{"id":23458,"date":"2012-05-18T23:45:50","date_gmt":"2012-05-19T03:45:50","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=23458"},"modified":"2012-05-19T06:37:39","modified_gmt":"2012-05-19T10:37:39","slug":"sleight-of-hand","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2012\/05\/18\/sleight-of-hand\/","title":{"rendered":"(sleight of hand)2<\/sup>…"},"content":{"rendered":"
I had sworn off vetting any clinical trials or meta-analyses for a while, but sometimes something special comes along. Neuroskeptic<\/font><\/strong><\/u><\/a> has already had his way with this one, but it had some features that seemed worthy of note. It’s a failed study [and how were they going to write JNJ-18038683<\/font><\/strong> on a pill anyway?]: <\/div>\n
\n
Translational evaluation of JNJ-18038683, a 5-HT7 receptor antagonist, on REM sleep and in major depressive disorder<\/font><\/strong><\/u><\/a>
by Pascal Bonaventure, Christine Dugovic, Michelle Kramer, Peter De Boer, Jaskaran Singh, Sue Wilson, Kirk Bertelsen, Jianing Di, Jonathan Shelton, Leah Aluisio, Lisa Dvorak, Ian Fraser, Brian Lord, Diane Nepomuceno, Abdellah Ahnaou, Wilhelmus Drinkenburg, Wenying Chai, Curt Dvorak, Steve Sands, Nicholas Carruthers, and Timothy W. Lovenberg<\/sup>
Journal of Pharmacology and Experimental Therapeutics<\/font><\/strong>
Published on-line May 8, 2012. [full text on-line] <\/div>\n

<\/p>\n

In rodents, 5-HT7 receptor blockade has been shown to be effective in models of depression and to increase the latency to REM sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT7 receptor antagonist, JNJ-18038683. In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers, JNJ-18038683 prolonged REM latency and reduced REM sleep duration demonstrating that the effect of 5-HT7 blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double blind, active- and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or citalopram separated from placebo indicating a failed study lacking assay sensitivity. A post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group MADRS<= 12] and from sites with no placebo response [MADRS>=28] are removed, there was a clinically meaningful and statistically significant difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.<\/sup><\/div>\n
 <\/div>\n<\/blockquote>\n
One would think, looking at that graph, that you might just put JNJ-18038683<\/font><\/strong> back on the shelf and move on to something else. This Clinical Trial<\/font><\/strong><\/u><\/a> dates back to 2007 and changed more times than Elizabeth Taylor changed husbands. Neuroskeptic<\/font><\/strong><\/u><\/a> noted that they seemed to change the name of the active comparator from escitalopram to citalopram back and forth in the text. That was about the only thing that didn’t change during the Clinical Trial according to clinicaltrial.gov [it was always escitalopram though it was published as citalopram]. And it was an all in house show – all 21 authors were JNJ employees.<\/div>\n

<\/p>\n

For starters, notice that they used all the graph pretty-fication tricks: mean change instead of raw scores, standard error rather than standard deviation bars, leaving off that it was last observation carried forward [LOCF] corrected. Standard fare. Recall that a positive study<\/font><\/strong> is when a drug and the active comparator separate from placebo. A negative study<\/font><\/strong> is when a drug doesn’t separate but the active comparator does. And a study where neither drug nor active comparator separates from placebo is a failed study<\/font><\/strong> – money down the drain and usually an indictment of the state of the clinical research industry and their recruitment methods. But this study added something new to me – a population enrichment window<\/em> strategy. Says Neuroskeptic<\/font><\/strong><\/u><\/a>:<\/div>\n
\n
Ouch! But it gets better. Unhappy that JNJ-18038683 bombed, Janssen reached for their copy of the Cherrypicker’s Manifesto<\/a><\/strong>. This is a new statistical method, proposed by fellow Pharma company GSK in a 2010 paper<\/strong><\/a>, which consists of excluding data from study centres with a very high [or very low] placebo response rate.<\/p>\n

Anyway, after applying this "filter" JNJ-18038683 seemed to do a bit better than placebo, but the benefit over placebo still wasn’t statistically significant –<\/em> with a p value of 0.057, the wrong side of the sacred p=0.05 line [on page 33].
Yet Page 33’s "trend towards statistical significance" magically becomes "significant" – in the Abstract:<\/sup><\/div>\n