{"id":69628,"date":"2016-12-23T21:16:51","date_gmt":"2016-12-24T02:16:51","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=69628"},"modified":"2016-12-23T21:16:51","modified_gmt":"2016-12-24T02:16:51","slug":"explanation-would-be-welcome","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/12\/23\/explanation-would-be-welcome\/","title":{"rendered":"explanation would be welcome…"},"content":{"rendered":"\n

I’ve been writing about Rapastinel<\/font>, an NMDA receptor partial blocker<\/font><\/em> touted to have Ketamine’s<\/font><\/em> antidepressant effects without being a psychomimetic [see a touch of paralysis…<\/a> and a block-buster-in-training…<\/a>]. It was developed by a Northwestern University neuroscientist who formed a private company [Naurex], later purchased by industry giant Allergan<\/font> for $560 M. They’ve recently registered four phase 3 clinical trials<\/a> – all now recruiting<\/font><\/strong>. Before discussing these trials, here’s a bit of a review. <\/p>\n\n\n
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A properly conducted clinical trial has a number of essential elements related to the efficacy analysis: <\/div>\n
    <\/p>\n
  1. \n
    Subjects are assigned to the various arms at random.<\/font><\/div>\n<\/li>\n
  2. \n
    It is blinded – neither subject nor rater knows the subject’s assigned arm.<\/font><\/div>\n<\/li>\n
  3. \n
    The outcome variables [primary and secondary] are declared a priori<\/em> [before the study begins] as is the plan for later analysis.<\/font><\/div>\n<\/li>\n

    <\/span><\/ol>\n

    Many clinical trials have been misreported in journal articles, and a common modus operandi for distorting the results has been to base the report on the outcome variable that give the most favorable results rather than those declared a priori<\/font><\/em>. Since the pharmaceutical companies that sponsor these trials insist that the raw data is proprietary [a secret], we don’t have the IPD [Individual Participant Data]<\/font>, the CRFs [Clinical Report Forms]<\/font>, the Protocol<\/font>, or the SAP [Statistical Analysis Plan]<\/font>. So our only shot at knowing what outcome variables were designated primary and secondary a priori<\/font> is the registration on ClinicalTrials.gov<\/font>.<\/font><\/em> And even registration is only useful if it’s before the study starts and the outcome variables are clearly stated.<\/div>\n<\/td>\n<\/tr>\n<\/table>\n

    And so to the Rapastinel Phase 3 trials. Three of the four are virtual clones of each other, differing only in the number of subjects [why?] and one has a second dose level. They all have the same cohort – subjects in a Major Depressive Episode that "[h]ave no more than partial response [< 50% improvement] to ongoing treatment with a protocol-allowed antidepressant.<\/font><\/em>" These three trials call for 4589 total subjects who have failed to respond to SSRIs, documented by a less that 50% response on some unspecified rating scale after a course of an antidepressant from some unspecified list of drugs. That’s a huge cohort<\/u> and it’s unclear why so many. There’s no power analysis included to explain it. Likewise, there’s a huge number<\/u> of sites [134]. I even wondered if they are piggy-backing on the end of a bunch of somebody else’s antidepressant trials to get cases? Some kind of explanation would be welcome.<\/p>\n

    <\/p>\n

    This is a medication that is given intravenously and the antidepressant effect lasts ~one week in the proof-of-concept study [see a block-buster-in-training…<\/a>], so they call for weekly injections. Here’s all<\/font> they have to say about the conduct of the study and the primary and secondary outcome variables:<\/p>\n