The purpose of the Advance study was to assess the effectiveness and safety of different courses of telaprevir when combined with and compared to standard therapy -- a long-lasting form of interferon called peginterferon and the nuke ribavirin. Results from this trial of telaprevir suggest that when combined with peginterferon and ribavirin, telaprevir results in very high cure rates in HCV mono-infected people. Further research with telaprevir is ongoing to try to simplify the dosing of this drug, as telaprevir currently needs to be taken every eight hours.
Study Details
Researchers enrolled nearly 1,000 HCV mono-infected volunteers and randomly assigned them to one of three groups. To summarize the plan for this trial, participants were treated for either 24 or 48 weeks; at the end of that time, they were monitored for an additional 48 or 24 weeks to find out if they were cured.
Participants were assigned to one of the following three treatment groups:
Group 1: telaprevir for 12 weeks (T12)
telaprevir + peginterferon + ribavirin, all three drugs taken for 12 consecutive weeks, followed by peginterferon + ribavirin for 12 additional weeks, for a total of 24 weeks of treatment. At the end of week 24, if participants had an early virologic response (EVR) -- that is, if HCV viral load became undetectable or fell at least 100-fold compared to baseline -- they were not given any further therapy and they were monitored for 48 more weeks to see if they achieved a sustained virologic response (SVR) or cure. If they did not achieve an EVR at the end of week 24, then participants were given a further 24 weeks of peginterferon + ribavirin (for a total of 48 weeks of treatment), followed by 24 weeks of monitoring to see if they achieved an SVR or cure.Group 2: telaprevir for 8 weeks (T8)
telaprevir + peginterferon + ribavirin, all three drugs taken for 8 consecutive weeks, followed by peginterferon + ribavirin for 16 additional weeks, for a total of 24 consecutive weeks of treatment. At the end of week 24, those participants with an EVR were then monitored for 48 more weeks. People who did not have an EVR at week 24 received a further 24 weeks of peginterferon + ribavirin (for a total of 48 weeks of treatment). This was then followed by 24 additional weeks of monitoring to assess if they achieved an SVR or cure.Group 3: peginterferon + ribavirin (PR) only
Participants received standard therapy with peginterferon + ribavirin for 48 consecutive weeks, followed by 24 weeks of monitoring to assess the durability of their SVR or cure.
Drugs and Placebo
Telaprevir was given at a dose of 750 mg every eight hours; ribavirin at a dose between 1,000 and 1,200 mg (depending on body weight) taken in two divided doses each day; and peginterferon-alpha-2a was used at a dose of 180 mcg injected once weekly. For part of the beginning of the study, some participants in groups 1 and 2 received placebo instead of telaprevir.
HCV Testing
The assay used to detect HCV was the Roche Taqman version 2. This test has a lower limit of quantification of 25 international units (IU)/ml. That is, it can accurately report copies of HCV as low as 25 IU/ml of blood.
There were about 360 participants assigned to each of the study's groups. The average profile of participants when they entered the study (baseline) was as follows:
40% females, 60% males
main ethno-racial groups were as follows: 90% White, 8% Black
age -- 50 years
proportion with a high baseline HCV viral load (800,000 IU/ml or greater) -- 77%
proportion of volunteers with severe liver damage (cirrhosis) -- 15%
Common HCV sub-types were as follows:
sub type 1a -- 59%
sub type 1b -- 40%
Results -- Dropouts
Volunteers withdraw or drop out of a study for many reasons -- including severe side effects and lack of effectiveness of therapy -- and these withdrawals can affect the results of the study. Overall, the proportions of participants who dropped out from the study groups were as follows:
T12: 26% withdrew
T8: 29% withdrew
PR: 44% withdrew
Among the people who dropped out of the study, people who received telaprevir were less likely to leave because of treatment failure. Here are the discontinuations in each group due to virologic failure:
T12 -- 10% (38 participants)
T8 -- 11% (40 participants)
PR -- 33% (116 participants)
Among telaprevir users, 10% left because of side effects, while 7% of people who received peginterferon + ribavirin alone left because of side effects.
Sustained Virologic Response (SVR) or Cure
The term SVR refers to people who have cleared HCV for 24 consecutive weeks since they last received therapy. Traditionally, this is the period after 48 weeks of consecutive therapy when HCV virus levels are monitored in clinical trials. In general, 72 weeks after entering a clinical trial (24 weeks after therapy has ended), if HCV remains below the level of quantification, a person is considered cured. SVR rates in each group were as follows:
T12 -- 75% cured
T8 -- 69% cured
PR -- 44% cured
These differences in SVR rates between telaprevir-containing regimens and standard therapy were statistically significant; that is, they were not likely due to chance alone.
Due to their genes, some people of African descent may not have as good a response to HCV therapy as people of other ethno-racial groups. However, in the Advance study, high rates of SVR were seen in Black people who received telaprevir.
Results -- Rapid Clearance of HCV
A rapid virologic response (RVR) occurs when HCV becomes undetectable after four weeks of therapy. People who develop an RVR are highly likely to experience an SVR with continued therapy. However, not getting an RVR does not predict the future failure of therapy.
In the Advance study, participants who received telaprevir were more likely to have an RVR. Participants who had an RVR in this study were distributed as follows:
T12 -- 68%
T8 -- 66%
PR -- 9%
Another phrase sometimes used is early virologic response (EVR). This occurs when HCV levels are either undetectable at week 12 or have decreased at least 100-fold from baseline at week 12. When an EVR does not occur in HCV-infected people who are on treatment and who have HCV sub types 1 or 4, continued therapy is unlikely to cure HCV infection. Rates of EVR were as follows:
T12 -- 58%
T8 -- 57%
PR -- 8%
These findings attest to the powerful antiviral activity of telaprevir-containing regimens.
Results -- Relapse
Suppression of HCV might occur early in the course of treatment only to later rebound; this is called relapse. Rates of relapse were very low among participants who received telaprevir compared to standard therapy:
T12 -- 6%
T8 -- 8%
PR -- 27%
Liver Damage
In general, among people in Advance, the less pre-existing liver damage they had, the better their response to therapy, though even in people with a moderate degree of liver damage from HCV, response rates were still generally good.
Results -- Side Effects
Here is the distribution of common side effects:
Fatigue
T12 -- 57%
T8 -- 58%
PR -- 57%
Itchy skin
T12 -- 50%
T8 -- 45%
PR -- 36%
Nausea
T12 -- 43%
T8 -- 40%
PR -- 31%
Anemia
T12 -- 37%
T8 -- 39%
PR -- 19%
Problems falling asleep or staying asleep
T12 -- 32%
T8 -- 32%
PR -- 3%
Diarrhea
T12 -- 28%
T8 -- 32%
PR -- 22%
Side Effects -- Focus on the Skin
Itch and rash were relatively common side effects in the Advance study. Here is the distribution of rash:
Any severity of rash (ranging from mild to life-threatening)
T12 -- 56%
T8 -- 53%
PR -- 37%
Severe rash
T12 -- 6%
T8 -- 3%
PR -- 1%
Rash so uncomfortable that people had to quit the trial
T12 -- 7%
T8 -- 5%
PR -- 1%
Focus on Anemia
Less-than-normal levels of hemoglobin were more common in telaprevir users.
T12 -- 36%
T8 -- 40%
PR -- 14%
Anemia related to telaprevir use resolved over time, as this drug was only used for between eight and 12 weeks.
Summary
Overall, telaprevir-based regimens were associated with higher rates of recovery from HCV infection compared to standard therapy. These rates of recovery were unaffected by race or ethnicity. Taking telaprevir for 12 weeks was associated with better results than taking it for eight weeks. Common side effects included itchy skin, rash, nausea, anemia and diarrhea. Telaprevir is likely to be approved in 2011 in the U.S. and in 2012 in Canada. As telaprevir needs to be taken every eight hours, research with this compound is still ongoing as the developer, Vertex, tries to find ways of simplifying the number of required daily doses.
Reference
Jacobson IA, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with peginterferon alfa-2a and ribavirin in genotype 1 HCV treatment-naïve patients:
Final results of phase 3 Advance study. In: Program and abstracts of the 61st Annual Meeting of the American Association for the Study of Liver Diseases, 29 October - 2 November 2010, Boston, MA. Abstract 211.