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1

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Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Hirschfield, Gideon M. ; Shiffman, Mitchell L. ; Gulamhusein, Aliya ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2023

In: Hepatology Vol. 78, No. 2 ( 2023-08), p. 397-415

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In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 78, No. 2 ( 2023-08), p. 397-415

Abstract: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) 〈 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p 〈 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p 〈 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: −3.14 ( p =0.02); placebo: −1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Type of Medium: Online Resource

ISSN: 0270-9139

URL: Article

DOI: 10.1097/HEP.0000000000000395

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2023

detail.hit.zdb_id: 1472120-X

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2

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Real-world use of avatrombopag in patients with chronic liver disease and thrombocytopenia undergoing a procedure

Satapathy, Sanjaya K. ; Sundaram, Vinay ; Shiffman, Mitchell L. ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2023

In: Medicine Vol. 102, No. 40 ( 2023-10-06), p. e35208-

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In: Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 102, No. 40 ( 2023-10-06), p. e35208-

Abstract: The phase 4 observational cohort study assessed the effectiveness and safety of the thrombopoietin receptor agonist avatrombopag in patients with chronic liver disease (CLD) and thrombocytopenia undergoing a procedure. Patients with CLD may have thrombocytopenia, increasing the risk of periprocedural bleeding. Prophylactic platelet transfusions used to reduce this risk have limitations including lack of efficacy and transfusion-associated reactions. Prophylactic thrombopoietin receptor agonists have been shown to increase platelet counts and decrease platelet transfusions. Effectiveness was assessed by change from baseline in platelet count and proportion of patients needing a platelet transfusion. Safety was assessed by monitoring adverse events (AEs). Of 50 patients enrolled, 48 were unique patients and 2 patients were enrolled twice for separate procedures. The mean (standard deviation) change in platelet count from baseline to procedure day was 41.1 × 10 9 /L (33.29 × 10 9 /L, n = 38), returning to near baseline at the post-procedure visit (change from baseline −1.9 × 10 9 /L [15.03 × 10 9 /L], n = 11). The proportion of patients not requiring a platelet transfusion after baseline and up to 7 days following the procedure was 98% (n = 49). Serious AEs were infrequent (n = 2 [4%] ). No treatment-emergent AEs were considered related to avatrombopag. There were 2 mild bleeding events, no thromboembolic events or deaths, and no patients received rescue procedures (excluding transfusions). This study found that in a real-world setting, treatment with avatrombopag was well tolerated, increased the mean platelet count by procedure day, and reduced the need for intraoperative platelet transfusions in patients with CLD and thrombocytopenia.

Type of Medium: Online Resource

ISSN: 0025-7974 , 1536-5964

URL: Article

DOI: 10.1097/MD.0000000000035208

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2023

detail.hit.zdb_id: 2049818-4

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3

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A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study

Sulkowski, Mark S. ; Moon, Juhi S. ; Sherman, Kenneth E. ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2021

In: Hepatology Vol. 74, No. 6 ( 2021-12), p. 2952-2964

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In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 6 ( 2021-12), p. 2952-2964

Abstract: Multiple direct‐acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. Approach and Results We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician‐recorded adverse events, patient‐reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%‐97.6%) and 97.4% (95% CI, 95.5%‐99.2%), respectively, with a difference estimate of 2.2% (−0.5% to 4.7%), falling within the “equivalence” interval (−5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient‐reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow‐up after treatment, limiting the ability to measure SVR12. Conclusions This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin‐free EBR/GZR and LDV/SOF.

Type of Medium: Online Resource

ISSN: 0270-9139 , 1527-3350

URL: Article

DOI: 10.1002/hep.32053

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

detail.hit.zdb_id: 1472120-X

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4

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A Machine Learning Approach to Liver Histological Evaluation Predicts Clinically Significant Portal Hypertension in NASH Cirrhosis

Bosch, Jaime ; Chung, Chuhan ; Carrasco‐Zevallos, Oscar M. ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2021

In: Hepatology Vol. 74, No. 6 ( 2021-12), p. 3146-3160

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In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 6 ( 2021-12), p. 3146-3160

Abstract: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm. Approach and Results Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome‐stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held‐out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver‐related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML‐HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P 〈 0.001). The ML HVPG score differentiated patients with normal (0‐5 mm Hg) and elevated (5.5‐9.5 mm Hg) HVPG and CSPH (median: 1.51 vs. 1.93 vs. 2.60; all P 〈 0.05). The areas under receiver operating characteristic curve (AUROCs) (95% CI) of the ML‐HVPG score for CSPH were 0.85 (0.80, 0.90) and 0.76 (0.68, 0.85) in the training and test sets, respectively. Discrimination of the ML‐HVPG score for CSPH improved with the addition of a ML parameter for nodularity, Enhanced Liver Fibrosis, platelets, aspartate aminotransferase (AST), and bilirubin (AUROC in test set: 0.85; 95% CI: 0.78, 0.92). Although baseline ML‐HVPG score was not prognostic, changes were predictive of clinical events (HR: 2.13; 95% CI: 1.26, 3.59) and associated with hemodynamic response and fibrosis improvement. Conclusions An ML model based on trichrome‐stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis.

Type of Medium: Online Resource

ISSN: 0270-9139 , 1527-3350

URL: Article

DOI: 10.1002/hep.32087

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

detail.hit.zdb_id: 1472120-X

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5

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Role of Noninvasive Tests in Clinical Gastroenterology Practices to Identify Patients With Nonalcoholic Steatohepatitis at High Risk of Adverse Outcomes: Expert Panel Recommendations

Younossi, Zobair M. ; Noureddin, Mazen ; Bernstein, David ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2021

In: American Journal of Gastroenterology Vol. 116, No. 2 ( 2021-02), p. 254-262

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In: American Journal of Gastroenterology, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. 2 ( 2021-02), p. 254-262

Abstract: Nonalcoholic fatty liver disease (NAFLD) is generally considered a silent and potentially reversible condition. The subtype of NAFLD that can be classified as nonalcoholic steatohepatitis (NASH) can progress to advanced fibrosis and cirrhosis. Because of the metabolic nature of the pathogenic mechanism underlying NAFLD and NASH, it is often accompanied by common comorbidities such as obesity, insulin resistance, and type 2 diabetes mellitus. The increase in the prevalence of these comorbidities has resulted in a parallel increase in the prevalence of NAFLD and NASH, globally, nationally, and even in children. In recent years, it has been identified that the stage of fibrosis is the most important predictor of liver outcomes; therefore, identifying patients with NAFLD and NASH with more advanced stages of fibrosis can be essential for optimal management. Several noninvasive tools for diagnosing and staging NAFLD and NASH are available, but simple and straightforward recommendations on the use of these tools are not. Recognizing these unmet needs, hepatologists who are members of the American College of Gastroenterology and the Chronic Liver Disease Foundation created a practical decision tree/algorithm to risk stratify NAFLD/NASH as a resource in gastroenterology/hepatology clinical practices. This review will provide insight into how this algorithm was developed, describe it in detail, and provide recommendations for its use in clinical practice.

Type of Medium: Online Resource

ISSN: 0002-9270 , 1572-0241

URL: Article

DOI: 10.14309/ajg.0000000000001054

RVK:

XA 18920

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

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6

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Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH

Loomba, Rohit ; Noureddin, Mazen ; Kowdley, Kris V. ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2021

In: Hepatology Vol. 73, No. 2 ( 2021-02), p. 625-643

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In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 73, No. 2 ( 2021-02), p. 625-643

Abstract: Advanced fibrosis attributable to NASH is a leading cause of end‐stage liver disease. Approach and Results In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3‐F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two‐drug combinations, once‐daily for 48 weeks. The primary endpoint was a ≥1‐stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo‐treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score ( P = 0.040) and a shift in biopsy area from F3‐F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2‐point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin‐18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%‐29% of cilofexor versus 15% of placebo‐treated patients. Conclusions In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer‐term therapy in patients with advanced fibrosis attributable to NASH.

Type of Medium: Online Resource

ISSN: 0270-9139 , 1527-3350

URL: Article

DOI: 10.1002/hep.31622

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

detail.hit.zdb_id: 1472120-X

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7

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Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial

Patel, Keyur ; Harrison, Stephen A. ; Elkhashab, Magdy ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2020

In: Hepatology Vol. 72, No. 1 ( 2020-07), p. 58-71

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In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. 1 ( 2020-07), p. 58-71

Abstract: We evaluated the safety and efficacy of cilofexor (formerly GS‐9674), a small‐molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). Approach and Results In this double‐blind, placebo‐controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging–proton density fat fraction (MRI‐PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI‐PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI‐PDFF was 16.3% and MRE‐stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI‐PDFF of −22.7%, compared with an increase of 1.9% in those receiving placebo ( P = 0.003); the 30‐mg group had a relative decrease of −1.8% ( P = 0.17 vs. placebo). Declines in MRI‐PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg ( P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg ( P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma‐glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well‐tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). Conclusions Cilofexor for 24 weeks was well‐tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

Type of Medium: Online Resource

ISSN: 0270-9139 , 1527-3350

URL: Article

DOI: 10.1002/hep.31205

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2020

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8

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Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient‐Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis

Younossi, Zobair M. ; Stepanova, Maria ; Noureddin, Mazen ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2021

In: Hepatology Communications Vol. 5, No. 7 ( 2021-07), p. 1201-1211

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In: Hepatology Communications, Ovid Technologies (Wolters Kluwer Health), Vol. 5, No. 7 ( 2021-07), p. 1201-1211

Abstract: Patient‐reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo‐controlled study of selonsertib, firsocostat, or cilofexor, alone or in two‐drug combinations (NCT03449446). PROs included Short Form 36 (SF‐36), Chronic Liver Disease Questionnaire (CLDQ)‐NASH, EuroQol Five Dimension (EQ‐5D), Work Productivity and Impairment (WPAI), and 5‐D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF‐36 and Fatigue and Worry of CLDQ‐NASH were significantly lower in patients with cirrhosis (total CLDQ‐NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P 〈 0.05). Lower baseline PRO scores were independently associated with age, female sex, greater body mass index, diabetes, clinically overt fatigue, and comorbidities (all P 〈 0.05). After 48 weeks of treatment, patients with ≥1‐stage fibrosis improvement without worsening of NASH experienced improvement in EQ‐5D and five out of six CLDQ‐NASH domains ( P 〈 0.05). Patients with ≥2‐point decrease in their nonalcoholic fatty liver disease activity score (NAS) also had improvements in PF and Role Physical scores and all domains of CLDQ‐NASH ( P 〈 0.05). Progression to cirrhosis was associated with a decrease in PF scores of SF‐36 ( P ≤ 0.05). Fibrosis regression was independently associated with greater improvements in PF and EQ‐5D scores, while NAS improvement was associated with improvement in fatigue and pruritus (all P 〈 0.05). Conclusion: Patients with advanced NASH experienced improvement in their PROs after fibrosis regression or improvement in disease activity.

Type of Medium: Online Resource

ISSN: 2471-254X , 2471-254X

URL: Article

DOI: 10.1002/hep4.1710

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2021

detail.hit.zdb_id: 2881134-3

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