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Telaprevir (Incivek):  REALIZE results: SVR, virologic failure, relapse

Feb 04, 2012 - 5 comments
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REALIZE results

,

SVR

,

virologic failure

,

relapse



Incivek: Prescribing Information

14.3 Previously Treated Adults

Study C216 (REALIZE)

Study C216 was a randomized, double-blind, placebo-controlled, trial conducted in subjects who did not achieve SVR with prior treatment with Peg-IFN-alfa-2a/RBV or Peg-IFN-alfa-2b/RBV. The study enrolled prior relapsers (subjects with HCV-RNA undetectable at end of treatment with a pegylated interferon-based regimen, but HCV RNA detectable within 24 weeks of treatment follow-up) and prior non-responders (subjects who did not have undetectable HCV-RNA levels during or at the end of a prior course of at least 12 weeks of treatment). The nonresponder population included 2 subgroups: prior partial responders (greater than or equal to 2-log10 reduction in HCV-RNA at week 12, but not achieving HCV RNA undetectable at end of treatment with peginterferon alfa and ribavirin) and prior null responders (less than 2-log10 reduction in HCV-RNA at week 12 of prior treatment with peginterferon alfa and ribavirin).

Subjects were randomized in a 2:2:1 ratio to one of two INCIVEK combination treatment groups (with and without a Peg-IFN-alfa-2a/RBV lead-in) or a control group. The T12/PR48 group received INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks (without a lead-in), followed by placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The T12(DS)/PR48 group had a lead-in (delayed start of INCIVEK) with placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The Pbo/PR48 group received placebo and Peg-IFN-alfa-2a/RBV for 16 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks.

The 662 enrolled subjects had a median age of 51 years (range: 21 to 70); 70% of the subjects were male; 26% had a body mass index greater than or equal to 30 kg/m2 ; 5% were Black; 11% were Hispanic or Latino; 89% had baseline HCV-RNA levels greater than 800,000 IU/mL; 22% had bridging fibrosis; 26% had cirrhosis; 54% had HCV genotype 1a, and 46% had HCV genotype 1b. Null and partial responders had higher baseline HCV-RNA levels and more advanced liver disease (cirrhosis) than relapsers; other characteristics were similar across these populations.
The lead-in and immediate start regimens produced comparable SVR and no SVR rates, so data from these two groups were pooled (Table 11).

Table 11: Response Rates: Study C216
Treatment Outcome All T12/PR48*% (n/N)
Pbo/PR48% (n/N)*
Lead-in and immediate start T12/PR regimens pooled†
On-treatment virologic failure includes subjects who met a protocol-defined virologic stopping rule or who had detectable HCV-RNA at the time of their last dose of INCIVEK and subjects who had viral breakthrough on peginterferon alfa/ribavirin.‡
Relapse rates are calculated with a denominator of subjects with undetectable HCV-RNA at the end of treatment.

SVR rate
Prior relapsers 86% (246/286) 22% (15/68)
Prior partial responders 59% (57/97) 15% (4/27)
Prior null responders 32% (47/147) 5% (2/37)

Treatment Outcomes for Subjects Without SVR

On-treatment virologic failure †
Prior relapsers 1% (3/286) 10% (7/68)
Prior partial responders 15% (15/97) 26% (7/27)
Prior null responders 50% (74/147) 22% (8/37)

Relapse ‡
Prior relapsers 3% (8/254) 63% (27/43)
Prior partial responders 20% (14/71) 0% (0/4)
Prior null responders 24% (15/62) 50% (2/4)

Among prior relapsers, 76% (218/286) achieved an eRVR and of those 95% (208/218) achieved an SVR. In an earlier, dose-finding clinical trial, 78% (52/67) of prior relapsers achieved an eRVR and were treated with 24 weeks of peginterferon alfa and ribavirin (T12/PR24); of those 94% (49/52) achieved an SVR.

For all populations in the study (prior relapsers, prior partial responders, and prior null responders), SVR rates were higher for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, age, ethnicity, body mass index, HCV genotype subtype, baseline HCV-RNA level, and extent of liver fibrosis.

Twenty-three percent of INCIVEK-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 87% (48/55) compared to 13% (2/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.

Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 65% (328/503) for Caucasians.

http://pi.vrtx.com/files/uspi_telaprevir.pdf



Comments
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1118724_tn?1357014191
by hcvJames, Feb 22, 2012
Can you attempt to interpret something for me? Willb had pointed me to this study a month or so ago and I promptly tied myself in knots trying to understand this part.

"Twenty-three percent of INCIVEK-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 87% (48/55) compared to 13% (2/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders."

Cirrhotics on 3x tx vs. Placbo/Peg Riba48 wks was 87% SVR ... after that I have no idea..

vs 13% of cirrhotics on pbo/pr48
OR
prior relapser as a stand alone group? Why would the compare the two?
OR
cirrhotics who were also prior relapser's?

My take away is tx naive (of soc I presume) cirrhotics have an 87% chance of SVR
but
Cirrhotic Prior Relapser's (of soc) have only a 13% chance of SVR.

I have a feeling this is really simple and I've over thought it.
Thanks for any input.

Avatar_f_tn
by Advocate1955, Feb 22, 2012
Hi hcvJames,

It is confusing reading and trying to understand these studies.  I am definitely not an expert, but here is how I interpreted the information you asked about above.  

This paragraph is comparing cirrhotics who were treated with INC/IFN/RBV to cirrhotics who were treated with Pbo/IFN/RBV.  I believe the information is referring to 3 groups within the group of patients who were cirrhotic (1) prior relapsers, (2) prior partial responders, and (3) prior null responders.  I believe that none were treatment naive, all had received previous treatment (possibly SOC or consensus therapy).  The Placebo/PR48 referred to in all 3 groups was Pbo/IFN/RBV for 16 weeks followed by IFN/RBV for 32 more weeks.

In the group of Prior Relapsers, 87% of cirrhotics attained SVR on INC/INF/RBV, while 13% of cirrhotics attained SVR on a Placebo with INF/RBV for 16 weeks and the IFN/RBV for 32 weeks

In the group of Prior Partial Responders, 34% of cirrhotics attained SVR on INC/INF/RBV, while 20% of cirrhotics attained SVR on a Placebo with IFN/RBV

In the group of Prior Null Responders, 14% of cirrhotics attained SVR on INC/INF/RBV, while 10% of cirrhotics attained SVR on a Placebo with IFN/RBV

My take away is that 87% of cirrhotics who were prior relapsers attained SVR using triple tx with Inc., 34% of cirrhotics who were prior partial responders were able to attain SVR on triple tx with Inc., and 14% of prior null responders were able to attain SVR on triple tx with Inc.  Thus, prior relapsers have the best chance, prior partial responders second best chance, and null responders lower chance.

I may not be interpreting this correctly, but this is my understanding.  Of course, this particular paragraph is only looking at the results of those in the study who had cirrhosis.

Advocate1955

1118724_tn?1357014191
by hcvJames, Feb 23, 2012
Thank you for taking the time to make this clarification for me. Had they explained it as well as you ... Ha, maybe they did IDK but you made better sense. This is the best possible numbers for me, being a cirrhotic prior relapser 87% sounds sweet. It's horrifying to think round of SOC would have only produced a 13% chance. I wonder how low there were for tx naive cirrhotics before SOC. Again, thank you.

1118724_tn?1357014191
by hcvJames, Feb 23, 2012
geeze ... " .. to think *another* round of SOC ..."

I wonder how low *they* were for tx naive cirrhotics before *INC.*

Avatar_f_tn
by Advocate1955, Feb 23, 2012
Yes, your chances for a cure with triple tx with Incivek are the best ever in history right now. Stay the course!
Advocate1955

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