A phase II, randomized, controlled trial of the safety and efficacy of S-adenosyl-L-methionine disulphate p-toluene-sulfonate (SAMe) in reducing serum alpha-fetoprotein (AFP) in patients with hepatitis C and moderately elevated AFP.

B144

Hepatocellular carcinoma (HCC) is a common complication of hepatitis C cirrhosis. Because of immigration from countries with a high prevalence of hepatitis B, as well as the increasing age of Americans who contracted hepatitis C during the 1960s through 1980s, the incidence of HCC is increasing in the United States, and is projected to double between 2000 and 2010. At present, there is no effective chemopreventive agent for HCC. Epidemiologic studies have reported an increased risk for HCC among males and in patients with cirrhosis, older age and elevated serum level of alpha-fetoprotein (AFP). SAMe has been used as a drug in Italy and other European countries for more than 20 years. It has an excellent safety profile. In the body, SAMe is a component of the methionine cycle and is found in all cells. Inactivation of methionine adenosyl transferase in cirrhosis reduces the conversion of methionine into SAMe. The resulting reduction in SAMe level may contribute to decreased synthesis of downstream products of SAMe, such as the antioxidant glutathione. In animal models of chemically-induced HCC, SAMe administration prevents HCC. Given the efficacy of SAMe in preventing HCC in animals, we designed a trial of the safety and efficacy of SAMe in reducing serum AFP in patients with hepatitis C cirrhosis. Methods: This is a prospective, randomized, double-blind, placebo controlled, Phase IIA study of the safety and efficacy of SAMe treatment in reducing the serum level of alpha-fetoprotein in patients with advanced liver disease due to chronic hepatitis C infection. Patients with advanced liver disease (cirrhosis) and with elevated serum AFP, but without detectable HCC by ultrasound imaging of the liver, will be eligible for enrollment into the study. Patients will be randomly assigned to treatment with placebo or escalating doses of SAMe up to 2400 mg/day. 50 patients will be enrolled into each group (total of 100 patients). Treatment will be for 24 weeks, with patients seen in at Week 4 (W4), W8, W12, W16, W20 and W24 during treatment and at 6 weeks after the end of treatment (W30). Interval history and routine biochemical tests of liver function will be performed at each visit to monitor safety. The primary outcome is change in serum AFP between the value at randomization (Week 0) and the value at W24 (end of treatment). Secondary outcomes include change in other serum markers of hepatocellular carcinoma (DCP, AFP-L3) and in markers of liver disease (e.g., ALT, hepatitis C viral load), oxidative stress (e.g., TNF-alpha, MDA, F2 isoprostane), SAMe metabolites (e.g., plasma SAMe, homocysteine, glutathione), and safety, tolerability and quality of life with SAMe treatment. Three medical centers will participate, with enrollment anticipated to begin in October 2006.