Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis (PBC)

The general aim of the study is to identify a safe and effective therapy for fatigue in patients with primary biliary cirrhosis. Specific aims include: 1) to determine the safety profile of modafinil in patients with primary biliary cirrhosis; 2) to evaluate the beneficial effects of modafinil on patients with primary biliary cirrhosis and fatigue as documented by a well-validated questionnaire (Fisk Fatigue Severity Score) to be applied at the beginning and end of the study period; and 3) to compare the performance of three questionnaires (Fisk Fatigue Severity Score, Fatigue Severity Scale and the fatigue domain of the PBC-40) as instruments to determine the benefits of a therapeutic intervention on fatigue by establishing the minimally important clinical difference of these measures of fatigue.

Inclusion criteria

• Primary biliary cirrhosis will be defined as present when 2 of 3 of the following criteria are met:

• Chronic cholestatic liver disease for greater than 6 months with alkaline phosphatase levels greater than 1.5 times the upper limit of normal prior to UDCA treatment.
• Positive AMA titer greater or equal to 1:40 or AMA greater than 0.1U. Liver histology in the past with features consistent with or diagnostic of PBC.
• A previous ultrasound, computed tomography (CT), or cholangiography of the biliary tree excludes biliary obstruction.
• Verbal report of fatigue for greater than 6 months.

Exclusion criteria

• Patients with other serious coexistent conditions such as pre-existing advanced malignancy or severe cardiopulmonary disease which would be expected to limit their expectancy to less than three years.
• Findings highly suggestive of liver disease of other etiology such as chronic alcoholic liver disease, chronic hepatitis B or C infection, hemochromatosis, Wilson's disease, 1-antitrypsin deficiency, non-alcoholic steatohepatitis or sclerosing cholangitis.
• Treatment of underlying PBC has been modified in the preceding six months.
• Anticipated need for transplantation in one year (Mayo survival model <80% one-year survival without transplant) or MELD above 15.
• Recurrent variceal bleeding, presence of diuretic-resistant ascites, or spontaneous encephalopathy.
• Active drug or alcohol use.
• History of drug and/or stimulant (e.g. methylphenidate, amphetamine, or cocaine) abuse.
• Serum bilirubin >4 mg/dl.
• Serum creatinine over 1.4 mg/dl.
• Pregnancy.
• Breast-feeding.
• Inability or unwillingness to practice contraceptive measures for the prevention of pregnancy if appropriate.
• Other fatigue related diagnoses such as anemia, thyroid disease, renal failure, use of beta-blockers and untreated depression.
• Known hypersensitivity to modafinil.
• Uncontrolled hypertension.
• Patients with hypertension and left ventricular hypertrophy documented on ECG in the last 2 years.
• Recent (<6 months) history of myocardial infarction or unstable angina.
• Patients with history of psychosis.
• Patients receiving cyclosporine, warfarin, tricyclic agents, carbamazepine, phenobarbital, rifampin, ketoconazole or itraconazole in the last 3 months.