Your opinions on new Hep-C trial of TMC435?

Hi,

I am new here, and have been reading the boards with much interest. I hope you all might have some advice for my husband and me regarding this clinical trial. (It is IRB #0904010341.)

First the background.  My husband has had HCV (genotype 1) for 25+ years.  He is asymptomatic, but his last biopsy showed progression, from stage 0-1 to stage 1-2.  Since he's in his late 40s he's thinking it might now be a good idea to try to treat while he's still young-ish and the disease is at an early stage.  

Given the low success rates and long treatment period of the SOC, he doesn't want this.  So the options are: 1) don't treat now and wait for Telaprevir or Boceprevir to be approved, or 2) participate in a clinical trial of this new and promising-looking protease inhibitor.  He has all the usual reservations about treatment in general, and clinical trials in particular; yet he likes the fact that he could do the trial now, and he will be seen very often and monitored very closely.

Here are the trial details. The company is Tibotec, a Johnson & Johnson subsidiary.  It is a Phase IIb trial, double-blind.  He would be seen by nurses at his usual doctor's office, whom he likes and feels comfortable with.  His doctor would be around and would check on him when necessary. The trial has 5 arms: each receives SOC for 24 weeks. Arm 1 gets TMC435 (the trial drug) at 75mg for 12 weeks; Arm 2 gets it at 150mg for 12 weeks; Arm 3 gets 75mg for 24 weeks; and Arm 4 gets 150mg for 24 weeks.  Arm 5 gets placebo and SOC.  So he'd have an 80% chance of getting the trial drug.  

The reports on TMC435 Phase IIa trials looks very good, as good or better than Telaprevir and Boceprevir. (These are 2 links to the reports on the Phase IIa trial.)
http://www.medicalnewstoday.com/articles/147661.php
http://www.eurekalert.org/pub_releases/2008-11/zg-tpi110308.php

The nurses say they feel it's a very promising and well-designed trial.  We did ask about rescue drugs: they will be allowed, but we were told that they would drop ribavirin dosages before giving Procrit (if hemoglobin goes below 10), which the nurse said they have been prescribing less freely of late because of dangers (they didn't detail).  They said anti-depressants, etc. would be given if necessary.

The stopping criteria is you stop if there isn't a 2 log viral load reduction by week 12; or if you aren't undetectable at week 24 (the SOC arm continues to 48 weeks if the patient is undetectable by week 24).

The other disadvantage is that there is no access to viral load test results until the 24 weeks is up.  There is access to other bloodwork.  I guess that liver enzymes give some small indication of how you're doing but not so accurately.  I've read on here about some people getting tests done outside of the trials on their own -- how does that work?

We are total newbies to all this though we've read a lot.  So any advice you more experienced people can give us, we very much appreciate.  I know how naive we are about all this, but we are taking it very seriously and want to be as prepared as possible, and make the best decisions we can. I love my husband dearly and hope to support him in every way I can.  Thanks in advance for any advice.

[banarep]

sounds very interesting.  i am on my second drug trial, so i would suggest if he can get in he should.

you might ask if there is a chance for a roll over, if he is on the placebo.  some trials will offer those study subjects on the placebo a chance to get the study drug after the trial is over - again for free.

[nygirl7]

I'm sorry I don't know an awful lot about this trial because I've been SVR for over two years and really don't keep up with them....I've gotten kind of lazy I guess.

There are obviously advantages to a new trial but as you know and see there are risks. I wouldn't drop my riba for anything or anybody - especially in the first 12 weeks when it is crucial.  I've been here for almost 5 years and never heard of anyone having trouble with Procrit at all.  It saved my entire course of treatment (72 weeks, I was on procrit for 69 of them).

I was a geno 1A and also 1B.  My VL did not go to Undetectible by week 12 because I hit this bizarre plateau that some people with a low starting VL have happen...so I opted to do the 72 weeks to improve my odds all I could. I think VLs are very important frequently during treatment so you can tell how you are doing and if you need to extend at all. Of course they aren't going to let you know so that is something I couldn't be comfortable with but that's just me.

Stage 2 isn't really that bad and you do have time to see if the Telepravir is approved in the next year or two. I was stage 3 and had no option I felt but to treat although I probably would have treated regardless.

Lots of decisions lots of pros and cons and I realize that this didn't help you at all but it's how I felt about stuff and since I have no science to offer regarding this new trial it's all I could offer you.

Good luck whatever you decide to do.  Treatment isn't fun but it was doable....for the most part.

[HCA]

Personally I would sign up for the trial.
I am currently participating in the final Tibotec telaprevir trials.
You should get a good standard of care and leading edge treatment (unless in placebo arm).
What you won't get is your data from Tibotec,so if you want to track the virological response you have to make your own arrangements.

[WriteItDown]

Thank you all.

NYgirl7:  Thanks for that -- I did not know that it is crucial not to drop the ribavarin -- another question to ask them. When would you think they should be offering Procrit? (BTW I read some of your other posts and the doc who is the study investigator in this trial is one you especially recommended.)

As for VL tests, what about making "your own arrangements," as HCA put it?  Any opinions on how that goes?

We know he COULD wait... but at the same time he's not getting any younger and there are no guarantees that Telaprevir will be approved by then.

I admit that reading some of the stuff on here about the possible side effects scares the bejesus out of me and I just want him NOT to do it... but then again I also don't want him to get ESLD. And, of course, it's his decision ultimately.

HCA, how have you found the trial?

[WriteItDown]

Forgive me, but I just want to bump this up in hopes of getting some more people's opinions.  Thanks in advance.

[HCA]

Fistly with regard to ribavirin it is not the dose that it is critical it is the serum level.
Anemia is a sign of absorbtion so don't get hung up on ribavirin dosing at this stage.
I found the telaprevir trial well run and I'm glad I'm on it.

[annieCinMD]

That trial sounds promising. It also sounds a lot like the one I'm doing. I'm on Schering Plough's SCH 90018 trial. It's another protease inhibitor, supposed to be second gen to Teleprevir and Boceprevir. I'm curious if they offer a crossover arm if you get stuck in the Control arm like I did. I would have actually been stopped because I didn't make the 2 log drop by week 12. Just missed it by like 3,000. Because I was greater than 1 log drop, I was offered to cross over to 12 weeks of the study drug, which I did. Cleared within 2 weeks of adding the study drugs. The protease inhibitors are looking really good. A lot of us are on trials and getting good results. I'd think seriously about getting in this trial. It sounds like they treat patients pretty well, too, as does Schering Plough. A lot of studies don't offer Procrit, as it is prohibitively expensive. It is a good sign that they offer it.

[WriteItDown]

HCA thanks for that comment.  Basically I know little about ribavirin levels and when they choose to drop the dose vs. when they give Procrit, but I'd read we should ask if they allow rescue drugs, so I asked and then reported here what they told us. Some people seem to think that dropping the riba dosage is BAD (like NYgirl), and they did tell us they would drop it before giving Procrit. Would that be a deal-breaker for anyone else?

Annie, thanks for adding your experience.  Too bad you got in the control arm, but it's great that they gave you the PI after and you cleared. Congrats!  I am definitely going to ask now about whether they might do that for us (is it called "rollover"? ) -- anyway another question I never would've thought to ask, so thanks.

About the Procrit, I don't think they pay for it -- I think they allow it if necessary.  The impression I got was that the protocol calls for dropping the ribavirin dosage first, but that if you then still need the Procrit they will let you have it and stay in the study.  I think regular insurance has to pay -- not sure. But I'm guessing this could be a problem?  Probably it is super expensive or else the insurance won't pay for it or something?  (Please understand we are trying to absorb a s**tload of information quickly, so forgive any ignorant questions.)  

And thank you all so much.

[WriteItDown]

Oops, I just re-read you post and saw that you said Procrit was prohibitively expensive.  Do you know if regular insurance would pay for it if you needed it as a result of a drug trial?  Or is it going to be an out-of-pocket deal?

Sooo many questions....

[WriteItDown]

Also wanted to ask, what would you all say is the best day to take the interferon shot?  I.e. how many days later is usually the worst?  Thanks again.

[annieCinMD]

I got put in a crossover arm. (Crossed over from the Control/SOC only arm to the study drugs after week 12 results. It actually happened at week 16, partially due to PCR tests taking 2 weeks to come back. I was still not clear at week 16 either. My personal experience with Procrit is this: My study supplies it, but when I needed it, they had 2 needles on site and they were too big of a dose for someone my size. Since 2 of my other blood counts were low, they stopped all meds for 2 weeks. I talk extensively to my study coordinator, and she has officiated over many trials and different drug companies. She has told me their nurse practitioner has had to argue with the insurance companies about prescribing Procrit. She said the woman has actually told the insurance company "Do you want the patient to die?" Apparently the insurance companies can really argue on prescribing expensive drugs. Maybe someone else will chime in on this, as I know others have taken Procrit and had to hit their insurance for it. As far as copay, I'm not sure. I've heard of people paying like a $50 copay for a very expensive drug, and that is with good insurance. As far as the best day to take the shot, I took a friend's advice and picked Friday evening so I could have the weekend to recover and make it to work on Monday. I've heard of people taking it mid-week, because it can actually peak mid week. I'm not positive of this, and my Friday thing works pretty well for me, but I've been noticing I feel feverish as late as Thursday evening. Saturday is usually going to be my worst day, but not always so. Good luck!

[WriteItDown]

Thanks for your insight.  I am definitely going to ask some more specific questions about the Procrit and who will pay for it.  

If you're still feeling bad Thursday night after a Friday shot it sounds like there is NO good time to take it -- which I guess is accurate.  Great, lol.

I am pretty darn scared about all this.... it's good to know many of you have gotten through it.  That helps.

[HCA]

Don't get hung up about procrit-you and others here are applying old SOC values to a study which incorporates a second generation protease inhibitor and there is no comparison.
Ribavirin (the anemia causing drug) needs to dosed optimally during the period that the wild type virus (the viral load)  is eliminated.
Under the old SOC protocol this was typically twelve weeks,however with TMC 435 it is almost certain to be far less.
Dose reduction of ribavirin in the Tibotec trials is commonplace and we can see by the published results it does not matter one jot.
A good drop in haemoglobin in the early weeks is desirable and is a sign of good serum levels.
Procrit,is at this stage a red herring.
Don't apply old treatment dogma to a leading edge study-just my humble opinion!.

[WriteItDown]

That is good to hear, HCA.  I am getting slowly up to speed with all this, but I did not know that ribavirin levels are less important when Protease Inhibitors are involved.  The nurses did seem to act as if reducing the ribavirin does would not be a big deal, but then NYgirl7 above (and others in other threads) cautioned against this.  Of course I am trying to take everything in and ask all the right questions before anything happens.

There seem to be many variables involved and I do so much appreciate everyone giving me their ideas and information.

[HCA]

The entire telaprevir programme has been conducted to start to finish without procrit and with ribavirin dose reduction where appropriate-look at the results on Vertex's own website.
The parameters are changing fast and 'You better start swimmin' or you'll sink like a stone' as Bob Dylan wrote many years ago.

[WriteItDown]

OK, quite possibly I am stupid, but I couldn't find any references to protocol w/r/t Hgb levels on the Vertex website.  I am trying to follow Zimmerman's advice, and don't want to use you as a life-vest, but maybe you could point me?

[HCA]

There is plenty of published material on the importance of ribavirin concentration as opposed to dosing.
These studies are based on SOC (no protease inhibitor) protocols.
Studies on tri-therapy variations will emerge once the protease inhibitors are released,but at present the drugs are still restricted.
Here is a piece I have pulled pretty much at random;

http://www.natap.org/2008/EASL/EASL_07.htm

Ribavirin is still very important-the no ribavirin telaprevir study arm had a very high relapse rate-however because of the potency of the protease inhibitors it is likely that ribavirin will be critical for a shorter time than hitherto,and that dose reduction is acceptable because by the time dose reduction is required and anemia becomes problematic the wild type virus will have already been eliminated.
Again these suppositions appear to be borne out by the results.

[WriteItDown]

Thank you, that's very kind of you.  And now I am off to read.

[HCA]

The first extract I pulled relates to geno 2 and 3-so not the best example.
It's late here in London and I'm on treatment so not as sharp as I would like.
Here's another,
http://www.ncbi.nlm.nih.gov/pubmed/14738562

Searching 'ribavirin plasma level,serum level 'ect brings a wealth of results

[WriteItDown]

OK, I will do that. Thanks again and have a good sleep..