Telaprevir - 18 yes 0 no

[frijole]

Whew - that was dicey.  One of the FDA advisory committee panelists was agressive in his pursuit of issues with the rash, but in the long run, he and everyone else on the panel voted to approve.

Now it goes to the FDA.  Approval date (or not) is May 23. Some people are betting that the FDA will announce both BOC and TEL on May 7 - the date for Boceprevir approval (or not)

[nygirl7]

Wow meet I had forgotten all about all that (and prettydamscared).  It's no wonder we all care about each other so much we have been through more than anyone could understand had they not gone through it with their internet support group.

Man I really just almost cried.

[mremeet]

cont...Anyway, long story short, I limped along after that for a total of about 40 weeks of tx. I missed 1 IFN shot during the rash fiasco and my riba dose was cut back from 1600mg/day (I think?) to about 800-1000 daily. I could only tolerate about 800mg of riba a day towards the end  because it irritated my skin so bad. Although the major rash was gone, my skin was still very sensitive and remained so until the end of treatment. I literally scratched the eyebrows off my face I itched so bad, but yet I had these freakishly long eyebrows. I looked like a Dr Suess character. Well, sort of a cross between Dr Phibes and a Dr Suess character.  ;-)

But guess what? I would go on to be cured. And looking back on it, now with 20/20 hindsight the Telaprevir was a critical hingepin in my successful treatment. It worked, no doubt about it. Any thoughtful and reasonably well informed doctor prescribing Telaprevir+IFN+riba nowadays (as opposed to the summer of 2006) should now know about the typical rash profile that occurs in those unfortunate enough to get the PI rash. The solution to it is to simply stop the drug once it gets going. Simple as that - identify it properly and stop it. Telaprevir works it magic over a relatively short period of time. Usually it does what it's going to do within about a month. The IFN and riba do the rest and they require a longer period of time to finish the job. But the point is that they can finish the job without the Telaprevir. That is, after it has decimated the virus to the extent that only a mopping up of stragglers is required in the final portion of the thankfully abbreviated treatment. Telaprevir offers tremendous utility, even in those that get the rash. As long as you can tolerate it for a few weeks, it can greatly help those people too (as it did me). You just take it as long as you can, and simply stop the drug when you have to and continue on with the other two drugs. With what we know today there's absolutely no need for anyone to go through what I did and others (namely "prettydamscared").

In fact, I've come to believe that in my case I was actually SVR by week 7. Of course there's no way for me to know for certain, but I know I was UND by week 2 and less than 2 IU/ml by week 3. I also had a robust reaction to the IFN and ribavirin with a very nasty flu-like reaction to my first shot (indicating a healthy physiological response).  I believe the telaprevir in conjunction with the other drugs did the virus in in a way that made my (1) early discontinuance to the Telaprevir, (2) prolonged exposures to prednisone and solumedrol and (3) my reduced riba dosages afterwards - irrelevant after week 7. And I know from some of the concurrent UK Prove 1 study participants (dointime etc) that there was a young woman who crashed and burned with a PI rash about the same time I did into treatment. Except she bailed and discontinued early, but yet she SVR'ed anyway. I know there have been others who match this profile as well.

Lastly, someone mentioned dointime and some others above. Dointime failed treatment but it wasn't because she burned out on the rash. She did get a rash, and she did suffer from it. But the main reason she failed tx is because she was not receiving ribavirin. At the time it was not known if ribavirin was an essential element of IFN+Telaprevir therapy. We now know that it is. Several others also failed for this reason, unfortunately. Also, prettydamscared was in the same trial I was in and we treated together with the same doctor. We both experienced  the rash and were treated with prednisone as described previously. Except she didn't take the solumedrol like I did.  She made it to about week 40 like I did and appeared to be well on her way to SVR-ing, but unfortunately was killed in a car accident about 3 months post tx.

Anyway, my vote is definitely in favor of Telaprevir. If it can work for me, it can work for almost anyone. You just gotta know how to use it and very carefully monitor how things are going as you move through those most critical early weeks of tx.

[mremeet]

I'm really happy to see that Telaprevir (formerly VX-950) is successfully making its way through the approval process and appears to be finally coming to market; it's long overdue in my opinion.

As a brief introduction for those who don't know me, I was in the Prove 1 trial which was the first full length triple therapy Telaprevir trial conducted (starting in summer of 2006). I received Telaprevir (I was not in placebo group) along with riba and IFN. Initially I started off in the trial without any undue side effects, other than a nasty flu like reaction to the first IFN shot (which is fairly common and cleared up by the 2nd shot). I was doing ok until about week 6 or so (it's been awhile, so my dates might be a bit off). That's when I started to get a peculiar rash that seemed to grow in intensity over several days. At first it wasn't clear what it was because there was no background data or experience to pull from. And since both IFN and riba can also cause rather severe rashes (either individually or in tandem) in some people, it wasn't clear the Telaprevir was the offending agent to either me or my doctor.

I tried to deal with the rash through week 6, but it just got worse and worse. It appeared as if it was going to derail my treatment which was an extremely depressing and upsetting thing at the time. My doctor just kept telling me to hang in there and let’s see what happens etc (again, mostly due to plain ignorance about the unknown side effect profile of Telaprevir at the time). By week 7 it was too much and something had to be done, including the possibility of discontinuance. I went to see the doctor and he reluctantly prescribed prednisone, which is an oral immunosuppressant. Immunosuppressants are essentially the opposite of immunostimulants and normally you would never want to take both at the same time. Interferon (and perhaps ribavirin) are immunostimulants, and normally you would never want to take a drug that would counteract their effects in any way during HCV treatment. Doing so could easily result in treatment failure, especially for the already hard to treat geno 1 patients. At the time I knew this and really didn't want to take prednisone, but due to the severity of the rash, I had no choice.

Prednisone is commonly used to stop nasty allergic reactions (which may be caused by all manner of things) and is also used to help prevent organ rejection in transplant patients. It's powerful medicine and it can have very bad side effects if overused (or misused). But the prednisone was a magic bullet to my rash at the time. My red, bumpy, itchy rash evaporated within hours of taking the medicine at first. It worked great and it appeared I was back on track with the trial, although with more bridges to cross in the weeks to come.

When prednisone is prescribed to address an allergic reaction of any type, usually two things happen. First is that the offending allergen and mode of exposure is identified and eliminated. Secondly, prednisone is initiated at a relatively high dose initially; I believe for me it started out at about 40 mg daily. Then the dose is tapered off over about 2 weeks by gradually lowering the dosage received as the days tick by. The reason this is done is because if you suddenly chop prednisone dosage off to zero overnight, your body can experience a severe allergic relapse in response to the abrupt change in internal body chemistry - even in the absence of the original allergen (I forget the exact mechanism but I think it might have something to do with histamines etc).

So after my initial positive reaction to prednisone, I began tapering down as the days went by. I also continued on full triple therapy which included the full dosage of telaprevir. Unbeknownst to me and my doctor at the time, I was one of the unlucky ones that had developed a severe allergy to telaprevir after about 5 weeks of exposure. The prednisone was successfully thwarting my allergic reaction to the drug as long as the dosage was high enough. But once my prednisone dose tapered off to about 5-10 mg daily, my body started once again to react to the telaprevir, except this time it was *different*.

Basically the rash exploded back into full flower at the lower prednisone dose, except this time it appeared much more ferocious. It was frightening how aggressive it grew and spread. My doctor told me to stop the Telaprevir, which I did promptly out of sheer fear of what was happening. He also told me to jack the prednisone dose back up to the original starting dose of 40mg, which I did. But this time, nuthin' doin. The rash would not go away, even several days after stopping the Telaprevir. So my prednisone dose was increased more and more, until basically I was eating it like candy. I maxed out at about 80mg a day, but the rash STILL wouldn't go away. I was getting terrified and sleep deprived and delirious (with daily rantings here on this forum lol) and my doctor was helpless to come up with any more answers on how to deal with it other than also stopping the IFN and riba as well. But I didn't want to do that, I wanted to finish off the virus and since I was only 7-8 weeks into treatment by this time I didn’t want to risk stopping and come out of it relapsing with a PI resistant strain (I knew I was UND at 3 weeks because I had a 2 IU/ml > PCR done "offstudy"). So as a last ditch effort I went to the emergency room with my leprosy face and body. All the people at the front desk gave way immediately as I walked forward, fearing I was going to give them whatever crud I had. It was pretty hilarious actually.

So the emergency room administered an IV drug called solumedrol, which again is a powerful immunosuppressant usually given to patients experiencing life threatening allergic reactions to bee stings, poison ivy etc. If you've ever seen those old Lon Chaney werewolf movies with the time lapse photography where his face is transformed from his werewolf form back into his normal self, then you know what happened to me. Because that's exactly what happened to my skin once that solumedrol flowed into my veins. You could literally see the red color draining from my rash as the drug took effect in just minutes. You could actually see the raised bumps start to flatten out, and within 15 minutes I was a new man, albeit completely drained from the whole ordeal. It wasn't an ideal situation at all because the solumedrol was very powerfully suppressing my immune system and weakening the effects of the IFN and riba to the extreme. I dreaded the thought that the virus was getting a foothold in my body again just as it was probably tottering on the brink of extinction. But it had to be done and I would just have to take my lumps in terms of risking a lost SVR.  cont...

[Andiamo1]

"How likely is an 8% difference to arise by chance alone in samples of that size if there were really no difference in patient screening? "

Possibly likely depending on the standard deviation.  This is a small selection out of a large group.  40% has been the published number for many years for SOC, so I would assume their number is quite accurate.

If you look at all the published SOC SVR rates, they seem to be in the 40 - 48% range and have been for many years.

[willing]

>That would have been evident after the Prove 3 trial, not before
agreed - but I believe it also suggests your positive experience with tela may not be accessible to someone who goes into triple tx as a prior null, not as  a relapser

>isn't there a slightly different formula where you need to subtract 1 from the denominator?.
yes, but that shows up in estimating the standard deviation of a continuous variable eg
http://en.wikipedia.org/wiki/Standard_deviation
which would be applicable if comparing a measurement like say HgB decline. However in comparing SVR rates the distribution is a discrete one with an outcome like a coin flip so the formulas differ. A description, including worked example, is here
http://www.stat.yale.edu/Courses/1997-98/101/catinf.htm
at the label "Comparison of two proportions".

Confidence intervals can shed some additional light on comparison because they incorporate the noise expected in estimates made from samples of a given size.

For example did Vertex's patient selection procedure for Advance  result in an easier-to-treat sample than in Merck's equivalent Sprint-2 study? Different SVR rates in the randomly assigned placebo arms would show this effect. For Advance, 361 pts were  assigned placebo and 166 reached SVR( 46%). In Sprint-2 363 pts were assigned placebo  and only 137 reached SVR (38%). How likely is an 8% difference to arise by chance alone in samples of that size if there were really no difference in patient screening?

Applying the equation from that Yale stat page above gives a 95% confidence interval of (0.01, 0.154)  Interestingly the CI does not include zero suggesting that for samples that large an 8% difference is unlikely by chance alone - but the lower bound is close to zero (they cheated, but only a little bit?)

The same approach could be used to sort out whether the difference in SVR rates among naives between tela and boce could easily have arisen by chance or suggests  separate underlying distributions (haven't done this).

[Andiamo1]

"Andiamo: though you didn't clear until w20 it looks as if you'd still be classified as a relapser by the Vertex criterion so your odds with them would have been about 80%."

That would have been evident after the Prove 3 trial, not before when they accepted me into the trial with no data at all on prior treatment.

"Agreed  that confidence intervals (which incorporate the standard error) are more informative than point estimates. For example, it makes no sense that a lead-in would reduce your SVR odds. The improvement may be small but shouldn't make things worse. "

Publishing the standard deviation would give us a better understanding of how to interpret the numbers.  For example: if the Telaprevir trial had results that showed SVR rates of 78% with a lead in and a standard deviation of +-3% then the results would read SVR rates of 75 - 81%.  If Telaprevir had results of 75% with a standard deviation of +-3%, then there results would read between 72 - 78%.  These numbers are within the standard deviation of the trials and are statistically identical.