Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Switching to placebo after week 18 resulted in greater elevations in serum bile acid levels and pruritus compared to patients who remained on maralixibat.

2. Maralixibat was well-tolerated with few self-limiting adverse events that were mild-to-moderate in severity.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Alagille syndrome is a rare autosomal-dominant genetic condition marked by an inability to drain bile. The resultant cholestasis may progress to liver damage which manifests symptomatically as jaundice, chronic pruritus, and xanthomas. Currently, there is no available pharmacotherapy for this disease with most patients ultimately needing a liver transplant. Apical sodium-dependent bile acid transporter (ASBT) inhibitors, such as maralixibat, are known to disrupt the enterohepatic circulation of bile and may be used to prevent cholestasis. This randomized controlled trial aimed to evaluate the safety and efficacy of maralixibat in patients with Alagille syndrome. The primary endpoint was a change in mean serum bile acid (sBA) levels during the randomized withdrawal period (RWD), while key secondary endpoints included changes in Clinician Scratch Scale (CSS) and Clinical Xanthoma Scale (CXS) score. According to study results, patients assigned to the placebo group had a significant increase in sBA levels and pruritus compared to those who remained on maralixibat. In addition, those on maralixibat showed a progressive decrease in sBA levels over time. Although this study was well conducted, it had a small sample size, impacting the validity of results.

In-depth [randomized controlled trial]:

Between Oct 28, 2014, and Aug 14, 2015, 36 patients were assessed for eligibility. Included were those 1-18 years of age with three times the normal sBA levels and uncontrollable pruritus. Enrolled patients (n=31) were given maralixibat 380 ug/kg daily for 18 weeks and assigned to continue maralixibat or placebo for 4 weeks (weeks 19-22; randomized withdrawal period [RWD]). All patients were subsequently given maralixibat to week 48. Mean age among those enrolled was 5.4 years (standard deviation [SD] 4.25) and the majority (66%; 19 of 29) of RWD follow-ups were male. Regarding the primary endpoint, patients who switched to placebo after week 18 showed increased sBA (94 umol/L, 95% confidence interval [CI] 23 to 164) and pruritus (1.7 points, 95% CI 1.2 to 2.2) compared to those who remained on maralixibat. Furthermore, a progressive improvement in both markers was noted for patients on maralixibat from baseline to week 48 (sBA: -96 umol/L, 95% CI -162 to -31 and pruritus: -1.6 points, 95% CI -2.1 to -1.1). Of the 15 participants who remained on maralixibat, the reductions in sBA persisted to week 204. No serious adverse events were noted. Overall, findings from this study suggest that maralixibat contains good safety and efficacy for management of cholestasis in patients with Alagille syndrome, although further studies are needed to confirm this.

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