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

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 ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS: 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: 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: Albireo Pharma, an Ipsen company.

Quality of life in Malaysian children with inflammatory bowel disease: An understudied population.

AIM: Quality of life (QoL) in children with inflammatory bowel disease (IBD) is often impaired by underlying disease. We evaluated factors affecting health-related QoL (HRQoL) in Malaysian children with IBD. METHODS: A cross-sectional study using IMPACT-III questionnaires evaluating HRQoL in children aged 8-17 years with duration of IBD of ≥6 months was conducted. IMPACT-III, a validated instrument designed to measure HRQoL in children with IBD, was used. Higher IMPACT-III (maximum = 100) score indicates better HRQoL. Impact of socio-demographic and clinical factors of IBD on the HRQoL was evaluated. Paediatric Crohn's disease (CD) and ulcerative colitis (UC) activity indices were used to classify disease severity. RESULTS: A total of 75 children (UC = 44, CD = 41; mean (SD) age at diagnosis 8.2 (3.5) years) were interviewed at mean age of 12.8 (2.7) years. Mean IMPACT-III score was significantly lower in children with more severe disease (mild: 71.8 (13.6) vs. moderate: 65.5 (10.9) vs. severe: 46.3 (14.5); P < 0.001), history of hospitalisation (yes: 64.0 (14.0) vs. none: 74.1 (12.2), P = 0.034) and a higher number of admissions (r = -0.352, P = 0.041) in preceding 6 months. Diagnosis at a younger age (r = -0.31, P = 0.007) and a longer duration of disease (r = 0.286, P = 0.013) was associated with higher score. A higher weight-for-age (r = 0.261, P = 0.023) or body mass index-for-age z-score (r = 0.235, P = 0.042) was correlated with a better body image domain score, respectively. CONCLUSIONS: In Malaysian children with IBD, HRQoL was adversely affected by a more severe disease. Better control of disease activity and maintaining long-term remission are important to improve the HRQoL in childhood IBD.

Environmental risk factors for inflammatory bowel disease: A case control study in Southeast Asian children.

AIM: Early-life environmental exposure, which has important implications in the pathogenesis of inflammatory bowel disease (IBD), is not well understood in Asian children. We examined environmental factors prior to the development of childhood IBD in a Southeast Asian population. METHODS: We conducted a case control study in IBD diagnosed before 18 years of age and controls matched by gender, age and ethnicity. A questionnaire recording medical, family, dietary and social histories, home environment, childhood diseases and immunisation status was used. RESULTS: In a multivariate analysis involving 70 children with IBD (Crohn's disease (CD) = 38; ulcerative colitis (UC) = 32) and 140 controls, childhood acute gastroenteritis (odds ratio (OR): IBD 6.9; CD 7.8; UC 5.8) and excessive antibiotic usage in early childhood (OR: IBD 5.3; CD 4.2; UC 4.8) were significantly associated with IBD, CD and UC. Having a fish or turtle aquarium (OR 6.0), major stressful life events (OR 5.6) and attending the same school concurrently with a sibling (OR 2.9) were significant risk factors for IBD. Duration of breastfeeding >6 months (OR: IBD 0.4; UC 0.2) and safe water consumption (OR: IBD 0.2; UC 0.2) reduced the odds of having IBD and UC, respectively. Being vaccinated for rotavirus reduced the odds of developing IBD (OR 0.1). CONCLUSIONS: Several risk and protective factors were identified in this environmental risk study in Southeast Asian children with IBD. This knowledge has important implications in understanding disease aetiology and future prevention strategies to reduce the development of IBD in Southeast Asian children.

Human TGF-ß1 deficiency causes severe inflammatory bowel disease and encephalopathy.

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

Characteristics and outcome of autoimmune liver disease in Asian children.

BACKGROUND: Little is known about autoimmune liver disease (AILD) in Asian children. We studied the clinical features and predictors of outcome in childhood AILD in an Asian population. METHODS: Retrospective review of AILD [autoimmune hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC)] seen at two pediatric liver units in Malaysia. RESULTS: At presentation, 17 (56%) of the 32 children [19 females, 59%; median (range) age 7.7 (1.8-15.5) years] with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9) had liver cirrhosis. At final review [median (range) duration of follow-up 4.8 (0.4-12) years], 24 patients (75%) survived with a native liver. Twenty-one (66%) were in remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on prednisolone and/or azathioprine, one on cyclosporine and another on mycophenolate mofetil. Three (AIH1 = 3) were in partial remission. Of the two who underwent liver transplantation (LT; 6.5%; both ASC), one died of primary graft failure after LT. Six patients (19%) died without LT (acute liver failure, n = 1; end-stage liver disease, n = 5). The overall survival rate (native liver and survival post-LT) was 78%. A delay in seeking treatment adversely affected the final outcome [survival with native liver vs. LT or death (duration between onset of disease and treatment; median ± standard error) = 2.5 ± 2.9 months vs. 24.0 ± 13.3 months; p = 0.012]. CONCLUSIONS: Although remission was achieved in the majority of patients with prednisolone and/or azathioprine therapy, delay in seeking diagnosis and treatment adversely affects the outcome of childhood AILD in Malaysia.