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Xywav: Does first to approval mean first-line treatment?

Dr Lynn Marie Trotti, clinician and researcher at Emory University wrote a paper recently that was published in the Lancet, Idiopathic hypersomnia: does first to approval mean first-line treatment? Click here to read Dr Trotti's commentary in full. If you have a problem accessing this link please let us know at info@hypersomnolenceaustralia.org.au and we will send you a copy. Dr Trotti's article is in response to a paper that was published in the same edition of the Lancet, Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study You may have seen press statements that Jazz Pharmaceuticals have made online where they make various claims about the results of this study. When reading this paper and Jazz's various statements please keep in mind that the paper was written by Jazz representatives and that the study was funded by Jazz. With regards to one of Jazz's statements they say "New clinical trial data shows that the medication Xywav, produced by Jazz Pharmaceuticals, significantly reduces the long sleep duration, sleep inertia, and excessive daytime sleepiness that are typical hallmarks of the sleep disorder idiopathic hypersomnia." Dr Trotti points out in her commentary that it would be difficult to know whether Xywav (lower sodium oxybate) had this effect on the majority of the study participates because more than half of them were still taking their regular wake promoting medications during the trial. "...the study cohort was not restricted to treatment-naive participants; rather, more than half of enrolled participants were taking wake-promoting medications and using lower-sodium oxybate as an adjunct treatment." Also, while it is possible that Xywav may reduce long sleep duration and sleep inertia this study didn't really demonstrate that because less than a quarter of the study participants had idiopathic hypersomnia with long sleep. Only 13 people with idiopathic hypersomnia with long sleep were part of the 'lower sodium oxybate' (Xywav) group. The authors mention this was a limitation of their study. They also said "The study included participants with and without long sleep time; thus, the population might be non-uniform. [27]". Reference 27 is "Diagnosis of central disorders of hypersomnolence: a reappraisal by European experts." Two of the authors of this paper are also authors of the recent Xywav paper, in fact one of them, Dr Yves Dauvillers, was the lead investigator and author of the Xywav study. In Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts paper the authors claim that idiopathic hypersomnia with long sleep is a separate disorder from idiopathic hypersomnia without long sleep. They "propose and define three diagnostic categories 1. "Narcolepsy" 2. "Idiopathic hypersomnia", 3. "Idiopathic excessive sleepiness". The "Idiopathic hypersomnia" category would include idiopathic hypersomnia with long sleep only. The third category, "Idiopathic excessive sleepiness" would include what is currently referred to as idiopathic hypersomnia without long sleep and narcolepsy type 2. Another paper, To split or to lump? Classifying the central disorders of hypersomnolence published around the same time as Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts also suggests that idiopathic hypersomnia with long sleep is a separate disease entity to idiopathic hypersomnia without long sleep. The authors of this paper also propose that idiopathic hypersomnia with long sleep should be a category of its own and that idiopathic hypersomnia without long sleep and narcolepsy type 2 should be grouped together in a separate category. So how much of this Xywav paper really relates to idiopathic hypersomnia if so few of the participates have idiopathic hypersomnia as defined by Dr Yves Dauvilliers himself and 20 of the other world's IH and narcolepsy researchers? There are other limitations of the Xywav study. Dr Trotti does a great job of pointing some of those out including the problem with randomised withdrawal trials. In this type of trial everyone tries the medication and then some are taken off it and put on placebo. There are a number of obvious issues with this including, "The lower-sodium oxybate study was a randomised withdrawal trial... In the study by Dauvilliers and colleagues, placebo exposure lasted only 2 weeks, despite dose optimisation extending up to 14 weeks. However, randomised withdrawal trials can also amplify differences between placebo and active treatment beyond what would be seen in parallel-group randomised controlled trials, by participant enrichment, placebo unmasking, and rebound effects." Also, "Enrichment of the study population for responders who tolerate medication is an intentional feature of randomised withdrawal trials. In the study by Dauvilliers and colleagues, 115 (75%) of 154 participants starting on lower-sodium oxybate continued to randomisation (six discontinued without benefit, 22 because of adverse events, and ten for other reasons). Thus, the lower sodium oxybate study estimated treatment effects in the three-quarters of participants who tolerated and benefitted from the medication, whereas (in previously carried out) modafinil randomised controlled trials estimated effects without such enrichment". And "Change to placebo can also result in inadvertent unmasking, because of the sudden absence of benefit or sudden absence of side-effects. Rapid loss of benefit in a randomised withdrawal trial might be more noticeable than gradual gain of benefit in a traditional randomised controlled trial. The corresponding loss of the placebo effect in those who are unmasked can then magnify treatment–placebo differences... the randomised withdrawal trial design could not guard against loss of the acute symptomatic effects of lower-sodium oxybate. Blinding questionnaires were not used in the study by Dauvilliers and colleagues, although they might help estimate the magnitude of unmasking in randomised withdrawal trials... ...in randomised withdrawal trials, symptomatic worsening in the placebo group can be exacerbated by drug rebound or withdrawal effects, further amplifying differences between placebo and treatment. Whether people with idiopathic hypersomnia might have rebound worsening of symptoms on lower-sodium xybate discontinuation, particularly on global scales such as the Patient Global Impression, is unknown... comparisons of randomised controlled trials and randomised withdrawal trials in other chronic diseases suggest that randomised withdrawal trials can increase differences between placebo and treatment and underestimate adverse events." Other limitations include, "No objective measures of sleepiness were employed". "No head-to-head comparison with any other active medication was done in this study". The positive of this trial by Dauvilliers and colleagues is that it recognises a condition that has long been poorly understood and, under-recognised and undertreated. However, "much work remains to establish how lower-sodium oxybate compares with other available treatments and how best to personalise treatment for patients" with all types of disorders of hypersomnolence. Studies that focus specifically on each of the hypersomnolence categories is also needed so that we have a clearer picture of what medications are best for each category rather than a one size fits all approach.

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