PI trials for F4 Geno1?

[mike716]

Anybody know if there have been any trials for F4 (and above) geno 1s, or if any are being slated?

I'm still toying with the idea of waiting for PI approval, in spite of now being F3/F4. Maybe it's crazy. But since my hospital can't offer me anything but SOC (less than 30% chance for me), and there aren't any PI trials coming up in my area, I don't really know what to do. If there were some data on whether the PIs can clear F4s, at least I'd have some idea of my chances if I wait. Or maybe I could just rule it out and go with what's available with a clearer mind.

Information is the name of the game.

Mike

[WriteItDown]

Hi Mike -- glad I didn't depress you over on your other thread... :)  Were you able to speak to anyone about the TMC435 trial? I don't want to keep pushing it on you, but it is a PI with good results so far and it is recruiting in several cities in Argentina.

Maybe someone else will have another good idea for you.

[mike716]

I'm so depressed at this point that it's hard to make it worse [grin].

Re TMC435, if you are referring to trial NCT00882908, I looked it over and was put off. There are so many arms, many without the PI (or with partial PI), that I didn't like it. Plus it's only a Phase II trial, and the results of previous trials are not in yet, I don't
t think. Also, Argentina is not listed as a trial site, and I wouldn't go back to the States for this trial.

But maybe you are thinking of a different trial?

[Marcia2202]

Hey my friend. You are treatment naive right? Why don't you take the bull by the horns and treat. If you get the PI drug that would be great, if not, you would still treat with SOC, and that's not a bad thing.

Just my 2 cents...

[Bali05]

I think Mike716 does not want to end up SOC without an adjunct.
If I were naive geno 1 with no other trial ect.. I would want to add at least
Alinia to the mix .
Anything to increase SVR.

[WriteItDown]

Hi Mike,

Well, I just took a look and it seems they changed the trial locations and Argentina is no longer there.  However, I can assure you it was there when I first recommended this trial to you.  Buenos Aires was a location, but unfortunately is now gone.... I don't know why they changed it.  IMHO that's a bummer for you, since I think it's a really good trial, and the docs at the excellent hospital where my husband is treating think so, too.

So this brings me to my next point: maybe your standards for what constitutes an acceptable trial are too high?  Obviously now that Buenos Aires is no longer a location for this trial, you can't be on it, but for the sake of discussion let's take a closer look at it.  

First of all, in four arms out of five (80%) the participants get the trial drug.  The two dosages, if you read the results for the Phase IIa trials, which are available, both achieved excellent viral response -- around a 4.5 log drop at week 1 and undetectable viral load in week 4 in around 90% of patients. Those are pretty darn good statistics.

Also, if you read about the PI's being brought to market first -- Telaprevir and Boceprevir -- you'll see that they are often dosed for only 12 weeks with very good results.  My feeling is that in all four arms of this trial where people get the PI there will be good SVR rates.... of course I can't say anything like that for sure now, but in a trial it's almost never for sure. Bottom line is: 80% of people who participate in this trial get access to the PI's at a dosage and for a duration that looks pretty likely, based on the Phase IIa results, to be effective.

Yeah, we all want to be in the Phase III trial of the next greatest thing, but if it's not available and we need to treat sooner rather than later, it seems to me it's worth it to do some research and take a chance. I certainly understand if you're risk-averse, but remember, there's also a risk in doing nothing.

But that's just me! Whatever you do I hope the very best for you. I like the idea of you tangoing for many more years....

[mike716]

I calculate my chances with 48-week SOC as around 20%. It just ain't good enough. I don't want to get on the non-response/relapse roller-coaster.

[mike716]

Well, your reading of the trial arms is undoubtedly better than mine. I frankly can't understand half of what I read on that website. But it seems to me that around half the participants are not getting 24 weeks of PI. Perhaps I'm mistaken.

And you can't really talk about results until the 6-month and 1-year VLs are in. Relapse from viral escape variants is, in my opinion, a major problem with the viral gene inhibitors. And if you relapse with a high VL of escape variants, you are in big trouble. Escape variants tend to be more virulent than the typical strains, as well as drug-resistant.

I'm not going to panic and do any old thing. The drug companies are hurrying these trials. For my money, they're not giving it enough time. Doing phase II trials when the info isn't really in yet for the Phase I trial is risky business.

TRials are risky anyway, of course. But, still, you've got to have a fighting chance. This one just doesn't look right to me.

Maybe I'm wrong. What do I know?

M.

[Marcia2202]

Okay, I understand. I guess you do not have a choice then to either go to NY and get into a trial or to wait until the PI's are out.

I really wish you good luck and hope that it will all work out to your best.

Hugs, marcia

[Rockerforlife]

You could TX just for 30 days and see if you RVR with SOC,if you ,your go to go that whole  ride.Just a thought,but once you start you wont wanna stop i bet,think about it,30 day RVR is 90-100% home run,,,,you asked,i asy do the SOC FULL FORCE...hit it with all you got.

[mike716]

Not sure what you mean, Marcy. But I appreciate the good wishes.

Mike

[mike716]

Do a test Tx for 30 days? Now, there's a novel idea! I think I'll bring this up with the hep MD I'm seeing on Friday.

[mike716]

I would still very much like to know if there have been any trials of PIs for geno 1, Metavir F4 and above. Does anyone have an idea about this?

Mike

[Marcia2202]

I don't think that there any trials which are divided by stage of fibrosis. Haven't heard of any trials like that.

I meant that since you are not going to do SOC, that there are only two choices. Either to follow a trial in NY... or maybe somewhere else in the US, since there doesn't seem to be any trials in Argentina. Or to wait until you can treat with a PI when they come out and they have them in Argentina. I don't know if I'm making any sense.

Hugs

[Rockerforlife]

You might not want to say to your doc you will stop at 30 days if you dont SVR,he may not treat you at all,you can always just stop the  TX anytime you want SOC or a trial.But ill garentee if you do RVR in 30 days you will happy.

[Rockerforlife]

Another thing,RVR  with SOC is the same as RVR with the PI ...dont matter what bat you hit the home run with

[WriteItDown]

In fact 24 weeks of PI's is likely to be overkill.  Read the results of the Telaprevir trials: ALL arms get the PI for only 12 weeks, and they have SVR rates of 80 - 85%.

I appreciate that you do not feel enough info is available for you to trust this trial (or likely many others).  However, the info for the Phase I and the Phase IIa trial IS in, which I stated in my previous post. It's readily available on the internet.

Lastly, I wish you wouldn't refer to this trial, which my dear husband is on, as "any old thing."  We researched it very thoroughly, and, even though I understand that it isn't right for you, it's much more well-designed than you are giving it credit for.

[Rockerforlife]

I even felt my 36 weeks of boceprevir was a bit of an overkill,not by the SX,just that 36 weeks of 18 pills a dy wa s abit much,if this virus is not killed now,it will never die.

[Trish77]

"I would still very much like to know if there have been any trials of PIs for geno 1, Metavir F4 and above. Does anyone have an idea about this? "

Mike, the trials that are run are usually done on the basis of treatment naive or not and are usually done for Genotype 1's.  You've got both things in your favour there when it comes to trials - you're Genotype 1 and you're treatment naive.

As for PI's for 24 weeks, that's not typically done on a trial.  Most are PI's or the trial drug for a shorter period of time and then SOC for the greater majority of the time.  I wouldn't let the fact that the trial drug is less than 24 weeks put you off at ALL.  I would look at it differently, that having an extra drug in there for any portion of time is a bonus on top of SOC.  I had a polymerase inhibitor for the first 12 weeks while I was, unknown to me at the time, getting half the usual dosage of interferon.  

If you decide to go SOC, Alinia can be prescribed off-label or purchased from an online drug company, you can add Alinia to the mix with SOC.  You can also talk to your doc about going with higher doses of ribavirin and/or interferon in the beginning if you want to hit this thing with a hammer.  I would also consider doing a lead-in with the ribavirin of 2-3 weeks.  

I would start cruising clinicaltrials.gov and look for Phase III trials for treatment naive Geno 1's but also consider how you'd like to do SOC treatment in the absence of a trial and start preparing to do either / or.   I was getting myself ready to do SOC and was getting ready to have my son bring Alinia in for me from Mexico - he was in San Diego at the time - and then the trial came along.  You may get to the point where you're so ready to treat that you're not waiting any longer for the perfect trial so you might as well plan out your SOC in the event a trial to your liking doesn't come along.

If you truly believe you are F4, then you don't have time to waste.  Geterdone, my friend.

[Trish77]

Furthermore, when looking at clinical trials, don't disregard the Phase II trials either - mine had 7 arms and more risk to it - some are less risk, less arms and decent odds.  Come to think of it, there is a Phase II that's been recruiting that a couple people have posted about that looked pretty good and I'll try to remember which one it was and post it to you for consideration.

[HectorSF]

Mike, Hope this helps to answer your question....and cheer you up.

In this study about 50% of patients that failed to achieve SVR with SOC were able to achieve SRV when retreated with Telaprevir added to SOC. This includes cirrhotics. In fact this study shows NO DIFFERENCE IN RESPONSE BETWEEN CIRRHOTICS AND NON CIRRHOTICS!

I realize you are treatment naive, but this gives you a good idea how much better the chances of acheiving SRV are when Telaprevir is added. Normally after failing SOC treatment due to non-response, viral breakthrough or relapsing when having stage 4, cirrhosis, is around that 10%. This study showed only 8% with cirrhosis and 15% without cirrhosis went on to SRV when be retreated.

I am currently waiting for Telaprevir myself as I am a non-responder with compensated cirrhosis with increasing signs of liver failure. My Hepatologist is saying Telaprevir should be the 1st PI to market before Boceprevir in about 1 1/2 years.

It is best to read the study yourself at "Clinical Care Options" as the columns below don't format into text. You can sign up for free to access website with great info on all the latest treatments and clinical studies. Here is the link to the study.

http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Copenhagen%202009/Tracks/HCV%20Treatment/Capsules/1044.aspx

"SVR Improved Upon Telaprevir Addition to Peginterferon alfa-2a Plus Ribavirin Therapy in Genotype 1 HCV Previous Nonresponders"

Posting Date: April 17, 2009

    * PROVE 3: randomized, multicenter, placebo-controlled phase II trial[1]

Summary of Key Conclusions

    * Higher SVR rates with all telaprevir-containing treatment regimens vs peginterferon alfa-2a/ribavirin alone
          o Even in previous nonresponders and relapsers
    * SVR rates higher with telaprevir plus peginterferon therapy when ribavirin included in regimen
    * Adverse events associated with telaprevir similar to previous phase II trials

Background

    * Genotype 1 HCV–infected patients not achieving SVR to peginterferon plus ribavirin a difficult-to-treat group
    * Telaprevir a novel inhibitor of HCV NS3-4A protease
          o Active and well tolerated in combination with peginterferon alfa-2a in phase II studies of treatment–naive patients (Capsule Summary)[2,3] and previously treated patients (Capsule Summary)[4] with genotype 1 HCV infection
    * Current study assessed efficacy and safety of telaprevir-based therapy for the treatment of genotype 1 HCV infection among patients who did not achieve SVR to previous peginterferon alfa-2a/ribavirin therapy

Description of Current Analysis

    * Primary endpoint: SVR
          o Defined as undetectable HCV RNA ( 100 IU/mL in patients with prior undetectable HCV RNA
          o Nonresponse
                + Week 4
                      # Control arm:  30 IU/mL)
                + Week 12 (all treatment arms): < 2 log10 IU/mL HCV RNA decline from baseline
                + Week 24: detectable HCV RNA
---------------------------------------------------------------------------------------------------------
Main Findings

    * Significantly higher SVR rate in all 3 telaprevir groups compared with placebo control arm  

  * SVR rates similar among patients with vs without cirrhosis !!!!!!!!!

SVR, % (n/N)
Control Arm
(n = 114)
12-Wk TPV + 24-Wk PegIFN/RBV
(n = 115)
24-Wk TPV +
48-Wk PegIFN/RBV
(n = 113)
24-Wk TPV + PegIFN
(n = 111)

With cirrhosis
8 (1/13)
53 (10/19)
45 (9/20)
18 (4/22)

Without cirrhosis
15 (15/101)
51 (49/96)
54 (50/93)
25 (22/89)

1. Manns M, Muir A, Adda N, et al. Telaprevir in hepatitis C genotype-1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa2a/b and ribavirin therapy: SVR results of the PROVE3 study. Program and abstracts of the 44th Annual Meeting of the European Association for the Study of the Liver; April 22-26, 2009; Copenhagen, Denmark. Abstract 1044.

2. McHutchison G, Everson GT, Gordon SC, et al. PROVE1: results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C. Program and abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-27, 2008; Milan, Italy. Abstract 4.

3. Zeuzem S, Hezode C, Ferenci P, et al. Telaprevir in combination with peginterferon-alfa-2a with or without ribavirin in the treatment of chronic hepatitis C: final results of the PROVE2 study. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 243.

4. McHutchison JG, Shiffman ML, Terrault N, et al. A phase 2b study of telaprevir with peginterferon-alpha-2a and ribavirin in hepatitis C genotype 1 null and partial responders and relapsers following a prior course of peginterferon-alpha-2a/b and ribavirin therapy: PROVE3 interim results. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 269.


Cheers!

Hectorsf

[KniteWolf]

im in  week  3 of this trial     http://www.clinicaltrials.gov/ct2/show/NCT00984620?term=BI+201335+and+ottawa&rank=210:36%20PM%2010/2/2009
and  am  also  ealry stage  4 cirr.   no placebo and  possible 24 week duration   ..   good luck     in your search  Regards
KW

[mike716]

I apologize. It was a stupid thing for me to say. I just got so confused and frustrated from what I was seeing on the website, which doesn´t make sense to me, that I gave up on it. And I didn´t realize that the PI trials were only for 12 weeks of the drug.

Anyway, I´m sorry for what I said.

Mike

[mike716]

Thanks for the info, Trish. To tell the truth, I´m so confused and befuddled at this point, from info-overlaod and too many choices, that I´m scared of doing anything. Maybe I´m already having some kind of encelopathic problem, but I can´t make much sense of any of this any more. How do people choose, when there are so many choices?

Your suggestions about Alinia and dosing and lead-in are going on my list of things to bring up with the doc. Although frankly the MDs here are scared to do anything the bslightest bit unorthodox.

M.

[mike716]

Thank you, Hector.

[mike716]

Thanks for the link. A few questions for you:

- How come there are no arms listed?

- Why do they call it a "Short Term" study, when the times are 12 & 24 for the PI and 24 & 48 for the SOC?

- What is "fundoscopy" (included in the criteria is "Normal retinal finding on fundoscopy within 6 months prior to Day 1")?

- Where can I find info on the results of the Phase I trial?

- To participate, do you have to volunteer before finding out who´s running it in your area? (They don´t tell on the website.)

Thanks!

Mike