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A 12 Week Randomized Placebo-Controlled Double Blind Trial of Clevudine in Patients with Chronic Hepatitis B with Post-Treatment Follow-up for 24 weeks
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Reported by Jules Levin
H-S Lee (Seoul National University Hospital) and colleagues
Clevudine is a pyrimidine analogue that is a potent inhibitor of HBV replication in vitro. In woodchucks, clevudine caused potent and durable post-treatment viral suppression. In a preliminary clinical trial of 4 week clevudine treatment, potent antiviral activity was demonstrated along with the marked post-treatment antiviral effect. Two studies of clevudine were presented at HEP DART.
The primary objectives of the first study were to evaluate the tolerability, safety, and antiviral activity of clevudine in a 12 week, double-blind, randomized, multicenter, phase II clinical trial and to assess the sustained antiviral response 24 weeks off therapy.
The safety and efficacy of clevudine (30 mg/day or 50mg/day, orally) were compared with those of placebo, and then each group was observed for 24-week off therapy (a total period of 36 weeks). The study was conducted at a total of 8 sites in South Korea. Eligible patients were female or male with HBeAg-positive chronic hepatitis B with HBV DNA levels greater than or equal to 3 x 106 copies/ml. Among a total of 99 patients enrolled, 68 patients (19, 25, and 24 in the placebo, 30mg and 50mg cohorts, respectively) have completed 36-week study period, the data of whom were analyzed.
Median HBV DNA level at baseline was 8.2, 8.4, and 8.1 log10 copies/ml, and the median change in HBV DNA levels from baseline at week 12 was –0.52, -4.24, and –4.45 log10 copies/ml in the placebo, 30mg and 50mg cohorts, respectively. Post-treatment antiviral activities were sustained with 3.55 and 3.19 log10 reduction until week 12 weeks off therapy and 2.56 and 1.75 log10 reduction until week 24 off therapy in placebo, 30mg and 50mg cohorts, respectively. In the placebo, 30mg and 50mg cohorts, 0 and 68 and 71% had HBV DNA levels below the lower limit of detection assay (4.7 x 103 copies/ml) at the end of 12-week treatment, and 5%, 12% and 13% at week 36, respectively. Normalization of alanine transminase level was observed in 19, 74 and 67% at week 12 and 44, 78, and 67% at week 36 in the placebo, 30mg and 50mg cohorts, respectively. Clevudine was well tolerated and most adverse events were comparable in all study groups.
The authors concluded that clevudine has potent antiviral activity against HBV with sustained viral suppression off therapy and was well tolerated.
CLEVUDINE SECOND STUDY
SG Lim (Natl University Hospital, Singapore, China) and colleagues.
This was a multi-center, international, randomized, double-blind study comparing 10, 30, and 50 mg CLV QD for 12 weeks. Patients were followed post-treatment for at least 24 weeks. Eligible patients had chronic HBV with baseline serum HBV DNA levels (VL) ≥ 3x106 copies/ml (c/ml), and were nucleoside treatment-naïve with out HIV, HDV, or HCV co-infection. VL was assayed using Digene Hybrid Capture II (lower limit of detection of 4700 c/ml). Results are presented for the first 12 weeks of the study.
31 patients were enrolled (10, 11 and 10 in the 10, 30, and 50 mg cohorts, respectively) of whom 55% were male, 84% Asian, and 81% HBeAg positive. At baseline, median VL was 8.7, 7.9, and 8.7 log10 c/ml and median ALT was 53, 63,, and 80 IU/L in the 10, 30, and 50 mg QD cohorts.
After 12 weeks of dosing, the median log10 VL change from baseline was –3.2, -3.7 and –4.1 log10 c/ml in the 10, 30 and 50 mg cohorts, respectively.
One of 10, 5/11 and 2/10 patients had VL below the assay LOD at week 12.
During the treatment-period, 2 patients in the 30 mg QD cohort seroconverted to anti-HBe, none had isolated HBeAg loss. CLV was generally well tolerated without any dose related adverse events, and no severe or serious adverse events were reported. One patient had a grade 3 increase in ALT and another a transient grade 3 CPK increase, on study drug.
The pharmacokinetics of CLV were dose proportional with a median plasmahalf-life of 60-70 hours. CLV was undetectable in plasma after at most 4 weeks following the end of dosing. Pharmacodynamic analysis shows that 97% of the maximal treatment effect was reached with a dose of 30 mg QD. No treatment emergent mutations in the HBV DNA pol conserved domain were observed at the end of dosing.
The authors concluded that these preliminary results confirm the antiviral activity of once daily clevudine and further demonstrate the antiviral potency and the tolerability of the drug over a longer period of dosing than the previous 4-week study. Based on these results the optimal dose of CLV appears to be 30 mg QD.
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