study investigating the prevalence of COVID-19 infection and outcomes in pediatric SOT (heart, liver, and kidney) recipients. We extracted demographic and clinical characteristics and COVID-19 testing (PCR or [Ab] test) results from medical records. Clinical characteristics were compared between patients who were positive for COVID-19 (PCR or Ab) and those who did not, using Mann-Whitney, Student's t test, or chi-square test. p value <.05 was statistically significant. RESULTS:A total of 108 SOT recipients with a median age of 13.1 (8.4, 17.8) years and median 4.2 (2.7, 7.9) years from transplant were checked for COVID-19 via a PCR or Ab test. A positive PCR was confirmed in 10 patients (9.3%), while 12 patients (11.1%) were positive for COVID-19 Ab. The patients who tested positive in our cohort were 9/50 (18%) heart, 6/68 (8.8%) kidney, and 7/50 (14%) liver transplant recipients. There were no differences in the clinical characteristics between patients with and without COVID-19 infection. All patients were either asymptomatic (50%) or had self-limiting symptoms. No changes were made to the immunosuppressive regimen. Only one patient was hospitalized and none had an oxygen requirement. CONCLUSIONS:In our cohort of pediatric SOT recipients, COVID-19 infection was asymptomatic or mild. This data may aid clinicians in counseling patients and families in this increased-risk population.
PMID: 34633125
ISSN: 1399-3046
CID: 5416332