Completed studies
Romark made the decision to initially focus on the potential treatment of chronic hepatitis C with nitazoxanide. Three phase II studies of nitazoxanide for the treatment of chronic hepatitis C have been completed and communicated in publications or presentations at national and international meetings[6–8]. The first study was a randomized, double-blind, placebo-controlled study of the treatment of chronic hepatitis C with nitazoxanide 500 mg twice daily in 50 adult patients with chronic hepatitis C infected with genotype 4[6]. Seven of 23 patients (30%) had a virologic end-of-treatment response (ETR) with undetectable virus, and a sustained virologic response (SVR) with undetectable virus 24 wk after the completion of treatment was observed in 4 of 23 patients (17%). All responders had low serum HCV RNA levels less than 400 000 IU/mL. This study was the first use of nitazoxanide in patients with chronic hepatitis C and for a longer time period than for its use for cryptosporidiosis and giardiasis, and the drug was well tolerated with the same number of mild gastrointestinal adverse events in the treated and placebo groups.
A second randomized, double-blind, placebo-controlled study (STEALTH C-1) evaluated the effects of nitazoxanide plus peginterferon alfa-2a (dual regimen) or nitazoxanide plus peginterferon alfa-2a and ribavirin (triple regimen) versus the standard of care (SOC) with peginterferon alfa-2a and ribavirin in 96 treatment-naive patients with chronic hepatitis C infected with genotype 4[7]. Nitazoxanide 500 mg twice daily was administered over a 12-wk lead-in followed by an additional 36 wk in combination with peginterferon alfa-2a 180 μg weekly with or without ribavirin 1000-1200 mg daily. The SOC group received the same doses of peginterferon alfa-2a and ribavirin for 48 wk. A rapid virologic response (RVR; undetectable serum HCV RNA after 4 wk of combination therapy) occurred in 38%, 54%, and 64% of patients receiving the SOC, dual regimen and triple regimen, respectively (P = 0.048, SOC vs triple regimen). A complete early virologic response (cEVR; undetectable serum HCV RNA at week 12 of combination therapy) occurred in 70, 68 and 86% of the SOC, dual regimen and triple regimen, respectively. The SVR rates at 24 wk post-treatment were 50%, 61% and 79%, respectively, demonstrating a 29% difference between the SOC and the triple regimen with nitazoxanide (P = 0.023).
A third open label study was carried out in 44 patients; 40 were infected with genotype 4, and 3 were infected with genotype 1, and 1 infected with genotype 2[8]. This study evaluated a shorter 4-wk lead-in phase with nitazoxanide 500 mg twice daily followed by 36 wk of treatment with a combination of nitazoxanide with peginterferon alfa-2a 180 μg weekly without ribavirin, and the results were compared with the historical results from the STEALTH C-1 study. The RVR, cEVR, and SVR rates were 59%, 82% and 80%, respectively, and the SVR rate of 80% in this study was significantly higher than the historical SVR rate of 50% in the SOC group (P = 0.006). The 3 patients infected with genotype 1 and the single patient infected with genotype 2 all had an SVR. The SVR rate of 80% raises the possibility using nitazoxanide in place of ribavirin, which requires further study.
In both this study and the STEALTH C-1 study, the administration of nitazoxanide in combination with peginterferon, with or without ribavirin, was associated with a low relapse rates (3 of 38 in the current study; and 3 of 20 patients receiving dual therapy and 1 of 23 patients receiving triple therapy, compared with 10 of 30 patients in the SOC arm in the STEALTH C-1 study). These low relapse rates, with or without ribavirin, suggest the possibility that nitazoxanide might play a similar role as ribavirin in reducing the relapse rate and be a possible substitute for ribavirin in combination with peginterferon for the treatment of chronic hepatitis C.
The results of these preliminary studies in Egypt in patients predominantly infected with genotype 4 were met with considerable interest in the hepatology community; but, studies conducted in the United States and the response to nitazoxanide in combination with the SOC in patients with genotype 1 were recognized as the next steps required to confirm these initial interesting findings.Completed studies
Romark made the decision to initially focus on the potential treatment of chronic hepatitis C with nitazoxanide. Three phase II studies of nitazoxanide for the treatment of chronic hepatitis C have been completed and communicated in publications or presentations at national and international meetings[6–8]. The first study was a randomized, double-blind, placebo-controlled study of the treatment of chronic hepatitis C with nitazoxanide 500 mg twice daily in 50 adult patients with chronic hepatitis C infected with genotype 4[6]. Seven of 23 patients (30%) had a virologic end-of-treatment response (ETR) with undetectable virus, and a sustained virologic response (SVR) with undetectable virus 24 wk after the completion of treatment was observed in 4 of 23 patients (17%). All responders had low serum HCV RNA levels less than 400 000 IU/mL. This study was the first use of nitazoxanide in patients with chronic hepatitis C and for a longer time period than for its use for cryptosporidiosis and giardiasis, and the drug was well tolerated with the same number of mild gastrointestinal adverse events in the treated and placebo groups.
A second randomized, double-blind, placebo-controlled study (STEALTH C-1) evaluated the effects of nitazoxanide plus peginterferon alfa-2a (dual regimen) or nitazoxanide plus peginterferon alfa-2a and ribavirin (triple regimen) versus the standard of care (SOC) with peginterferon alfa-2a and ribavirin in 96 treatment-naive patients with chronic hepatitis C infected with genotype 4[7]. Nitazoxanide 500 mg twice daily was administered over a 12-wk lead-in followed by an additional 36 wk in combination with peginterferon alfa-2a 180 μg weekly with or without ribavirin 1000-1200 mg daily. The SOC group received the same doses of peginterferon alfa-2a and ribavirin for 48 wk. A rapid virologic response (RVR; undetectable serum HCV RNA after 4 wk of combination therapy) occurred in 38%, 54%, and 64% of patients receiving the SOC, dual regimen and triple regimen, respectively (P = 0.048, SOC vs triple regimen). A complete early virologic response (cEVR; undetectable serum HCV RNA at week 12 of combination therapy) occurred in 70, 68 and 86% of the SOC, dual regimen and triple regimen, respectively. The SVR rates at 24 wk post-treatment were 50%, 61% and 79%, respectively, demonstrating a 29% difference between the SOC and the triple regimen with nitazoxanide (P = 0.023).
A third open label study was carried out in 44 patients; 40 were infected with genotype 4, and 3 were infected with genotype 1, and 1 infected with genotype 2[8]. This study evaluated a shorter 4-wk lead-in phase with nitazoxanide 500 mg twice daily followed by 36 wk of treatment with a combination of nitazoxanide with peginterferon alfa-2a 180 μg weekly without ribavirin, and the results were compared with the historical results from the STEALTH C-1 study. The RVR, cEVR, and SVR rates were 59%, 82% and 80%, respectively, and the SVR rate of 80% in this study was significantly higher than the historical SVR rate of 50% in the SOC group (P = 0.006). The 3 patients infected with genotype 1 and the single patient infected with genotype 2 all had an SVR. The SVR rate of 80% raises the possibility using nitazoxanide in place of ribavirin, which requires further study.
In both this study and the STEALTH C-1 study, the administration of nitazoxanide in combination with peginterferon, with or without ribavirin, was associated with a low relapse rates (3 of 38 in the current study; and 3 of 20 patients receiving dual therapy and 1 of 23 patients receiving triple therapy, compared with 10 of 30 patients in the SOC arm in the STEALTH C-1 study). These low relapse rates, with or without ribavirin, suggest the possibility that nitazoxanide might play a similar role as ribavirin in reducing the relapse rate and be a possible substitute for ribavirin in combination with peginterferon for the treatment of chronic hepatitis C.
The results of these preliminary studies in Egypt in patients predominantly infected with genotype 4 were met with considerable interest in the hepatology community; but, studies conducted in the United States and the response to nitazoxanide in combination with the SOC in patients with genotype 1 were recognized as the next steps required to confirm these initial interesting findings.