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`and t.he other question. Sir.ce there are factors
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`that can influence someone:'s subiective feelings of
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`sleepiness, do you have any objective measures that
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`support the indication of daytime sleepiness?
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`Specifically, the one trial that I am aware of that
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`had an MST..T and did daytime sleepiness as a primary
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`outcome measure, in fact, appears to be not
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`supportive of the indication.
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`DR. HOUGHTON: Yes, in the Scrima trial he
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`used the MSLT measure and that was not
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`statistically significant, as shown. The objective
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`data that we propose supports very strongly the
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`effect of adequate dosing of GHB was the SXB-20
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`trial that Dr. Black discussed. That is not only a
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`profound improvement in the ~WT at the 9 g dose but
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`a defined dose response across all doses. That is
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`very positive data.
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`DR. KAWAS:
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`In ten patients, it appears.
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`DR. HOUGHTON, Twenty-one.
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`DR. MAN!: May I also add that that was an
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`open-lab~-~, non-randomized study?
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`DR. HOUGHTON: Sure, but using an
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`obiectivc measure.
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`DR. RISTANOVIC: T am I am Ruzica
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`25
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`F.istanovic, medical director of Sleep Disorders
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`Center. in Evanston, Illinois.
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`I would like to
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`comment on add-on Xyrem in the presence of otheY"
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`stimulants. Other studies attempt to try to
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`document the effectiveness of other stimulants i~
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`narcolepsy-related sleepiness documents, including
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`the most rigorous trial of modafinil in
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`double-blind, placebo-controlled studies. They
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`document that these drugs improve sleepiness but
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`vet·y seldom outside of the range of pathological
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`sleepiness as measured by Multiple Sleep Latency
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`Test and Maintenance Wakefulness Test. So, the
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`patients remain sleepy. That is the message.
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`Add-on treatments are approved for other
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`indications in other neuro1ogical diseases, such as
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`epilepsy. So, I assume that this application for
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`that particular indication is not for monotherapy
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`but. as an add-on to concurrent use of stimulants.
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`I would like to bring this to your attention. So,
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`pat ient.s do remain sleepy on stimulants and they
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`need additional treatments.
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`DR. KAWAS: Dr. Temple?
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`DR. TEMPLE: Dr. Houghton also seemed to
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`be distinguishing between monotherapy and add-on
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`t.het·apy. That is not the problem. The p~·oblem i.s
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`wl~et.her there is adequate support for use as an
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`addition for whatever else t!~e patient is or.., ar..d
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`2 wl:ether there are well ·controlled studies that
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`support that. So, add-on would be perfectly fine.
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`That is usually true in a 1ot of conditions, r:ot
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`just neurological ones, whe1~c- you continue to givt"'!
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`standard therapy and try to improve it.
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`I just want to make one observation about.
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`the evidence. We do expect to see replicated or
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`reproduced findings.
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`Some of the issues here are
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`10 whether the fact that the endpoints are secondary
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`and need some correction means that there isn't
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`adequate support. A lot of these things are
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`13 matters of judgment that. the committee can weigh in
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`on. Not everything is, you know, a yes/no.
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`Some
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`of the things are moderately subtle and that is why
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`this is being brought t.o you for judgment. There
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`is one study that is obviously stronger than the
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`rest but the others can be considered, and you sort
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`of have to think about how many real endpoints
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`there really are; how much of a correction is
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`needed. Those are difficult discussions but worth
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`considering.
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`DR. KAWAS: Dr. Katz"?
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`DR. KATZ:
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`I agr~~. but I think we would
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`still have to have the app1ication meet the
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`standard of independent replication, in other words
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`two trials. You can decide that one of the other
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`trials actually does meet the usual standa~d,
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`again, taking into consideration the multiplicity
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`and that sort of thinq. All I am saying is that I
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`don't think we can say we have one study that looks
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`good.
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`If you believe that GHB looks good and the
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`others sort of contribute to a feeling that it
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`probably is okay, I mean, we really need two
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`independent sources that you believe demonstrate
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`the effectiveness.
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`The only other point I wanted to add is to
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`something, Claudia, you said which has to do with
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`14 Dr. Houghton's view that they are not going for a
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`claim of daytime sleepiness; they just want, I
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`guess, to have language in the labeling that says
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`that it improves that symptom. Most of the drugs
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`we approve are for symptomatic claims, so there is
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`no question that the inclusion of this language in
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`the indication is a claim as we always understand
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`that term.
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`DR. KAWAS: Dr. G"J.illeminault, followed by
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`Dr. Wolinsky, please.
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`DR. GUILLEMTNAULT:
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`If you look at all the
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`published data on rnodafinil, on amphetamine, on
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`1 methylphenidate, none of these drugs ever
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`normalized all the objective tests on alertness and
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`daytime sleepiness. None of them, including the
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`4 modafinil data which were approved by the FDA. The
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`MSLT and MWT fa~- ull these drugs are pitiful. The
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`only data which shows significance was the Epworth
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`Sleepiness Scale, which is a subjective scale, in
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`all these trials. So, we cannot expect to have any
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`positive result with subjective tests in any of
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`these drugs. We will always have to rely on
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`subjective tests even if the subjective test is not
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`great. Everybody in the field agrees that the
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`Epworth Sleepiness Scale is the most used scale
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`despite the fact that it has a lot of downfall, and
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`we have to remember that when we
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`look. at what has
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`been approved and what is being used.
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`DR. KAWAS: Thank you, Dr. Guillemir.ault.
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`I think that many people would agree with those
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`comments, but my question to you would be not
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`20 whether or not the Epworth Scale subjective
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`21 measurements are good but do we have two
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`randomized, contro~l~d trials that show an
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`improvement in subjective sleepiness.
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`DR. GUILLEMINAULT: That was my initial
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`question because my understanding is, when the
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`statistician from the FDA responded, she said that
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`when she did a nonparametric analysis she found O'...lt
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`that she had a p value of 0.03. So, my
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`understanding is that she had a significant finding
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`even when she did the reanalysis. That was my
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`understanding of her response.
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`DR. KAWAS: Would you like to comment, Dr.
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`Yan?
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`DR. YAN:
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`I am sorry, the previous number
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`is not right.
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`I checked. The number for the
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`nonparametric analysis, the p value was 0.0109.
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`DR. WOLINSKY:
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`I have a couple of
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`questions first for some information bcfo~e I ask
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`the real question. For the informational questions
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`perhaps Dr. Mignot could help with. So, the first
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`question I have is if you could enlighten us or
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`re-enlighten us about how many patient.s that have
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`narcolepsy have had cataplexy as a component
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`symptom. What proportion?
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`DR. MIGNOT:
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`In most case series it is
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`about 70 percent.
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`DR. WOLINSKY: The second question is that
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`at least for most of these studies which were done
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`and presented to us since cataplexy was being
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`25 measured, as is appropriate, t~e r.umber of
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`cataplectic attacks was relatively high.
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`I tl:ink
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`in these studies it was arou~d 20 cataplectic
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`attacks per week. So, how many of the 70, 75
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`percent of patients with narcolepsy who have
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`cataplexy have cataplectic attacks at that level?
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`DR. MTGNOT:
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`I would guess 20 percent.
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`DR. WOLINSKY: Thar.k you very much.
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`DR. MIGNOT: Yes, roughly.
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`DR. WOLINSKY: And then they would fall
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`down below that level for the remainder of the 55
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`percent of narcoleptics with cataplectic attacks.
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`DR. MIGNOT:
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`If you analyze the spread of
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`the number of cataplexy episodes per week, but you
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`have to balance that also with the efficacy of
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`current treatments. A lot of people that currently
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`have cataplexy that is relatively mild ;ust don 1 t
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`want to take the antidepressants because they have
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`so many side effects, especially sexual side
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`effects, dry mouth, all these problems --
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`DR. WOLINSKY: This is not the question
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`though. So, now the question to Orphan which has
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`really, truly become an orphan drug question, is
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`since all of the studies that have been done have
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`enriched for cataplexy, do we have any data that
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`25 would suqgest. that if cataplexy is adequately
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`controlled or if there is no cataplexy so we don't
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`have to worry about the control of cataplexy the~e
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`would be any effect of the dru~~ on daytime
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`sleepiness in non-cataplectic narco·leptics?
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`DR. REARDAN'
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`I think Jed Black wants to
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`make a comment on that.
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`DR. BLACK:
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`Just a comment on the
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`prevalence of cataplexy in the 70-75 percent of
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`folks with narcolepsy that had cataplexy, the
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`frequency of events -- this is something that Dr.
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`11 Mignot is not aware of, the cataplexy was
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`subdivided into major events and minor events.
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`About 20 percent or so would have the major events
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`to that level, but when we look at the minor events
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`a far greater percentage of that 70 percent, which
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`may be up to 80, 90 percent of that: ·;o percent,
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`17 will have that number of minor effects. Those are
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`not compl~te attacks where they full down.
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`In
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`fact, with most narcoleptic patients, they
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`distinguish between the two und they will often
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`only repo~·t to the physician the m'3.jor events. But
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`in the diaries that Orphan had set up all the
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`events are characterized.
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`DR. WOLINSKY:
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`So,
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`t.he second q'...lestion -(cid:173)
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`DR. BLACK: We have no ido::a. That is an
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`excellent question that I t~ink ne~ds to be
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`determined, but in the studies that have been
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`completed that question cannot be answered.
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`DR. REARDAN,
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`Jed, the only study I can
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`think of maybe is SXB-20 where cataplexy was not an
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`entry criterion and I don't know what the cataplexy
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`incidence in that trial was. Bill is shaking his
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`head -- we didn't record it and we didn't
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`quantitate it.
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`DR. BLACK: We can't comment on that.
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`DR. REARDAN:
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`It is true that in most of
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`our studies patients were selected because at entry
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`criteria they had to have a baseline cataplexy.
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`DR. KAWAS: Dr. Penix?
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`DR. PENIX: Before we address the two
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`separate indications issue -- and I guess, Dr.
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`17 Black, I could direct this question to you
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`in
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`the GHB-2 study you did look at all cataplexy
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`events, I guess, and then total a~d partial
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`cataplexy.
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`In the backgrour.d material, in the
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`separation of the two it appea1~ect that there was no
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`significant difference in any of the three doses of
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`GHB on total or complete cataplexy but your effect
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`was p~imurily in partial cataplexy.
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`Is that
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`correct?
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`[No verbal response]
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`So, my question in that :!:"egard is what is
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`the clinical significance of partial cataplexy, and
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`you mentioned that patients frequently do not want
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`tr~atment for partial cataplexy. So, is this a big
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`problem?
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`I presume that the patients that would
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`perceive a problem would be the ones with the
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`complete cataplexy but there we see no significant
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`difference. So, is t.here a problem there with
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`that?
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`DR. BLACK:
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`I think this is a good point,
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`and the difficulty comes in trying to separate the
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`two because it is not sort of a box of partial and
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`a box of complete; it is a gradation, you know,
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`ranging from small partials to .!.arge partials and
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`the completes. So, I think this analysis is
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`difficult to perform. Clir.ically the degree of
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`improvement with traditional anticataplectic
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`19 medications that we use is similar. So, the
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`reduction in partial -- if that is all that is
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`being seen here and I am not convinced that
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`clinically that is the case -- while the
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`statistical analysis didn't demonstrate a
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`significant difference in the complete cataplexy
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`ar.tacks, clinically t~ere is an improvement in all
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`the different categories, and it is ve~y
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`substantial in traditiondl ar1ticataplectic
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`3 medications as well as wit~ GHB.
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`DR. PENIX: Could Dr. Mignot comment on
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`the clinical significance of partial cataplexy?
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`Is
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`it a big problem?
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`DR. MIGNOT, Yes, it is a big problem.
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`In
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`fact, the problem is especially the social aspect
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`of cataplexy, when you have to realize that you a:r-e
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`just in the middle of a crowd and are meeting some
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`friends, and you can never tell when it is going to
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`happen.
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`It may happen in very odd circumstances.
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`So, often even the docto;s don 1 t know what it is
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`and they just look at it and they wonder why this
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`15
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`person is kind of losing s~ight control and has to
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`sit down. There is also almost a social aspect
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`17 with fear of cataplexy that can occur at any time,
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`any moment and, yes, it is a very significant
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`problem.
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`Again, it is a balancing act because t~e
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`drugs that we use are somewhat effectlve but they
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`t~ave all these sid~ effects and you just have to
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`choose between two evils.
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`I am pretty sure that,
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`for example, GHB, based on my relatively limited
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`experience, has less side effects than
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`anticataplectic classical tricyclic
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`antidepressants, and that a lot of patients wou:ct
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`prefer to take GHB even for partial cataplexy.
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`DR. PENIX: The case that you showed of
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`the nine-year child I assume is complete cataplexy
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`DR. MIGNOT, Yes.
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`DR. PENIX:
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`-- but you are also saying
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`that patients with partial cataplexy have a
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`significant impairment of their life.
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`11
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`DR. MIGNOT: Absolutely. But, as Dr.
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`12 Black mentioned, it is not an "all or none.''
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`I
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`13 mean, most patients, the ones that are complete,
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`14
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`have a lot of partial cataplexy. You never know
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`how bad it is going to be. Most of them are small,
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`little attacks, and sometimes they may even be
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`perceived only by the patient. Sometimes the face
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`may melt; the head drops. Sometimes they just have
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`to sit down; sometimes they don't have to sit. down.
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`I showed a young kid because it is more dramatic,
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`but you would see the same thing in some of the
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`patients with pa~tiu.l cataplexy occasionally.
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`DR. BLACK:
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`I am realizing that a
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`definition may be useful here.
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`In general when we
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`were describing patients who documented the partial
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`versus complete, we told them to t~ink about
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`complete as an episode where t~1ey fall to tb..e
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`ground with complete paralysis or where, if they
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`ground with complete paralysis. Otherwise,
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`anything else is partial -- so, slurred speech,
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`head drops, di·opping things are the pa~·t ials, and
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`those become very important for quality of life and
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`daytime performance. Driving, those kinds of
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`things can become a very significant event for
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`partials.
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`DR. MIGNOT: Yes, one thing I should also
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`emphasize is that in a very large number of series
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`that, for example, have analyzed several hundred
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`patients with narcolepsy and cataplexy, as a mean
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`the large majority of patients have several attacks
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`per day, several attacks per week. Between several
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`attacks per day and several attacks per week, that
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`is generally parti.al or complete attacks and it is
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`not something that appears just once, you know,
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`every ten yea!.·s.
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`It is real~y something that
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`occurs regularly and sometimes totally
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`unexpectedly.
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`DR. KAWAS: Dr. Falkowski?
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`DR. FALKOWSKI: That leads me to a
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`question just for clarification. For the p'..Irposes
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`of these clinical trials, were the cataplectic
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`events something that was just perceived by the
`
`patient. and recorded in a diary, o~· were they
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`verified by some third party?
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`DR. REARDAN: These were tuken from
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`patient diaries. So, it is patient recorded
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`episodes.
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`DR. HAGAMAN:
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`I am Dr. Hagaman and I just
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`10 wanted to address the partial versus the complete
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`11
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`cataplectic events.
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`I think that you have to take
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`it on an individual basis. We have patients that
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`come in that are teenagers that have tests in front
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`of them and they have a partial cataplectic event
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`and they drop their pencil; people that cut hair
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`16
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`that have scissors in their hands and they drop
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`their scissors. So, even though they huve not had
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`a complete event, this has been a very debilitating
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`19
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`event in their lives. So, it is a continuum and I
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`think you just have to really look at each person
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`as an individual and what they are doing.
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`DR. KAWAS: Dr. Dyer?
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`DR. DYER: How variable in the sume
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`patients a~e the number of cataplectic attacks per
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`week? W!"lat is the variance in that?
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`a bit.
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`DR. MIGNOT: We have looked at that q~1ite
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`3 Actually, I did some diaries in a iarge number of
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`patients with cataplexy.
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`It is really totally
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`unpredictable and that is one of t~e most scary
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`parts about cataplexy when you have narcolepsy. Of
`
`course, if something emotional is going to happen,
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`say a patient is going to go to a wedding, often
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`they will kind of fear that event much more because
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`they think it is very likely that they are going to
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`have cataplexy in front of everyone and, indeed,
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`they may actually have a lot more cataplexy because
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`it is an emotional event.
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`Still, I have followed, for example,
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`patients and sometimes they may have like 80 for
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`one week and then the following week they may have
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`only three or four.
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`I mean, it can really vary
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`quite a bit. And, one of the main reasons is
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`really that emotion is something that is very
`
`variable.
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`In fact, someone mentioned how easy it
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`is to observe cataplexy.
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`It is very difficult to
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`get it on tape because typically t~e patient come
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`to your office; he really wants to show you what it
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`is but, you know, he is tense a~d it just will not
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`occur but as soon as he leaves the office and
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`something happens -- boom, he- is going to collapse.
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`So, it is very difficult to predict and it is quite
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`variable.
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`DR. ROMAN,
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`For Dr. Mignot also, you
`
`5 mentioned that cataplexy p~obably is the result of
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`7
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`8
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`9
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`what you called dissociated REM. However, if I
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`recall correctly, the polysomnographi.c unalysis has
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`shown that Xyrem actually decreases the amount of
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`REM sleep and increases delta sleep. Would you
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`10
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`like to speculate on what could be the mechanism of
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`11
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`action to .improve the cataleptic component?
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`DR. MIGNOT: That is a very, very
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`difficuJt question. One of the difficult
`
`questions, of course, is the mode of action of GHB.
`
`I have looked into it myself for quite a while
`
`because I was trained as a pharmacologist, and it
`
`is not clear. There are two camps.
`
`Some people
`
`think it acts on GHB receptors, specific receptors;
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`ot.hers think that it acts th~·ough tl~e GABA-B
`
`receptors. We know that it has some st-rong effect
`
`on dopamine transmission.
`
`If you inject GHB in
`
`animals the rate of activity of dopamincrgic cells
`
`shuts down and dopamine can inc2·easc in the brain
`
`proportionally to the dose. We hav€ done quite a
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`25
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`bit. of .studies that have s~owr: t.h-3.t t~e
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`dopaminergic system is very import.ant to regulate
`
`both wakefulness ar.d also cataplexy and the
`
`regulation of emotion.
`
`I be~ieve it is by changing
`
`the balance of the dopaminergic system, that
`
`improves cataplexy the following day maybe by
`
`increasing dopamine in the brain during the night,
`
`but this is highly speculative and a lot more
`
`research needs to be done.
`
`The fact that it does not increase REM
`
`first, it is quite variable because some studies
`
`have shown that it does increase REM and this
`
`contrasts dramatically with what all hypnotics do.
`
`If you take MVN or all the other
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`benzodiazepine-like hypnotics, what they do is
`
`actually, rather, reduce slow wave sleep and reduce
`
`REM sleep. Xyrem doesn't do that.
`
`It actually
`
`promotes slow wave sleep and, if anything, would
`
`promote REM sleep or doesn't change it. That is
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`still, you know, much more in the right direction
`
`of promoting normal sleep, including REM sleep.
`
`The last comment I want. to mention is that.
`
`it is not sufficient -- if you know a lot about
`
`narcolepsy, it is not sufficient to just explain
`
`narcolepsy as a disorder of RE~ sleep.
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`Indeed,
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`they have all this transition to aEM sleep but they
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`also have impaired wakefulness per se. For
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`example, if you do MSLTs they don't always go into
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`RF.M. They will often just foll asleep into no~mal
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`sleep. So, it is not only REM sleep that is
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`disregulated in narcolepsy, it is also wakefulness
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`and by improving slow wave sleep you presumably
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`also can improve the wake aspect of narcolepsy. My
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`answer may be a little complicated but I would be
`
`happy to discuss it in more detail.
`
`DR. KAWAS: Dr. Van Belle?
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`DR. BLACK:
`
`Just another comment on that,
`
`the Broughton study showed an increase in REM at a
`
`lower dose. The first dose of the SXB-20 that I
`
`participated in showed at 4.5 g the first night an
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`15
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`incn=~ase in REM, which was then followed by a
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`16
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`do.£:;e ·related decrease in REM over time, which is
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`17
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`vet·y different from REM suppressant agents where
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`24
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`th~~rt-:: is a robust, or in fact. t.he largest effect
`
`that can often be seen on th·= first night of
`
`administration.
`
`So, we don't know exactly why it is that
`
`ove~ time the REM with highe: doses is reduced, and
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`wt:y with the first dose, and with the lower doses,
`
`as hus beer. demonstrated here with Rage~
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`25
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`Bro~qhton's work, why the REM is increased. There
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`has been established sort of a competitive reaction
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`Dctween slow wave sleep and :;!F.t-1 sleep.
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`!t appea~s
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`that there may be factors that regulate sJ.ow wave
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`sleep that also are important in regulating the
`
`appearance, or lack thereof, of REM sleep.
`
`It. may
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`be that gama hydroxybutyrat.e is sort of normalizing
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`slow wave activity which then results in a more
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`normal control or regulation of the REM or
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`REM-related events.
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`DR. KAWAS, Can r ask for my
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`clarification, what dose the company is proposing?
`
`DR. REARDAN: Bill, can you take that
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`question?
`
`DR. HOUGHTQ~, Yes, the dosage regimen
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`that we are proposing is that patients be started
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`at 4.5 g and then titrated between the range of 3·9
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`g to clinical efficacy. Although in the stricteBt
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`18 mathematical sense the only statistical efficacy in
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`19
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`the GHB-2 study was clearly defined at 9 g, that
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`20
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`21
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`22
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`23
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`may well represent that the study was too short
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`b€cause
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`in the open-label study that followed, as ~
`
`showed, the maximum nadir occurred at 8 weeks, and
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`w~en those patients were followed over t~e course
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`~~
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`of 12 months they maintai~ed efficacy across the
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`25
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`dose range. Certainly, there i.s an advantage in
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`terms of the important side effects to dose
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`titration.
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`In all of the treatment IND protocols
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`and the safety studies the data was generated at
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`between 3-9 g. Now, 80 percent of the patients
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`were maintained between 6 g and 9 g, but there was
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`certainly facility for down-titration from the 4.5
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`or maintenance there as well.
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`DR. KAWAS: Thank you. Dr. Van Belle?
`
`DR. VAN BELLE:
`
`It seems to me that there
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`is reasonable agreement with respect to efficacy
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`for cataplexy at least between the FDA and the
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`sponsor. So, I would like to get back to the
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`secondary endpoints.
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`I would like to ask a
`
`question to the sponsor's statistician, Dr. Trout.
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`15
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`as to whether he thinks that multiple comparisons
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`is a problem. Secondly, if multiple comparisons
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`are a problem, how he would adjust.
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`DR. REARDAN: Do you want to put this in
`
`relation to a specific trial or all the trials in
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`general?
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`DR. VAN BELLE, Well,
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`I bring it up in
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`connection with the analysis of Dr. Mani w~ere he
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`clearly comes to ccnclusions that differ from yours
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`with respect to th~ efficacy of some of these
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`secondary endpoints.
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`DR. TROUT: You know, it is ha1·d to answer
`
`that question.
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`I think the way I would answe:r- t~1at
`
`is as follows: The GHB-2 analysis, the results
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`that we found and also that were expressed eor1ier
`
`5 were very strong. So, even with the fact thut
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`6
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`7
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`8
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`9
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`there is some multiplicity, we also have, remember,
`
`some other outcome measures which were related to
`
`this particular general area in terms of daytime
`
`sleep attacks. So, there were at least two
`
`10 measures that suggested improvement with respect to
`
`11
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`12
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`13
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`14
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`15
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`that particular outcome.
`
`The other second study that has been
`
`discussed is the Lammers study, and that study is
`
`obviously much smaller.
`
`It is obviously a weaker
`
`study, and there is some issue with regard to
`
`16 whether the appropriate method of analysis was
`
`17
`
`18
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`19
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`20
`
`21
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`22
`
`2 3
`
`:24
`
`there. So, I think that is a harder one to
`
`address.
`
`Now, there are two kinds of multiplicity
`
`going on here, which you are well aware of. One is
`
`the multiplicity with regard to the multiple dosing
`
`levels and that was accounted for in ou~ analyses.
`
`The question that was brought up by Dl·. Mani wi. th
`
`regard to the multiplicity of secondary endpoints,
`
`25
`
`and I am not a betting man but I think tl:crc is
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`certa:i.nly evidence to suggest that daytime
`
`sleepiness is being affected possibly. But I don't
`
`go to Las Vegas nor Atlantic City.
`
`DR. KAWAS: Actually, while we have Dr.
`
`Trout up, T would ask him with regard to excessive
`
`sleepiness on the Epworth Scale in the GHB-2 study,
`
`7 while there certainly was a difference in the two
`
`8
`
`9
`
`groups, there were also major baselir.e differences
`
`in sleepiness for the responders and the
`
`10
`
`non-responders.
`
`In fact, those that appP.ared to
`
`11
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`22
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`23
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`24
`
`respond had a baseline that was better than the
`
`improvement in the other group. There was a
`
`significant difference. Are you conccrr.ed about
`
`these and how these might affect the :r·esuJ.t.s?
`
`DR. TROUT: There is always concern about
`
`baseline differences, and that was attempted to be
`
`accounted for in two mechanisms, one, WP.
`
`looked at
`
`change from baseline and we also did a covariate
`
`adjustment to try to account for that.
`
`DR. KAWAS: Dr. Katz?
`
`DR. KATZ:
`
`I would like to ask Dr. Trout a
`
`question also. Dr. Yan mentioned that we didn't
`
`believe that the data were no~·mally dist!:ib":Jted,
`
`and when you transformed the data it didn't. really
`
`25
`
`help very much.
`
`I don't want to get bogqed down in
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`a hyper-arcane discussion abO":.It no!·mu.lly
`
`distributed data, but when we did thut. we got a p
`
`value for that comparison -- I guess it was the
`
`Epworth, of about 0.01
`
`DR. MANI'
`
`I am sorry, it wasn't the
`
`Epworth. You are talking about the Lammers study
`
`where you are talking about the frequency --
`
`I thought we were talking about
`
`GHB-2.
`
`DR. MANI: Oh, sorry, fine.
`
`DR. KATZ:
`
`So, if we are right, it takes
`
`the p value which was 0.0001 or something like that
`
`to 0.01, and then when you get to the multiple
`
`comparisons issue it makes it less weak. I agree if
`
`15
`
`you take a p value of 0.001 or 0.000.1, no matter
`
`16 what you do to it as far as a multiple comparison,
`
`17
`
`18
`
`it is still going to be significant. But if it is
`
`0.01 it is a little different story. So, T am just
`
`19 wondering, again without getting into excruciating
`
`20
`
`details, what about this question of the data being
`
`21
`
`22
`
`23
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`24
`
`25
`
`normally distributed and not necessarily being
`
`improved very much by transforming it?
`
`Is there
`
`common agreement about that or not?
`
`DR. TROUT: My recollection, and it has
`
`been sometime since I have seen the results of the
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`analysis, is that it suggest~d that we didn't sec a
`
`particular problem with the r.o'!'.·mal di.st.:i.buti.on as,
`
`for example, was the case with cataplexy which was
`
`clear.
`
`I am not sure if Dr. Yan did a
`
`nonparametric covariance analysis or not.
`
`I
`
`haven't seen those analyses. And,
`
`I think the
`
`point was made earlier that that would be, I think,
`
`an appropriate thing to do in order to account for
`
`some potential baseline differences.
`
`If she did,
`
`then whcth~r it is a reflection of a decreased
`
`sensitivity of a nonparametric analysis or whether
`
`it is a normal distribution -- I can't answer that
`
`13 without seeing the data. Maybe it was just a
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`standard, nonparametric analysis which might help
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`account tor the difference.
`
`[Comment away from microphone; inaudible]
`
`DR. TROUT: No,
`
`I know that but Dr. Yan
`
`did a nonpa.rametric analysis bec;;~use she was
`
`concerned a. bout the normality, and d i.d look at the
`
`log transformation and it didn't have any impact on
`
`t!lat, w:-tich doesn't surprise me at all.
`
`::JR. KAWAS:
`
`I would 1 ike to ask the
`
`sponsor, I mean, there clearly was a dose
`
`re:!.a.tion;::;hip in terms of the adverse events. Were
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`25
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`any othAr factors looked at that may bP. related to
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`1
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`the adverse event profile, things like age, ever.
`
`previous psychiatric history, ott1er medications?
`
`3 Whether or not they drank alcohol? Anything?
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`4
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`6
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`7
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`8
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`9
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`DR. HOUGHTON: No, we didn't go as far as
`
`an alcohol history. Certainly for the major
`
`psychiatric, a preexisting history of major
`
`psychiatric disease emerged. Major psychiatr)c
`
`disease was actually a protocol exclusionary
`
`criterion, but in those that, for instance
`
`10
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`attempted suicide, post-study it was discovered
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`that they had a previous psychiatric history and in
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`actual fact in one of the patients a previous
`
`suicide attempt had been made. There was major
`
`depressive disease reported in those, but for those
`
`who developed psychosis there was definite recorded
`
`preexisting psychiatric history.
`
`In terms of age, we haven't done a
`
`breakdown of the database, and in most instances
`
`there was not a dose relationship. There were just
`
`instunces that were mentioned in the presentation.
`
`Confusion and sleepwalking suggested a dose
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`relationship.
`
`In the GHB-2 protocol which was
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`23
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`obviously blinded, there was the ussociation with
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`m3

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