Multicenter databases as contextual comparators to current clinical trials may be advantageous in Alagille syndrome (ALGS) and other rare diseases, according to a new study published in Hepatology Communications.

The investigation led by Shneider analyzed a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) that met the inclusion and exclusion criteria from a maralixibat trial in patients with ALGS (ITCH NCT02057692). Data from a natural history or clinical care cohort of 59 patients with ALGS and their native liver was matched to the age distribution of the ITCH trial by frequency weighting.

After a control visit at the 2-year mark, weighted survival in the ALGS national history cohort was 91%. Likewise, clinician scratch scores significantly decreased in 73% of the cases, suggesting an improvement in pruritus, and 9 of these patients had complete resolution of this symptom.

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“One could also hypothesize a potential bias of clinicians to support the value of their clinical practice by identifying an improvement in one of the major manifestations of the disease that they are treating in their patients,” the authors said. “As [clinician scratch scores] is clinician-scored, this potential bias could have affected the change over time in this parameter.”

Although platelet count values lowered considerably (-65.2 [16.2] -98.3, -32.1) in 58% of the individuals, total bilirubin, alanine aminotransferase, albumin, and weight remained stable.

Other less frequent events included recently developed evident ascites without variceal hemorrhage in 3 patients and surgical interruption of enterohepatic circulation in 3 cases. A total of 13 participants had a liver transplant at a mean age of 5.3 years. Finally, 3 children died with their native liver at 3.5 years on average.

“The current studies have shown that prospective longitudinal database registries can be used to provide important and unique contextual information regarding interventional clinical trials in rare diseases, especially in those that are single-arm studies or lack a control population,” the authors concluded.

“The findings from this kind of real-world evidence are critically important, given the difficulties of conducting long-term placebo controlled trials in orphan diseases.”


Shneider B, Kamath B, Magee J, et al. Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—examination of cholestatic liver disease in Alagille syndrome. Hepatol Commun. Published online May 4, 2022. doi:10.1002/hep4.1970