Cross-linking clinical trial

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MEHeyedoc
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Cross-linking clinical trial

Postby MEHeyedoc » Mon 30 Apr 2012 9:14 pm

Hello everyone,

Moorfields Eye Hospital is in the process of setting up a clinical trial of a new type of cross-linking (CXL). We hope to start the trial from next year, but in the meantime we are looking for help from this forum. Nearer the time, we hope that some of you will volunteer to take part in the trial, but for the moment your views, thoughts and suggestions would be very useful.

The trial is to compare a new form of CXL (transepithelial CXL) with placebo (no treatment) in patients with early KC (i.e. those who are still able to see reasonably well with the right spectacles).

To remind you, conventional CXL is effective in halting corneal shape deterioration in 90% of treated patients, and in a few patient some reversal of the steep corneal shape occurs. The problem is the treatment is painful and has risks, with about 3% of patients losing a couple of lines on the reading chart, even with the right glasses or contact lenses. These risks are mainly due to removal of the top layer of the cornea (epithelium) that is performed at the time of the CXL operation.

Because of these risks, CXL is normally reserved for patients with definite corneal shape deterioration. But for some patients, locking in the shape after significant deterioration has already occurred may be too late, and this delay may make the difference between being able to see well with spectacles (and thus being suitable for other effective treatments like lens implantation) and being reliant on rigid contact lenses.

So we would like to treat patients at first diagnosis. Transepithelial CXL, which does not require removal of the epithelium, is painless and much safer. The early results from Italy look very encouraging. So far two small trials of 71 patients have been published showing that all patients’ corneas treated with transepithelial CXL stopped deteriorating. Some even got better vision. Although these results are exciting, we need to do a much bigger trial to conclusively prove that it works.

All patients entering the trial (whether in the CXL or placebo group) would still be able to receive conventional CXL if their corneal shape deteriorated. So there would be nothing to lose by participating. If transepithelial CXL is effective, you could avoid the need for conventional CXL later on. Knowledge gained from the trial will, we hope, move us further towards the aim of intercepting corneal shape deterioration in KC before significant problems with vision develop.

The trial would involve an initial assessment and treatment at Moorfields followed by 6 monthly corneal shape scans (either done at a local eye unit or Moorfields), then a further assessment at Moorfields 2 years after treatment.


So, just to get things rolling, here are a few questions we’d like your views on:


1. If you were eligible for this trial, would you be keen to participate?

2. If you weren’t eligible (e.g. KC too advanced, rigid contact lens wearer or you’ve had a corneal graft), would you have been likely to participate if you could wind the clock back?

3. For those of you living outside London, would travel to London for treatment and assessments be problematic? We would reimburse all your travel costs.

4. Are there specific things that would stop you participating in the trial, even if you were eligible?


Any comments/questions/suggestions welcome!

Many thanks,

Dan Gore
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andytraill
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Re: Cross-linking clinical trial

Postby andytraill » Mon 30 Apr 2012 11:13 pm

1. If you were eligible for this trial, would you be keen to participate?
Probably not if I was at that stage, I'd be subjecting myself to risk for little/uncertain gain.
2. If you weren’t eligible (e.g. KC too advanced, rigid contact lens wearer or you’ve had a corneal graft), would you have been likely to participate if you could wind the clock back?
Knowing what I know now, at that stage on my right (bad) eye yes but not my left ("seeing") eye.
3. For those of you living outside London, would travel to London for treatment and assessments be problematic? We would reimburse all your travel costs.
I would travel no problem, even without reimbursement.
4. Are there specific things that would stop you participating in the trial, even if you were eligible?
At the stage you are looking at the risk would put me off. Early KC might not progress at all. So benefits of being in the trial are unknown but the risks are*.

Aside from those comments are you doing both eyes on people or single eyes? If single do you do the worst or best eye?

*To follow on to me early stage KC can be monitored and a change reacted to, early cross-linking while it predictably provides benefit (which through monitoring you might not even need) it also infers risk.

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Re: Cross-linking clinical trial

Postby MEHeyedoc » Tue 01 May 2012 6:23 am

Thanks for your post Andy.

You're right, this all boils down to a balance between risk and benefit. In hindsight, it's easy to say who should have had CXL (notwithstanding that we can't even offer on the NHS at the moment!). Most people's KC isn't symmetrical, with one eye usually progressing at a faster rate and often becoming the weaker eye. Some eyes never progress that much; other patients require corneal grafts in their teens. While we can't predict this risk of progression for any given individual, research does, however, tell us who is most at risk of deterioration, with age and ethnicity (non-Caucasian) being the most important factors. So a teenager whose optician first picks up repeated changes in spectacle prescription and who is subsequently confirmed to have KC is much more likely to become dependent on rigid contact lenses and need a graft, than someone in their late twenties presenting for the first time. Certainly by the time you get to your mid 30s, the risk of continued progression is extremely low

That's why conventional CXL (3% risk of permanent loss of 2 lines on the reading chart and a further risk of temporary (few months) corneal haze) is reserved for patients whose topography (corneal shape scan) and/or vision has deteriorated (usually assessed over a 1-2 year period). So far, the results of transepithelial CXL look much safer: in the 2 trials totalling 71 treated eyes I mentioned before, only 2 eyes developed temporary cornea haze that disappeared after 1 month. No infections were recorded. No patient lost vision. So the argument is why wait?

One issue following on from this is what age patient are we hoping to treat? The regulatory authorities, rightly, get quite twitchy if you include children in a clinical trial. Conversely we know that teenagers are most at risk of progression and therefore the most important people in whom to intervene early. We are hoping to include patients aged 16 -35, but that's still to be confirmed.

To answer your specific question, we're hoping to treat both eyes (assuming they both have KC). Whether this would be at the same time or, say, a week apart has not been confirmed yet.

Dan

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Re: Cross-linking clinical trial

Postby Lynn White » Tue 01 May 2012 11:12 am

I'd just like to step back and widen the discussion a bit, as most of the recent posts on this forums have been about specific or new procedures and I think we all need to take a look at the broader picture.

The idea, as far as I see it, of this trial is to establish the efficacy of a safe, quick procedure that can be used early in the condition to prevent progression. If caught quickly enough, then in future years, people at risk could be treated before they develop levels of astigmatism and distortion that makes wearing contact lenses the only option to see. I really do not have to point out to this audience what a difference that would make to quality of life.

One issue is that up until now, there has been very little point in monitoring early changes in keratoconus and how the condition progresses as, simply put, there was no possible cure for it anyway. Now that CXL has been developed, we can start looking at how to detect KC earlier, how it progresses and how it affects people even if it does not progress.

Many of you with "stable" KC do find that vision and symptoms vary over time. They tend to fluctuate, some days are good and some are not so good - and this is likely to be a result of having a soft, relatively unstable cornea that does not heal well in response to any kind of small abrasion.

At the moment, many people have CXL on eyes that are really problematic and tend not to risk their better eye - an understandable approach. I have patients, though, who for sheer peace of mind have gone ahead and had the better eye done as well.(In some cases against my cautious advice). The interesting thing is, these eyes become more stable. It is really noticeable because they are not regularly turning up in my practice asking for prescription changes or complaining as much of various other issues like glare and ghosting. Looking back at topography data confirms that these corneas are much more stable. So this is a possible future benefit as well.

Risk balancing
The risks of scarring and haze are, as Dan says, more associated with advanced KC rather than milder conditions and also associated more with the epi off procedure. Its the removal of the epithelium that increases the risk of infection and damage. However, up until recently, leaving the epithelium on has made the procedure safer and more comfortable but tended not to give the same depth of CXL effect. Of course, we don't actually KNOW for sure that you need the full depth effect to work in every case.

Looking at this another way, if you are progressing in one eye, left untreated, that eye is going to develop more distortion and there is a risk of developing scarring anyway plus an added risk of hydrops.

With the method outlined below, risk is more related to whether it will be effective in halting progression or not, rather than any damage to vision. If anyone is considering CXL as an option, then this study is a good opportunity, as they are offering conventional CXL if this procedure does not work.

Even if you are not in the treatment group, you will still be offered conventional CXL if you progress, so in effect, this is a monitoring situation where CXL will be performed, one way or another, if there is progression - which is what one would normally do anyway.

It would be good if we can debate what you all feel about this trial. Like it or not, acceptance of medical advances by the establishment ONLY comes about using evidence gained in clinical trials. The only people who can move this forward are those who have the condition.

Despite heroic attempts, trying to turn back the clock once your KC has advanced does not really work for most people. The real trick to beating KC is to stop it the moment its detected. CXL is currently the only treatment that has a hope of doing that, which is why any trial using CXL is very important. But they cant do it without you!

Lynn
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email: lynn.white@lwvc.co.uk

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Re: Cross-linking clinical trial

Postby longhoc » Tue 01 May 2012 1:09 pm

Hey there Dan... My two pennies' worth:

1. If you were eligible for this trial, would you be keen to participate?

No. My "good" eye gives me getting on for 20/20 with a glasses lens. With an RGP, it's better still. I've thought long and hard about "preventative" crosslinking. Given that at 9 months post-graft I rely so heavily on my good eye, I'm unwilling to do anything to risk it. It would only be if the odds of any redution in visual acuity were 1:10,000 or less that I'd consider any procedure. Of course, you don't know that yet, hence the trial !

Probably worth me asking for a clarification for everyone considering this if I may Dan -- is the trial open to those in my sort of situation (one good enough to manage with glasses eye and one not good enough eye ?) Or do you need two good enough for glasses eyes ?


2. If you weren’t eligible (e.g. KC too advanced, rigid contact lens wearer or you’ve had a corneal graft), would you have been likely to participate if you could wind the clock back?

N/a

3. For those of you living outside London, would travel to London for treatment and assessments be problematic? We would reimburse all your travel costs.

No, I'd always pay whatever it took (within some reasonable upper bounds) to get the best treatment for my eyes. Travel costs are incidentals.

4. Are there specific things that would stop you participating in the trial, even if you were eligible?

For my "bad" eye, my attitude is pretty much anything goes. Experimental treatments, riskier treatments, marginal improvement only treatments -- wouldn't bother me at all. This is because I'd be in the "nothing much to lose" category. But as I mentioned earlier, I'm loathed to tinker with my last remaining method of hanging onto anything like reasonable vision. I cannot help but feel a sense of guilt/regret in 'fessing up to this stance. If everyone acted like I did, there'd be no way of ever establishing enough evidence for the safety and effectiveness of this protocol. But in the end, self interest has to win out... (everyone should refer to Lynn's comments to set mine in context)

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Re: Cross-linking clinical trial

Postby taffer87 » Tue 01 May 2012 5:46 pm

1. If you were eligible for this trial, would you be keen to participate?

Yes.

2. If you weren’t eligible (e.g. KC too advanced, rigid contact lens wearer or you’ve had a corneal graft), would you have been likely to participate if you could wind the clock back?
N/A
3. For those of you living outside London, would travel to London for treatment and assessments be problematic? We would reimburse all your travel costs.
N/A
4. Are there specific things that would stop you participating in the trial, even if you were eligible?
Need to know more about risks involved, but thinking about cross linking anyway. If the risks are the same then will go for it.

Where can we get more details?

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Re: Cross-linking clinical trial

Postby andytraill » Tue 01 May 2012 6:10 pm

Dan sorry I was half asleep when I replied to that, I think I miss-interpreted the first question.

If the first question was would I be willing to be part of the trial as my corneas are now then I probably would. In fact it would possibly make most sense for my left/good eye (correctable with glasses largely), I think my right is that bad that CXL wouldn't make a difference at this stage it'd need to be a last gasp go at keraflex/transplant. I have noticed some instability in my "good eye" it so epi-on CXL would probably make sense for me personally but I don't know if it would for your trial (it's relatively stable so I'd assume it could end up being a false positive for you?).

I had wrongly assumed you meant the hypothetical situation where I was a "patient at first diagnosis would I do this". I also hadn't realised it was epi-on CXL (which I think does have quite a lot of results behind it) rather than a completely new form (I'm potentially wrong here again).

Sorry for the confusion.

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Re: Cross-linking clinical trial

Postby MEHeyedoc » Tue 01 May 2012 10:20 pm

Thanks for the comments, in particular Lynn. I endorse everything you wrote; you've explained the issues far better than I can!

Just to clarify a few points:

Transepithelial is the same as epi-on, ie epithelium not removed. As Lynn said, the serious risk of CXL are almost all associated with removing the epithelium which exposes the risk of infections, scarring and pain.

The trial will likely be randomised. This means patients won't know whether they've had CXL or just a sham blue light shone at their eye. This may sound like a raw deal for those volunteers who don't get treated, but this is same for all randomised controlled trials.

In my initial intro I was a bit vague about who might be eligible. That's because this project is a long way off from starting, hopefully next year some time. A lot of the details (e.g. exactly who might be eligible) haven't been finalised yet. I don't want to raise any false expectations that this is happening any time soon, so please please be patient. The main thing we're hoping to understand from this forum at the moment is whether, in principle, this sort of trial sounds appealing and what sort of things might encourage/discourage patients to volunteer.

Dan

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Re: Cross-linking clinical trial

Postby liam82 » Wed 02 May 2012 10:24 am

1. If you were eligible for this trial, would you be keen to participate?

Yes. Im considering having my right eye done, as its getting worse slowly but surely. I was thinking of having the epi on version this time, as it sounds slightly less risky

2. If you weren’t eligible (e.g. KC too advanced, rigid contact lens wearer or you’ve had a corneal graft), would you have been likely to participate if you could wind the clock back?

Im not in any of those camps

3. For those of you living outside London, would travel to London for treatment and assessments be problematic? We would reimburse all your travel costs.

I already do, as I had cxl on my left eye treated on harley street and pop back for regular checks

4. Are there specific things that would stop you participating in the trial, even if you were eligible?

Not really, though I guess the placebo thing might- the thought of delaying it without realising would be worrying. Though after experiencing CXL, im pretty sure i'd spot the difference if all you did was shine a blue light in my eye. My experience of CXL was for at least a few days the vision was really blurry.

I dont think the epi on cxl would have no effects at all, where you wouldnt notice anything.

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Re: Cross-linking clinical trial

Postby Chris_J » Thu 03 May 2012 12:05 pm

1. If you were eligible for this trial, would you be keen to participate?
Yes I would - especially what I know now, but then I guess that's hindsight for you.

2. If you weren’t eligible (e.g. KC too advanced, rigid contact lens wearer or you’ve had a corneal graft), would you have been likely to participate if you could wind the clock back?
There is no way I can participate (Too advanced)but yes I would have done. When I first got my lenses I was always told the lens would help stop the condition getting worse which is obviously is known not to be the case now.

3. For those of you living outside London, would travel to London for treatment and assessments be problematic? We would reimburse all your travel costs.
That would have been no problem; I'd have happily paid myself if it had a chance of stopping my eyesight getting worse
4. Are there specific things that would stop you participating in the trial, even if you were eligible?
No

Any comments/questions/suggestions welcome!
[b]I think it's worth nothing that this treatment isn't very well known it seems - I only found out about it through this forum. I'm going on may 21st to see someone, but at this stage it's very probably that my left eye (The one I want done) it too advanced to do anything about and I wonder if I'd have known about it a few years earlier whether I'd have been able to have it done. (Obviously I don't know it's too far advanced at this stage but the hospital seemed to think it would be).

Also the comment from Lynn about people not having it done on their stable eye is a fair point. I must admit I'd not even considered it on my right eye given it's been stable for over 5 years now (and probably a fair bit longer than that). I'd say certainly if it does get any worse then the first thing I'd do it look to getting it done and maybe I should consider it when I go to see the specialist on May 21st.

Cheers

Chris


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