Vertex abandoning 12 wks of treatment?

[Sincebirth]

I saw an interview the the CEO of vertex saying that he thinks the future treatment will most likely be 12 weeks with the new drug.  But after looking at the lastest Prove 3 study trial ARMS, none of the study arms have only 12 weeks of treatment.  

Could the preliminary conclusions from the Prove 1 trials be suggesting that long treatment is needed to achieve acceptable higher SVR rates and therefore Vertex has structured their studies to reflect this?



PROVE 3 STUDY ARMS BELOW:
Group A: Patients will receive placebo (a sugar pill made to look like the study drug but does not contain medication), Pegasys® and Copegus® for 24 weeks. Then, 24 weeks of Pegasys® and Copegus® only. Patients in Group A will have the option to receive telaprevir through a roll-over study.
Group B: Patients will receive the study drug telaprevir, Pegasys® and Copegus® for 24 weeks. Then, 24 weeks of Pegasys® and Copegus® only.
Group C: Patients will receive the study drug telaprevir and Pegasys® for 24 weeks.
Group D: Patients will receive telaprevir, Pegasys® and Copegus® for 12 weeks. Then, 12 weeks of placebo (sugar pill), Pegasys® and Copegus®.

[web52]

i could be wrong, but i thought this trial was for nonresponders. if that is true, they may need longer tx than naive patients.

[jmjm530]

As "Web52" suggests, I wouldn't read anything into it other than Prove 3 is for prior non-responders and for whatever reasons -- regulatory perhaps -- they are taking a more conservative approach. The fact that Bolger is stating 12 weeks as a sort of objective seems encouraging.

Mre, Maybe this "roll-over" for the Placebo group seems to be the "carrot" Vertex is giving the placebo group. Unless I read it wrong, not much of a carrot as they will subject them to another 48 weeks of SOC and then offer them Vertex if they relapse. Unless they're offering more, don't think I'd want to be in that group. The shame, of course, is how many doctors are going to fully explain to these previous non-responders the actual ramifications of another 48 weeks of SOC after they failed the first time.

-- Jim

[web52]

i dont know what the exclusion criteria are for prove-3, but i hope they are including those whose condition warrants a possible 2 more rounds.

[jmjm530]

I somehow get the decision that whoever is regulating the trial may not be as knowlegeable how things work as one would like and perhaps Vertex is just going along with it to get the trial through. Just something not right about that placebo arm and I can't see why anyone would want to enroll in Prove 3 if given all the facts.

-- JIm

[pln]

Group D: Patients will receive telaprevir, Pegasys® and Copegus® for 12 weeks. Then, 12 weeks of placebo (sugar pill), Pegasys® and Copegus®.

Well, that is what I did being in group C , just minus the sugar pill the last 12 weeks.

[jmjm530]

Group "A" is the problamatic group, not "D". Group "A" is basically SOC for a group of non-responders who didn't respond to SOC the first time.

[pln]

O,h, I see now. That would be very sad. I really don't see how they will fill this study up with non-responders who didn't respond to SOC the first time. WOW.

    
  













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[jmjm530]

They will fill it up because the doctors will most probably not explain the ramifications very well to the prospective subjects. How much did you know about treatment protocols before you started? Well, I knew next to nothing, and I imagine there are many who treated unsuccesfully the first time who, not taking the time to educate themselves, still know next to nothing. Unless things are changed, or the "rollover" means something other than a third treatment, the uninformed will be those that enroll in group 3. Maybe I'm just naive and this goes on all the time in trials, but I find it highly irresponsible both with Vertex and any doctors who enroll patients in Prove 3, unless something changes with Group "A".

-- Jim

[jmjm530]

Let's see, thinking about it again, if "rollover" means that Group "A" will be unblinded sometime before week 48 and then given the opportunity to continue treatment another 24 weeks or so (perhaps with some VX-950) thrown in, then I suppose the case could be made that they're no worse off than if they had signed up for a 72-week extended treatment like many relapsers do. So, if that's the case, and folks understand going in that those in Group "A" may have to extend beyond 48 weeks to have a decent chance of SVR, then I temper my previous comments. Hopefully, Group "A"'s options will be clearly spelled out.

-- Jim

[orleans]

Hey, Folks will sign up for the 75% chance of not being in "A". Do the math, up to this point all 1a treat for about a 30-40% chance of clearing. Many non responders treat more than once with no chance to get the 950. For me w/ cirrosis just starting, I am still hesitant to treat the 1st time. I may just take my chances with ESLD and HCC. Right now I feel just dandy! Have a consult with a nathropath on the 15th and an appointment with a big wig hepatologist on the 19th. We'll see. jm

[jmjm530]

As long as folks understand what's going on, and they're basing their decision as you suggest, then no foul. Just not sure if everyone has got it figured out as well as you have.

-- Jim

[mari74]

I just happened onto this conversation tonight...could this be the same trial?


There will be 5 groups to be in...It was told to me something like this...

Group 1..receives Peg & Riba for 6 mos + 6 mos more ...
no "New" medicines.

Group 2..Peg & Riba for 6 mos, if positive then add Protease(Spelling it right or wrong?)for 6 + months.

Group 3..Peg + Riba+ New Drug(Protease) for a total of 7 mos.

Group 4..Peg + Riba for 4 weeks, then Peg + Riba + New Drug for 6 mos.

Group 5..Peg + Riba for 4 weeks, then Pega + Riba for 44 weeks.

The hospital will put in a the group they feel you need. The drugs are suppose to be the real. But no relief drugs will be given???

I do have insurance, BSBC, but still undecided if a trial study is worth it. And if they will really be given the real medicine. I cannot take that chance, because of the condition of my liver.

I just happened onto this site conversation tonight...could tis be the same trial?

[miked]

My hepatologist is the coolest; I really like the way he treats me as a partner for my health decisions. This weekend we had an hour conversation about the Prove 3 trial.

Group A is the placebo group but will be offered VX-950 at week 12 of SOC if still detectable VL.  I understand that two groups will treat for 24 weeks and two groups for 48 weeks.  I did not hear about a 5th group.  The formal protocol is being emailed to me very soon.

Per my doc, he'd like to see me in the trial because I'm in good health, educated and motivated.  My wife and I discussed it and she too would like to see me move forward with the trial.  I have a type-A personality that would function much better once this HCV was behind me.

My stats: Male, age 49, geno 1b, minimal scarring and inflamation (inflammation), started tx two years ago with 3M VL, slow but gradual drop to 15,000 VL but viral breakthrough around week 32; game over.  During the slow/gradual decline I kept asking my old doc (who I fired) to either up or change the Interferon from Peg-Intron to Pegasys.  I got the initial 4 log drop but something needed to be changed.  By doing nothing but SOC, I believe that the virus found a way around the INF + RBV.  That's why I'm excited about VX-950 because it should clobber the shxx out of the virus upfront and then let INF + RBV do it's work.

I have to say that I'm really leaning toward joining the trial.  Any comments?

During my earlier tx I worked everyday.  The Peg-Intron brought on headaches and the like upfront but was tolerable.  Over time was my problem because around week 24 or so I started to feel like an absolute Zombie.  I hear that Pegasys is not as harsh as Peg-Intron. My doc said that the Pegasys that will be administered is not weight-based like the Peg-Intron.   Also any comments?

[Skepsis]

Rollover with telaprevir as early as after 12 weeks would be ethically just tolerable, but what is the extra information than that could be achieved by this control arm...? How much more EVR is to achieve with Telaprevir?; How effective could be the addition of telaprevir after failing SOC-EVR with non-responders?;
Is it nearly as effective as in the whole NR-population without failed EVR?...
Some possible outcomes could elucidate the resistance question, while some others leave it unanswered...

To the original question whether Vertex abandoned their 12 weeks concept or not:
Vertex has strong financial interests to start with longer therapy for non-responders: the revenues pro therapy will be proportional to the amount of drug consumption during individual therapy. Non-Responders are a very significant proportion of need-to-treat HCV patients. This is a strong potential to exploit during initial market introduction.  

A follow-up therapy of SOC for non-responders has a such low SVR-rate that improving response rate alone would be a significant achievement even without shortening therapy time. It is conceivable, that such long term therapies (or even longer?) will be necessary or about optimal to achieve SVR with previous non-responders. If not, i.e. shorter time will be enough in most cases, this optimizing correction can be done after marketing phase as well. It is very probably, that some individual gain some advantage from longer therapies, so the  above strategy can be OK.

Other benefits for vertex and FDA: more long-term therapy side effects data be gathered through this Phase II trial (Prove3) as well. As a matter of fact, there are some risks with this longer-term trial for Vertex: if some patients should die during prolonged period, the whole project could be thrown back seriously. (Spontaneous deaths in such a large population in such long time are not a rare event, not even without such strong stressing factors as IFN-combination: think of a village population with some hundred inhabitants, there occur sudden death cases as well all the time.)

One further benefit: the data gained from 48 Weeks regimes provide directly comparable differences to SOC (achieved just by the addition of telaprevir, without changing anything else).

One question remains open: what does it mean that no arms without Ribavirin should be defined: I guess the preliminary data with Prove 2 are showing not enough benefits (occurence or severity of such Sx as rush) or are showing the signs of lowering efficacy of a combination without the Riba.

Skepsis

[orleans]

Hey, Anybody know if they are allowing stage 3/4 into the trail? Methinks they wouls avoid that as they are harder to clear. Us guys are needin' a little hope too!!

[lab-rat]

Since you asked for opinions on joining the trial...I say go for it!  I'm currently in the the Prove 1 trial, but since I'm in the placebo group (week 27) I can't comment on either the vx or the peg-intron comparison.  However the trial in general has been a positive experience for me - I'm currently responding to the meds, feel well, haven't missed any work, exercise, travel, etc.  

I think the whole placebo arm for non-responders is ridiculous, but since they say they will give you vx if still detectable at week 12 that makes a huge difference.  The only caveat would be the lack of rescue meds - did you need them when you treated before?  Because you probably won't get any for at least the first 12 weeks.  Others will offer more educated opinions on what you may be risking by joining the trial, but I wanted to offer my perspective as a trial participant.

Besides I question some who say a person has plenty of time to wait just because a biopsy says stage 1.  I was stage 1, then within 3 years I was stage 3. It can happen quickly (or maybe it was a different chunk of my liver, who knows?)  Best of luck whatever you decide!

[jmjm530]

I agree with above comments. Still don't think they needed group "A" but some sort of control may be mandated. As long as they are going to give you the option to "roll over" at week 12, then I think the trial is a worthwhile opportunity to consider for many previous non-responders.

-- Jim

[miked]

My doc is also saying go for it.  Knowing my stats, my heart and head tells me that the 24 week arm with VX950, INF and RBV would kill the bug for me.

[jmjm530]

I'm assuming that as a prior non-responder that you either have significant liver damage or for your own personal reasons, you're highly motivated to kill the virus, no matter what. In either case, on reflection, sounds like Prove 3  might be a very reasonable choice, given what's currently available. Ideally, you would be able to hold off a few more months until hopefully more Prove 2 post treatment data comes out, but sometimes you just have to take a chance.

-- Jim

[miked]

Two years ago my biopsy grade came back with no inflammation and less that a grade 1 (doc says like .5).    However one year ago a chemical marker came back that I'm a grade 2.  I asked my doc and he said that he trusts the gold standard of biopsy.  

Reading tells me that the biopsy may have sampled only one area of the liver.  The last thing I want is to sit here fat-dumb-somewhat happy to learn that my liver is in bad shape afterall.

Plus I really can not stand the thought of this thing alive in me and trying to take over.  I wish it dead.

[drofi]

sorry to tell you, but there seems to be a misunderstanding. There is *NO* roll-over at week 12 for group A!
It is a blinded study and there is no difference between group A and B before unblinding:
• Group A: Patients will receive placebo (a sugar pill made to look like the study drug but does not contain medication), Pegasys® and Copegus® for 24 weeks. Then, 24 weeks of Pegasys® and Copegus® only. Patients in Group A will have the option to receive telaprevir through a roll-over study.
• Group B: Patients will receive the study drug telaprevir, Pegasys® and Copegus® for 24 weeks. Then, 24 weeks of Pegasys® and Copegus® only.

A rool-over study means that group A can step into a *new* phase 3 study AFTER the phase 2 study named "Prove 3" is finsihed for this person.
It is questionable if Vertex could find a more ethical design than this, but to be honest, telaprevir seems to be great stuff and a chance of 3:1 with a roll-over is not too bad if you have in mind what a cirrhosis could do before the marketing authorisation is there. It is a very personal decision and depending from how much time you will probably have. Ask your physician, not only a virtual community in the www...

[jmjm530]

We've now had at least two definitions of what "roll-over" means. Isn't there something in WRITING out there on this? If what "Milked" suggests is correct, then I think the trial is quite ethical although not sure why they organized group "A" like that. However, if "Drofi" is correct, then I think it's quite bordeline in terms of being ethical. Don't really like that one chance out of three means someone who relapsed will be treated the second time with probably the same protocol they relapsed with.

Drofi, as to your last statement, "Milked" apparently did get this information from his doctor, if I read his previous post correctly. Maybe Milked can confirm his source. And Drofi, I'm assuming your source is your doctor as well? That's why I'd like to see something official in writing as it appears we have one doc saying this and one doc saying that. Not unusual by any means but very important to figure out which is which. Also, could it be possible that the protocol's differ in Europe from the states? I know one thing for certain. If I was a candidate for Prove 3, I'd dig and call until I got collaboration from some very creditble sources IN ADDITION to my treating doctor, and I'd want to see it in black and white.

-- Jim

[miked]

Drofi,  thanks for the information; where did it come from?

My information that after 12 weeks the palcebo group can roll-into getting VX950 came fro the main trial doctor.

Whoever is right will have a large bearing on my decision.

Thanks.

Mike

[jmjm530]

Have nothing in writing, but did a little research and this is what I found out. For those interested, you should get hold of the trial CONSENT FORM. Supposedly, it's all there in black and white. So ask for a copy of the consent form well in advance of making your treatment decision.

Here's my version of how they're running group "A" :)

Group "A" will be given placebo, Pegasys and Copegus for 12 weeks. If patient does not achieve a two-log drop at week 12, then therapy will be STOPPED. The patient will then be giving an option to roll over into 24 weeks of Triple therapy (Vertex, Pegasys, Ribavirin. This triple therapy would start at what would be week 24. So in effect, there would be a 12-week gap between treatments -- actually probably a little less than 12 weeks since it probably will take a week or so to get back the blood results from the week 12 test.

To me, this protocol, while not ideal, is ethical, in that it gives non-responders the opportunity to quickly roll-over, thereby limiting their total exposure to only 36 weeks.

Again, the best way to confirm the above is to read your trial CONSENT FORM, but at first glance, this seems like the most reasonable protocol discussed so far.

-- Jim

[Willy50]

This is from Vertex, by e-mail.  I didn't find the terms very descriptive at clinicaltrials.gov

Dear Mr.     :
Thank you for your unsolicited inquiry regarding telaprevir (VX-950), a drug candidate for the
treatment of the hepatitis C virus (HCV).
PROVE3 is a clinical trial designed to evaluate the efficacy and safety of telaprevir in 440 patients
with genotype 1 HCV who have not achieved a sustained viral response (SVR) with a previous
interferon-based treatment. The trial is planned for more than 50 centers in the U.S., Canada, and
Europe. In the trial, patients will be randomized equally across the following four treatment arms.

• 12 weeks of therapy, with telaprevir dosed at 750 mg every eight hours (q8h) in
combination with standard doses of pegylated interferon alfa-2a (peg-IFN) and ribavirin
(RBV), then continuing for another 12 weeks with peg-IFN and RBV alone; or

• 24 weeks of therapy, with telaprevir dosed at 750 mg q8h in combination with standard
doses of peg-IFN. Patients in this arm will not receive RBV; or

• 24 weeks of therapy, with telaprevir dosed at 750 mg q8h in combination with standard
doses of peg-IFN and RBV, then continuing for another 24 weeks with peg-IFN and RBV
alone; or

• A control arm with peg-IFN and RBV dosed for 48 weeks. Patients in this arm who do not
respond to therapy at week four or beyond will have the option to roll into treatment with
telaprevir, peg-IFN and RBV under a separate protocol.

This trial initiated patient recruitment in the beginning of 2007. Based on predetermined inclusion
and exclusion criteria, enrollment selection is determined by the investigators at the centers.
Vertex Pharmaceuticals Incorporated can not maintain a database of patients interested in
participating in this trial or future trials.
PROVE3 trial information and the location of trial sites are posted on www.clinicaltrials.gov.
Clinical trial site contact information will only be listed for those sites that are open to recruitment
and able to accept patients. As is the case with most large clinical trials, all clinical trial sites will
not be open for enrollment simultaneously. Thus, we recommend that you frequently check
www.clinicaltrials.gov for the most up-to-date information on those sites that are open to
recruitment and able to accept patients.
The contents of this letter should be discussed with your healthcare provider, who is in the best
position to advise you and make any recommendations regarding choices of medication for your
personal health.

-------that may have been more than you needed but the ink is cheap.

You can debate what "rollover" means but this is what Vertex sent me.  At least these are the terms from Vertex and they may help refine questions or thinking on the subject.

By the way......I just got this a few hours ago and haven't really read it or had a chance to think about it (busy doin chores).  I just thought I'd get it up here.

best,
Willy

[jmjm530]

Per my post above, "rollover" means they will be given the opportunity to take Vertex, Peg and Riba for 24 weeks, starting at what would have been week 24. Apparently, it's all in the CONSENT form which anyone interested in the trial should read very carefully and then discuss with their doctor.

[miked]

thanks guys.

[drofi]

I read the info at http://www.prove3.com/aboutprove3.html
and vertex writes that Group A "will receive placebo, Pegasys® and Copegus® for *24* weeks."
It makes little sense to create a placebo group if you step to verum after some weeks. Hence I *think* (not *know*) that they will unblind the study after 24 weeks and will offer the chance to step into a separate protocol later.
The simple question for vertex would be: "what exactly is the individual week of unblinding?"  Just to decide about a roll-over into Telaprevir treatment from the a response would make little sense, since you would never know from a *missing* "response", that it is not the VX-950. What, if the person is on telaprevir, but the virus does not respond at all, because a resistence happens early during treatment? That is exactly what the FDA wants to know, the percentage of response.
Therefor the only question for us is the question of the time of unblinding.
However, we could discuss this for decades, only a statement from vertex about the week of unblinding is what will help to clear this up.

Sorry again for my english... I just write down my thoughts and do not invest time for grammar and vocabularies.

[Willy50]

From the final "arm" of the trial I posted;

"• A control arm with peg-IFN and RBV dosed for 48 weeks. Patients in this arm who do not
respond to therapy at week four or beyond will have the option to roll into treatment with
telaprevir, peg-IFN and RBV under a SEPERATE PROTOCOL."(my emphasis-willy)

As you pointed out Jim, that may be spelled out elsewhere.  It simply isn't clear in this post and I'd recommend reading and understanding the issue since there is a reasonable chance of getting into that arm and a good chance (as a previous non-responder)of ALSO not responding to basic SOC.  

Furthermore......since this is a treatment failure trial some people may have "failed" due to low WBC or RBC  and been pulled off TX as opposed to insufficient response.  What will happen if that repeats this time?  There are many ways that you could fail in this leg.  I'd recommend understanding the all the "what ifs" to the several different scenarios that could happen; discontinued due to rash, gastric issues, low RBC/WBC, other emergencies, slow response, rebound mid treatment, rebound post TX. (and the timetables that would also apply and under what conditions and where rescue drugs are permitted)(LOL..... they'd probably tell me to get lost : ))

I will also note that on boards we sometimes meet people who for some unknown reason succeed on a second and third attempt even though one might also reason that they could be less likely to clear (due to resistance or mutations).  I'm sure that we all know a few examples of different people who have had successful outcomes after treating a few times.  I agree; it still looks like a reasonable chance to me even getting into the no Telaprevir arm.  (or call it the deferred Telaprevir arm) : )

best,
willy