Newly pubished studies Cladribine and Fingolimod

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Newly pubished studies Cladribine and Fingolimod

Postby ama » Wed Feb 03, 2010 10:11 am

Just read the newly published studies in the New England Journal of medicine about Cladribin and Fingolimod.
There I observed some couriosity.
Who can help me interpret the following graphics?

a) http://content.nejm.org/content/vol0/is ... 533f1.jpeg
b) http://content.nejm.org/content/vol0/is ... 494f2.jpeg

Observe the Placebogroup in graphic B Cladribine in comparison to Fingolimod graphik A
take notice of the placebogroup for the first relapse at the end of the studies one time 96 weeks about 2 years and after 720 days after 2 years.
Whats wrong with their placebo groups?
What does this indicate?
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Postby gkalman » Wed Feb 03, 2010 12:37 pm

I would guess that they had different criteria for study participants. For example if one study required one relapse within two years, while the other required two relapses within one year, one would expect placebo groups (as well as other groups) to be very different.
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Postby ama » Wed Feb 03, 2010 12:44 pm

gkalman wrote:I would guess that they had different criteria for study participants. For example if one study required one relapse within two years, while the other required two relapses within one year, one would expect placebo groups (as well as other groups) to be very different.


But why is there such a high significance between the groups if the difference is just one relapse. What conclusion we can be drawn out of this?
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Postby gkalman » Wed Feb 03, 2010 1:01 pm

I am not familiar with either protocol (though, I probably should be since my wife was in the fingolimod study). However, my only point is that studies are designed so that apple to apple comparison is made between the groups within the study. Differences between the studies can exist for a variety of reasons. E.g.,

(1) different inclusion protocol. There from the two graphs, one would conclude that the general population of the fingolimod study had stronger MS (for one reason or another)

(2) the definition for a relapse may be different between the studies. Again, one would need to look at the protocols and inclusion criteria for participating doctors and patients.
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Postby gkalman » Wed Feb 03, 2010 3:04 pm

I think you are making good points and it is bothering me also since you pointed it out.

As I mentioned before, one possible explanation is that an event was more likely to be called a relapse in the Finglimod study. See below.

For the Cladribine study, it says, "A relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement."

For the Fingolimod study, it says, "To constitute a confirmed relapse, the symptoms must have been accompanied by an increase of at least half a point in the EDSS score, of one point in each of two EDSS functional system scores, or of two points in one EDSS functional-system score (excluding scores for the bowel–bladder or cerebral functional systems)."

Also, I looked at the inclusion criteria, and wasn't sure how to interpret the wording, but in the Fingolimod study, they said, "one or more documented relapses in the previous year or two or more in the previous 2 years". While in the Cladribine study they said, "had at least one relapse within 12 months before study entry". I.e., may be "documented" changed the distribution? Though, that as an explanation may be a long shot.
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Postby ama » Thu Feb 04, 2010 12:00 am

Thanks a lot gkalman,
please excuse my bad english i am not used to write in english.

First there is a significant unexplained decrease in all groups of the fingolimod study after day 630.
I was very surprised, when reading the studies, about this high significant differences between the study groups. It seemed to me as there were two different kind of MS. But if you look at the EDSS Scores you cant see this significant differences. So obviously the degree of severity should not differ.
Another point I was surprised was the fact that the T1 pictures showed an average lesion count of about 0.7 in both studies with a standard deviation of +-2 despite that is statistical nonsense. This means to me that the majority of the partitipants had no lesions at all at the T1 scan. Isnt one of the diagnosis criteria for MS in general the presence of lesions?
There are two problems right now for me in interpretation of the results.
The quantity of both studies is so big, there shouldnt happen a such great difference in MS population between the studies. The inclusion and exclusion criterias are not so significant different to explain this differences in relapsing rate.
And what does it mean that there are almost no T1 Lesions to be found?

There is a third study
http://content.nejm.org/cgi/content/full/362/5/402/F2
Fingolimod versus Betaferon I.
If I compare the results of both Fingolimod Studies, does the comparison of the placebo group after 1 year with the Betaferon group after one year suggests that there is no effect of Betaferon at all?
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Postby gkalman » Thu Feb 04, 2010 8:47 am

ama,

Don't worry, English was not my first language either and yours is very clear.

This is the way I understand lesions, though, I could be wrong. Lesions disappear with time. A lesion is either an active inflammation in the brain or what used to be active and is in the process of "healing" or more precisely, disappearing. One problem with MS is that eventually the lesions take a toll on the size of the brain. I.e., lesions disappear not because the brain regenerates, but because that part of the brain collapses onto itself. There is some scar tissue left, but that is not what they are calling lesions. (If someone who knows more about this and I am not right, please correct me.)

For example, when my wife had her first episode, the MRI found about half a dozen lesions. At the second episode a number of years later, her second MRI found about the same number. After the second episode, she started in her first study where she got MRIs once a month. The lesion count went to zero in about six months and stayed there for quite some time. I don't think that is unusual in MS. I would even guess that it is the norm in RR stage. I would also guess that her lesion count was zero between the first and second episode, but it was just never measured.

In any case, my wife has now been through two studies. The protocols between the two were very different. (The frequency she went in to be observed, the tests they did for her observations, etc.) It would be nearly impossible to compare much about the two studies between each other. I am not even sure if EDSS scores would be very comparable at under half a point because the tests they used per protocol were different.
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Postby gkalman » Thu Feb 04, 2010 8:57 am

Oops, per your last question, I am not able to see the third study (I don't have a subscription). But, I thought that Betaferon was only very marginally helpful. I looked into it some years ago, so I don't remember all the details. However, the lack of effectiveness is one of the main reasons my wife decided to do studies as opposed to going on approved medication.
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Postby ama » Thu Feb 04, 2010 10:37 am

gkalman wrote:Oops, per your last question, I am not able to see the third study (I don't have a subscription). But, I thought that Betaferon was only very marginally helpful. I looked into it some years ago, so I don't remember all the details. However, the lack of effectiveness is one of the main reasons my wife decided to do studies as opposed to going on approved medication.


I made this table by myself with the data from the study 3 and hope you dont loose orientation
1.FINGOLIMOD 2.Interferon Beta
1a)1.25mg(N=420) 1b)0.5mg(N=429) 2a)(N=431)
Annualized relapse rate(primary end point) - no. (95%CI)
1a)0.20(0.16 to 0.26) 1b)0.16(0.12 to 0.21) 2a)0.33(0.21 to 0.42)
Patients with no confirmed relapse %(CI95%)
1a)79.8(75.9 to 83.7) 1b)82.6(79.0 to 86.3) 2a)69.3(64.8 to 73.8)
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Postby gkalman » Thu Feb 04, 2010 11:50 am

I am just wondering what the MRI lesion load difference between placebo and betaferon is in the two fingolimod studies. If my memory serves me right, that was where they had stronger results. In other words, back when Betaferon meds were going through their studies, researchers were targeting MRI lesion reductions because the thinking was that was the way to combat the disease. The idea that reduction in lesion load may not help much with relapses was outside the scientific dogma of the day.
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