Safety and Efficacy Study of Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis
Condition: Primary Sclerosing Cholangitis
MeSH terms: Cholangitis; Cholangitis, Sclerosing
Study type: Interventional
Phase: Phase 1

Summary: 
      Primary sclerosing cholangitis (PSC), although uncommon, is a devastating and insidiously
      progressive liver disease, resulting from advancing inflammation, fibrosis and obliteration
      of the bile ducts in the liver, leading to cirrhosis and end-stage liver disease. Although
      prognosis in children may be somewhat better than that of adults, approximately one third of
      pediatric patients require transplantation by adulthood. Other than transplantation, there is
      to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid
      (UDCA) improves biochemical markers of liver disease, although in high doses does not clearly
      improve the long-term outcome in adults, and in a recent study may have actually worsened
      outcome. Childhood PSC is different from that of adult PSC in many ways, and children may
      derive more short-term, as well as long-term, benefit than adults. This unique multicenter
      study will carefully monitor the effects of withdrawal and restarting UDCA on liver injury
      and inflammation in children with PSC. The preliminary data will help in the design of a more
      definitive larger study to determine if UDCA has a beneficial role in the treatment of PSC in
      children. Funding Source - FDA OOPD
    

Detailed description: 
      Primary sclerosing cholangitis (PSC), a devastating and insidiously progressive cholestatic
      liver disease, results from advancing inflammation, fibrosis and obliteration of the intra-
      and extrahepatic bile ducts, leading to cirrhosis and end-stage liver disease. PSC is an
      uncommon disorder (prevalence in the US of 8-14/100,000 with even lower prevalence in
      children). Although prognosis in children may be somewhat better, approximately one third of
      pediatric patients require transplantation by adulthood. Other than transplantation, there is
      to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid
      (UDCA) improves biochemical markers of liver disease, although in high doses does not clearly
      improve the long-term outcome in adults. Furthermore, a recent large adult trial of high-dose
      UDCA therapy suggested a higher incidence of serious adverse events and poor outcomes with
      UDCA treatment, leading many centers to discontinue UDCA therapy in adult patients. Childhood
      PSC is different from the adult disease including a stronger association with both autoimmune
      markers and histologic features and a trend to higher transaminases at diagnosis.
      Furthermore, in response to intermediate-dose UDCA therapy, there is a more striking and
      prompt improvement in biochemistries as compared to adults. In light of the prompt
      normalization of liver enzymes and the fact that UDCA is well tolerated in children,
      pediatric hepatologists are reluctant to generalize the adult UDCA study results to children
      and to stop UDCA therapy. This presents a significant dilemma: Should UDCA therapy be stopped
      in pediatric PSC patients to avoid a possible adverse influence on long-term prognosis at the
      risk of losing a possible beneficial effect on disease progression in children? Additional
      factors in children with PSC/autoimmune hepatitis (AIH) overlap are the long-term adverse
      effects of corticosteroids and azathioprine use. If UDCA therapy is effective as monotherapy,
      these complications may be avoided. Therefore, we propose a preliminary UDCA withdrawal and
      reinstitution trial in pediatric PSC patients to collect data to support the design of a
      larger, longer-term randomized, placebo-controlled trial of UDCA therapy in childhood PSC.
      This pilot study, which will utilize the infrastructure and participating centers of the
      STOPSC (Studies of Primary Sclerosing Cholangitis) consortium, will test the following
      hypotheses: 1) UDCA therapy yields a rapid biochemical response in children with PSC, thus
      withdrawal would lead to increased biochemical evidence of disease. 2) UDCA therapy
      suppresses liver and biliary inflammation in children with PSC, thus withdrawal of therapy
      would result in a burst of inflammatory activity and an increase in serum cytokine
      biomarkers, 3) Biochemical control of childhood PSC with histologic features of AIH is
      dependent upon treatment with immunosuppression in addition to UDCA, therefore childhood PSC
      without histologic features of AIH will worsen significantly with UDCA withdrawal compared to
      PSC with histological features of AIH.
    

Intervention name(s): ursodeoxycholic acid (UDCA)
Intervention type(s): Drug
Intervention description(s): Pediatric PSC patients already receiving UDCA therapy will enter a four-phase trial consisting of baseline data collection (phase I, 4 weeks), 50% reduction in UDCA dose (phase II, 4 weeks), discontinuation of UDCA (phase III, 8 weeks) and reinstitution of therapy at a dose of 20 mg/kg/day (phase IV, 8 weeks). Surveillance and endpoint evaluation for each phase will include liver chemistries and clinical data. Comparisons will be made between baseline and the end of phase III (primary outcome) and between the end of phase III and the end of phase IV (secondary outcome). Serum cytokine biomarkers will be measured and compared between baseline and the end of phase III and between the end of phases III and IV.
Other intervention name(s): Ursodeoxycholic acid; URSO 250; URSO Forte; Actigall; Ursodiol; UDCA
Intervention MeSH terms: Ursodeoxycholic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Primary sclerosing cholangitis; Autoimmune hepatitis; Cholestatic liver disease; Cirrhosis; Children; Primary Sclerosing Cholangitis/Autoimmune Hepatitis Overlap