Vertex Prove2 trial - when to get an off-study PCR?

[dointime]

Hello Everybody,

I have been following all the VL results that have been posted from the Prove1 trials.  My thanks to everybody who was kind enough to share their info.  It is really helping me prepare myself for when I get my own VL results at the end of my 12 weeks.  My Prove2 bloods are all being sent to a lab called COVANCE in Geneva, Switzerland.  I assume (but have not been able to confirm) that the sensitivity of the PCR tests will be the same as you have had in the US, ie. quantitative down to 30 iu/ml and qualitative between 10-30 iu/ml.

So my question is - do you think that I should get an off-study PCR done at week 10 of the study?  The blood taken at this time by Vertex will be used to determine if I am UND by the end of treatment at 12 weeks.  This information will be used to decide if I should discontinue all treatment or switch over to SOC.  Who will fund SOC if I need it is still to be determined, but never mind that for the moment.  As a PCR is expensive and I would have to pay for it myself, I want to time it to maximise it's usefulness.  Maybe I should just wait till I get the Vertex results?  After all, it is really only relevant if Vertex shows me as UND.  If the Vertex tests show that I still have the virus then I won't need an off-study PCR, will I.  On the other hand, the reports of PCR's hovering between 29 and UND are ambiguous and in a case like that an independent PCR would seem to be a help.

Any advice please?
thanks, dointime.              

[friole]

I have been reading about all these trial results too and if I were in a trial, I sure would get my own test run -- probably the Quanta Sure at LabCorp.  I think your test results at week 12 are critical and you should have the best most sensitive test available.
frijole

[jmjm530]

I'm not sure what you mean by "ambiguous". APK's doctors has confirmed that "29" means you are detectible between 10 and 30 IU/ml. And that a "<30" on the report means that you are below the detection limit of both the PCR and the qualitative, so in effect you are  non-detectible to a sensitivity of 10 IU/ml. Of course, confirm this with your study doctor but I wouldn't get another test just because you can't read the results of the one the study gives you. On the other hand, if you want another test for other reasons, at this point you can use Heptimax by Quest Diagnostics (or) HCV NGI Quantasure ( LC#140639)by Lab Corp. Both tests are highly sensitive, so use whatever is most convenient and covered by your insurance.


-- Jim

[jmjm530]

Just like to add that while in theory getting the most sensitive test available is the way to go, 10 IU/ml is still an extremely sensitive test and no doubt much care will go into lab choice and sample handling, etc, as part of this important trial. And while I'm sure it's happened, I really don't remember anyone here reporting a viral load between 2 IU/ml and 10 IU/ml on any of the more sensitive tests. Point being I wouldn't spend the money based solely on the assumption that you're not getting a sensitive viral load test with the trial, because you are.

[mremeet]

Hey dointime good to hear from you, hopefully your rash has resolved? As far as PCR's I'm not sure what you're situation is in the Prove 2 trial. Are you guys blinded with a placebo group like we are? For some reason I thought you were not, and that you already know you're receiving telaprevir and IFN (with no riba). And if they have disclosed that information to you, then I would suspect your VL's are not blinded (the only reason to blind your PCR's would be to keep you from guessing if you're in a VX or placebo group). If I have that right, then I agree with jim that the tests you're receiving (and presumably have ongoing access to) should be fine on their own. And 10 IU/ml is very sensitive and should be suitable for the purposes of ascertaining your progress for now.

On the other hand, if they are witholding your VL results until week 10, then I'm not sure if an offstudy PCR would have much value. The reason I say that, is because I'm almost certain that statistically speaking the odds of rapid and successful viral decline would be significantly better with telaprevir+IFN than it would be on SOC alone. So lets assume for a moment you had an offstudy PCR at week 4. Lets say you had a fairly average starting VL of 3 million IU/ml, and you found out you had only dropped to 750,000 IU/ml by week 4. Since your viral load did not reach UND levels within 4 weeks and your response was somewhat disappointing - would it then be advisable to withdraw from the trial and switch over to SOC alone? That's hard to say.

On the one hand, it's possible you could be more responsive to IFN+riba than you would be to telaprevir+IFN, but like I said I think that's pretty unlikely. The limited test data revealed so far generally demonstrates IFN+telaprevir to be a more potent combo than IFN+riba (although NO SVR performance has been demonstrated yet). On the other hand, you know you could extend your treatment to 48 weeks and beyond on SOC, which obviously is much longer than the 12 weeks of telaprevir+IFN treatment you're currently scheduled to receive. Whether or not replacing telaprevir with ribavirin and adding that additional time might bring you an SVR is very hard to say. But in general, if you were responding poorly to telaprevir+IFN, I would not be optimistic that replacing the telapravir with ribavirin would increase your performance - chances are it would lower your performance.

But, considering the same hypothetical scenario above, if you did demonstrate poor performance by week 4, then I'd think your odds of achieving an SVR with a mere 12 weeks of treatment would be quite poor. And considering that's the case, then you'd probably stand to lose very little by at least trying ribavirin instead of blithely "cruise controlling" yourself to the end of the 12 weeks with nearly no chance of an SVR. You could very well also be breeding an IFN/telaprevir resistant strain of HCV during a failed short 12 week course. A strain that could haunt you later with attempted followup treatment(s).

Also, considering that rescue drugs are prohibited during the trial. If your neutrophils drop below a certain level (they used 750 for us) or if your HGB drops below 10 or so, then they'll want to lower your dose of IFN to address the neutrophils and/or they'll probably want to drop your telaprevir dose to raise HGB. Telaprevir has been shown to exacerbate anemia in some patients when dosed with IFN+riba. However, I do not believe telapravir's impact on anemia is nearly as bad as ribavirin in most people. I took telaprevir and riba and IFN all together, and my HGB held up ok. I think most others did too, so I don't think it's a powerful driver for anemia in most people. So generally speaking a telaprevir dose reduction is probably unlikely, but an IFN dose reduction can definitely happen. The point of explaining all this is because this adds yet another layer of complexity to the decision making process you're grappling with right now. You'd have access to rescue drugs on SOC, which could prevent dose reductions and thereby maintain maximal chance of achieving SVR. In the study, if they dropped your dose of either drugs during such a short course of 12 weeks, then that could hurt your chances very badly for scoring your SVR.

Anyway, welcome to the world of trial participant anxiety. You'll mull these issues, variables, potential situations over and over, constantly attempting to estimate your odds and re-assess your ever changing situation. Meanwhile, while you're deprived of the critical information you need (VL's and placebo/VX placement) to accurately assess that complicated situation, things are dynamically and constantly changing as you progress through the trial. And simultaneously your mental faculties are degraded and stressed to the limit by the meds and side effects more and more. You'll come to realize just how much "sport" there is in these trials, more than you imagined when you first enrolled. You can really go bonkers stressing out over it! ;-)

[Skepsis]

Excellent points!

We should chose a strategy and then follow it consequently instead of switching back and forth between possible strategies.

The strategies tested by vertex protocol are all valid strategies with respect to  patient interests, as mremeet's detailed consideration also reveal that.

Therefore I would best take that very chances which I can get from my randomized arm and not to try to mix them up...

Think of Murphy's law: "The other queue is moving faster...", regardless whether you are changing the queues or not...

(I admit this is not always true, but our the urging need to switch we often feel is an even more common problem psychologically than inactivity by ignorance or procrastination.)

I conclude: the best way to get psychologically equipped for investing and trading on the stock exchange is to go through some of our anti-HCV therapies :-)

Skepsis

[dointime]

Hi and great to get your replies.  I think finally the brain fog has crept up on me because I have found it difficult to think this through, so thanks for applying your brains to it for me.  

Jim you are right, I didn't really want to say 'ambiguous' but couldn't think of the right word.  Maybe I meant messy or confusing but that applies as much to my brain right now as the results.  Anyway you've managed to state the case clearly and I'll just go with the Vertex results.

Mremeet hi there again.  I love it - trial participant anxiety!  Yes, the combinations and permutations and subtleties that come up and then brain fog strikes .... jeez.  I never dreamed this would be such a wild ride.  

Anyway I should have explained this better.  I know that I am in the group that does 12 weeks of VX and Pegasys because no ribavirin was supplied.  Maybe Vertex couldn't be bothered knocking up a placebo for the ribavirin, who knows.  Otherwise the double blind concept holds, ie. I don't get my VL results until my last treatment day at week 12.  So there's nothing for me to do for now except keep on taking the pills till then or till the next adverse event, whichever comes first.  I'm stressing about what options will be available to me after week 12 but that will probably be the subject of another post.

My rash went and so far didn't come back.  Another 2 people in my study of 9 got it and got over it with the help OTC antihistamines, so that is 33% with rash, but not severe.

An angst-ridden dointime.