Study of Tauroursodeoxycholic Acid for Hepatobiliary Disease in Cystic Fibrosis

PROTOCOL OUTLINE: Objective I: This part of the study is a dose-response study to determine
the optimal dose of tauroursodeoxycholic acid (TUDCA). Twenty-four patients are randomized
to receive one of three different doses of TUDCA for 3 months.

Objective II: This part of the study is a double-blind crossover study to compare optimized
doses of TUDCA with optimized doses of ursodiol in 15 patients stratified according to age
(less than 10 vs 10-20 vs more than 20 years). Patients are randomized to receive either
TUDCA or ursodiol orally for an initial 3 month period, followed by a 3 month washout period
in which no drug is administered. Patients then receive the alternate drug for 3 months.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

- Cystic fibrosis-associated liver disease, defined by at least one of the following
criteria: (1) Documented increase in serum concentrations of any of the liver enzymes
(at least once in the preceding year) ALT at least twice normal AST at least 1.5
times normal Alkaline phosphatase at least 1.5 times normal GGT at least 1.5 times
normal (2) Persistent hepatomegaly of more than 6 months duration defined by
percussed liver span greater than 1 SEM for age (3) Splenomegaly, defined as a
palpable spleen greater than 2.0 cm below the left costal margin (4) Abnormalities of
ultrasound scan (increased size, dishomogeneous echogenicity, nodular liver,
irregular margins, splenomegaly) within 6 months prior to study entry

- Patients enrolled in the first part of the study (objective I) are eligible to
participate in the second part (objective II)

--Prior/Concurrent Therapy--

- At least 3 months since prior ursodiol

- At least 3 months since treatment with drug with choleretic properties or effects
that influence bile acid metabolism

--Patient Characteristics--

- Hepatic: No decompensated cirrhosis No hepatic neoplasm or cholelithiasis

- Pulmonary: No significantly impaired pulmonary function with FEV1 less than 50%

- Other: At least 15 kg body weight No severely compromised clinical or nutritional
state