Nitazoxanide
Increases Response to Pegylated Interferon plus Ribavirin in
Treatment-naive and Non-responder Hepatitis C Patients
By
Liz Highleyman
Nitazoxanide
is a broad-spectrum thiazolide drug being developed by Romark
Laboratories that has demonstrated activity against a variety
of micro-organisms including protozoa, hepatitis
B virus (HBV), and hepatitis
C virus (HCV).
Treatment-naive
Patients
Investigators at both conferences presented final data from
STEALTH C-3, a Phase 2 clinical trial of nitazoxanide in previously
untreated patients with genotype
1 chronic hepatitis C.
The study included 112 participants at 13 U.S. centers who were
randomly assigned (2:1) to receive either 500 mg twice-daily
nitazoxanide or placebo along with pegylated
interferon alfa-2a (Pegasys) plus ribavirin for 48 weeks.
About one-third of patients had advanced liver fibrosis
or cirrhosis
(stage F3-F4).
The primary study endpoint was sustained virological response
(SVR), or continued undetectable HCV viral load 24 weeks after
completing treatment. The researchers also looked at rapid virological
response (RVR), or undetectable (< 10 IU/mL) HCV RNA at week
4; complete early virological response (EVR), or undetectable
HCV RNA at week 12; partial EVR, at least a 2 log drop in viral
load at week 12, and end-of-treatment response (ETR), or undetectable
viral load at completion of therapy.
Results
 |
Patients
receiving nitazoxanide had higher response rates than those
taking placebo by 12 weeks, but not at 4 weeks: |
| |
 |
RVR:
12% in nitazoxanide arm vs 19% in placebo arm; |
|
Complete
EVR: 62% vs 49%, respectively; |
|
ETR:
63% vs 46%, respectively; |
|
SVR:
44% vs 32%, respectively. |
|
|
SVR
rates were consistently higher for nitazoxanide recipients
in difficult-to-treat patient sub-groups: |
| |
|
High
baseline viral load (> 800,000 IU/mL): 41% vs 29%
respectively; |
|
African-Americans:
38% vs 20%, respectively. |
|
|
Nitazoxanide
was generally well-tolerated |
|
Rates
of serious adverse events were similar in the nitazoxanide
and placebo arms. |
|
The
only adverse events significantly associated with nitazoxanide
were mild-to-moderate diarrhea and urine discoloration.
|
"Consistent
with previously reported results in naive genotype 4 patients,
the addition of nitazoxanide increased the SVR rate in genotype
1 naive patients by more than one-third," the investigators
concluded.
Treatment-experienced Patients
The Phase 2 STEALTH C-2 trial evaluated nitazoxanide in combination
with pegylated interferon plus ribavirin in genotype 1 chronic
hepatitis C patients who previously failed to achieve a sustained
response with standard therapy alone.
This study, conducted at 10 U.S. centers, included 64 participants.
About 60% were null responders to prior treatment (< 2 log
drop in HCV RNA after 12 weeks), while 20% were partial responders
(> 2 log drop after 12 weeks but never undetectable) and
20% had insufficient date. About 7% were black and 40% had stage
F3-F4 fibrosis or cirrhosis.
Participants were randomly assigned (2:1) to receive 500 mg
twice-daily nitazoxanide or placebo for a 4-week lead-in period,
followed by nitazoxanide or placebo plus pegylated interferon/ribavirin
for 48 weeks.
Patients discontinued the study if they did not achieve at least
1 log drop in HCV RNA after 4 weeks of combination therapy,
at least 2 log drop after 12 weeks of combination therapy, or
undetectable HCV RNA after 28 weeks of combination therapy.
Again, the primary endpoint was SVR, with secondary endpoints
including RVR, complete and partial EVR, and ETR.
Results
|
HCV
viral load did not change significantly during the 4-week
nitazoxanide monotherapy lead-in period. |
|
Patients
receiving nitazoxanide had higher response rates than those
taking placebo, but rates were low overall and differences
did not reach statistical significance: |
| |
|
RVR:
5% in nitazoxanide arm vs 0 in placebo arm; |
|
Complete
EVR: 7% vs 0, respectively; |
|
Partial
EVR: 38% vs 29%, respectively; |
|
ETR:
14% vs 0, respectively; |
|
SVR:
7% vs 0. |
|
|
The
3 patients who achieved SVR were white and had high baseline
viral load (> 800,000 IU/mL), 2 of the 3 were partial
responders to prior treatment, and 1 had advanced fibrosis.
|
|
2
sustained responders achieved RVR and all 3 had complete
EVR. |
|
3
late responders who achieved ETR but not EVR relapsed during
post-treatment follow-up. |
|
Again,
nitazoxanide was generally well-tolerated. |
|
The
only adverse event attributed to nitazoxanide was mild-to-moderate
diarrhea. |
|
No
serious adverse events attributable to nitazoxanide were
reported. |
"This
was a particularly difficult-to-treat patient population,"
said Romark Chairman and Chief Science Office (and nitazoxanide
discoverer) Jean-Francois Rossignol, MD. "The data suggests
that nitazoxanide will be most relevant in patients with partial
response to prior therapy or in prior relapsers."
Based on studies to date, Romark has decided on a nitazoxanide
dose of 675 mg using a controlled-release tablets to achieve
better bioavailability. This formulation will be further evaluated
in Phase 3 trials. Researchers plan to test nitazoxanide with
a shorter 24-week duration of pegylated interferon, with and
without ribavirin (which helps prevent post-treatment relapse),
and in combination with new direct-acting anti-HCV agents. In
addition, the AIDS Clinical Trials Group (ACTG) is studying
nitazoxanide plus pegylated interferon/ribavirin in HIV/HCV
coinfected patients.
Investigator affiliations:
DDW
Bacon abstract: Romark Institute for Medical Research, Romark
Laboratories, Tampa, FL; Division of Gastroenterology and Hepatology,
Stanford University Medical Center, Stanford, CA; Division of
Gastroenterology and Hepatology, St. Louis University Medical
Center, St. Louis, MO; Liver Institute of Virginia, Bon Secours
Health System, Newport News, VA; Section of Digestive Diseases,
Yale University, New Haven, CT; Florida Center for Gastroenterology,
Largo, FL; Georgetown University Medical Center, Fairfax, VA.
EASL Shiffman abstract: Liver Institute of Virginia, Bon Secours
Health System, Newport News, VA; Division of Gastroenterology
and Hepatology, Stanford University Medical Center, Stanford,
CA; Division of Gastroenterology, Weill Cornell Medical College,
New York, NY; Nashville Gastrointestinal Specialists, Inc.,
Nashville, TN; The Romark Institute for Medical Research, Romark
Laboratories, Sausalito, CA.
EASL Bacon abstract: Division of Gastroenterology and Hepatology,
St Louis University Medical Center, St Louis, MO; Liver Institute
of Virginia, Bon Secours Health System, Newport News, VA; Section
of Digestive Diseases, Yale University School of Medicine, New
Haven, CT; Florida Center for Gastroenterology, Largo, FL; Georgetown
University Medical Center, Washington, DC; The Romark Institute
for Medical Research, Romark Laboratories, Sausalito, CA; Division
of Gastroenterology and Hepatology, Stanford University Medical
Center, Stanford, CA.
5/28/10
References
BR Bacon, ML Shiffman, JK Lim, and others. Phase 2 randomized,
double-blind, placebo-controlled study of nitazoxanide plus
peginterferon and ribavirin in naive patients with chronic hepatitis
C genotype 1 infection: final report. Digestive Disease Week.
New Orleans. May 1-5, 2010. Abstract
711b.
ML Shiffman, A Ahmed, IM Jacobson, and others. Phase 2 randomized,
double-blind, placebo-controlled study of nitazoxanide with
peginterferon alfa-2a and ribavirin in nonresponders (NR) with
chronic hepatitis C genotype 1: final report. 45th Annual Meeting
of the European Association for the Study of the Liver (EASL
2010). Vienna, Austria. April 14-18, 2010. Abstract.
BR Bacon, ML Shiffman, JK Lim, and others. Phase 2 randomized,
double-blind, placebo-controlled study of nitazoxanide plus
peginterferon and ribavirin in HCV genotype 1 naive patients:
week 12 sustained virologic response rate. 45th Annual Meeting
of the European Association for the Study of the Liver (EASL
2010). Vienna, Austria. April 14-18, 2010. Abstract.
Other sources
Romark Labratories. Romark Announces Final Data from Clinical
Trial of Nitazoxanide in Treatment-naïve Patients with
Genotype 1 Chronic Hepatitis C. Press
release. May 4, 2010.
Romark Labratories. Romark Announces Data from Clinical Trial
of Nitazoxanide in Patients with Genotype 1 Chronic Hepatitis
C Who Previously Failed Treatment with Peginterferon Plus Ribavirin.
Press
release. April 19, 2010.
Romark Labratories. Romark Announces Data from Clinical Trial
of Nitazoxanide in Treatment-naive Patients with Genotype 1
Chronic Hepatitis C. Press
release. April 15, 2010.
