Hepatitis
C
U.S. Hepatitis C Trial
This was a randomized, placebocontrolled, double-blind, multicenter
trial comparing Zadaxin plus IFNα-2b
combination treatment to IFNα-2b
monotherapy or placebo.
| Patients and
protocol: |
| • |
110 patients enrolled and
randomized |
| |
| – |
IFNα-2b
alone |
| – |
Zadaxin (1.6 mg
SC BIW) plus IFNα-2b
(3 MIU SC TIW) combination |
| – |
Placebo |
| – |
107 patients considered
evaluable |
| – |
109 patients used
in investigator’s intent-to-treat analysis |
| – |
110 patients used
in sponsor’s intent-to-treat analysis |
| – |
103 patients considered
evaluable by investigator |
| – |
107 patients considered
evaluable by sponsor |
|
| • |
6-month treatment period
|
| |
| – |
Treatment identities
unblinded after treatment |
|
| • |
6-month follow-up of responders |
| • |
Nonresponders to monotherapy
and combination therapy offered 6-month combined regimen
of Zadaxin plus IFNα-2b |
| • |
Primary clinical endpoint: complete
biochemical response defined as normal ALT level on last
two study visits at the end of the 6-month treatment period |
It should be noted that the primary clinical endpoint definition
in this study was more stringent than what was reported in the
literature with IFN monotherapy at the time, where the single
last ALT is used to determine end-of-treatment response.
| Results: |
| • |
Evaluable patients |
| |
| – |
Combination
response of 42% was significantly greater than IFNα-2b
response of 19% (P = 0.04) |
| – |
Combination
response of 42% was significantly greater than placebo
response of 5% (P < 0.001)
(Figure 12) |
|
| • |
Partial responders were considered
as nonresponders in efficacy analysis |
 |
Figure 12.
Results in the US hepatitis C trial at 6 months.
The figure shows the complete biochemical response (ALT)
at the completion of the 6-month treatment for the three
treatment groups. Patients were treated with either Zadaxin
plus IFNα-2b,
IFNα-2b, or placebo.
N = 107 evaluable. Data on file. (159) |
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Normalized ALT levels were evident in all IFNα-2b
monotherapy end-of-treatment responders (ETR) after 12 weeks
of therapy. Patients receiving Zadaxin plus IFNα-2b
combination therapy, however, continued to demonstrate normalization
of ALT levels throughout the treatment period, thus accounting
for the observed differences in ETR. Figure
13 shows that the Zadaxin plus IFNα-2b
combination enhances later treatment response for a longer duration
than typically seen with IFN alone.
ZDX + IFN vs IFN, P = 0.007
ZDX + IFN vs PBO, P = 0.0001
IFN vs PBO, P = 0.009
|
Figure 13.
Time to first ALT normalization in the US hepatitis C
trial. The figure shows that Zadaxin plus IFNα-2b
combination therapy enhances later treatment response
for a longer duration than typically seen with IFN alone.
This cumulative biochemical response accounts for the
observed differences in end-of-treatment response between
Zadaxin plus IFNα-2b
combination and IFNα-2b
alone. (105) |
| Intent-to-treat
analysis: |
| • |
Viral clearance defined
as end-of-treatment viral load compared with viral load
at baseline |
| • |
Significant difference
between Zadaxin plus IFNα-
2b and placebo groups (P < 0.001) |
| • |
Statistical trend in the
difference between Zadaxin plus IFNα-2b
and IFNα-2b (P
= 0.1) in HCV RNA levels |
| • |
Patients with histological
activity index (HAI) score improvement >2 points |
| |
| – |
Zadaxin plus IFNα-2b
group: 47% (16/34) |
| – |
IFNα-2b
group: 36% (12/33) |
| – |
Placebo group: 14%
(5/36) |
| – |
P = 0.01 among the
three treatment groups |
| – |
P = 0.004 between
Zadaxin plus IFNα-2b
combination and placebo |
|
| • |
Concordance in both active treatment
groups between improved HAI and response on the basis
of ALT (data on file) |
After 6 months of therapy, 11 patients who did not respond to
IFNα-2b were placed
on a 6-month combined regimen of Zadaxin plus IFNα-2b.
Ten of the 11 patients (one patient dropped out after 12 weeks
secondary to pre-existing coronary artery disease) completed
6 months of the combined regimen.
| Re-treatment
results: |
| • |
40% showed
normalization of ALT |
| • |
80% demonstrated
at least a 50% decrease in viral titer |
| • |
30% classified as complete
virological responders (viral titers below assay’s
detection limit) |
Following 6 months of treatment, patients were followed for
6 months to evaluate sustained response. Patients who relapsed
were offered an additional 6 months re-treatment with the same
treatment: combination IFNα-2b
plus Zadaxin or IFNα-2b
monotherapy. Re-treated relapsers were then followed for 6 months
to evaluate sustained response.
| Sustained response
results: |
| • |
Analysis included patients
treated for 6 months and relapsers retreated for a total
of 12 months |
| • |
Sustained biochemical response |
| |
| – |
19.2% for Zadaxin
plus IFNα-2b |
| – |
9.4% for IFNα-2b |
|
| • |
Zadaxin plus IFNα-2b
combination therapy was superior to single-agent IFNα-2b
in treatment of patients with CHC |
| • |
Treatment was generally well tolerated
|
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