{"id":259,"date":"2014-06-09T04:03:03","date_gmt":"2014-06-09T04:03:03","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=259"},"modified":"2014-08-31T16:26:22","modified_gmt":"2014-08-31T20:26:22","slug":"trial-pains-secondary-to-placebo-effect","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2014\/06\/09\/259\/trial-pains-secondary-to-placebo-effect\/","title":{"rendered":"Trial Pains Secondary to Placebo Effect?"},"content":{"rendered":"
\"morphine\"<\/a>
Morphine<\/figcaption><\/figure>\n

An interesting report has just been published showing that Naloxegol is beneficial in OIC [i].\u00a0 Naloxegol is a \u00b5 opioid receptor (MOR) antagonist which \u2013 by virtue of pegylation \u2013 acts peripherally and not centrally.\u00a0 Hence, the analgesic effects of opioid therapy are unaffected while the very bothersome side effect of constipation can be overcome.<\/p>\n

<\/p>\n

Overcome?\u00a0 Not really when you look at the numbers.\u00a0 After all, only patients in the higher-dose treatment arms had an increase of 1 (sic!) more SBM \/ week than controls.\u00a0 Hardly a normalization of bowel activity (but better than nothing, presumably).<\/p>\n

However, some other information provided in the Naloxegol article merits attention.<\/p>\n

#1 – A consistently high placebo effect:<\/span><\/h4>\n

In the Naloxegol trials, exactly 29% of study participants in the placebo arm were \u2018responders\u2019.\u00a0 In an earlier Phase 2 trial, the placebo success rate was even higher, at 35%[ii].\u00a0 This despite rather tough endpoint criteria for \u2018response\u2019 which require \u2265 3 SBMs during \u2265 9 of 12 weeks of observation, plus several other measures of improvement.\u00a0 Now these were the same patients that consistently had < 3 SBMs during their 4-wk run-in period, and no response to laxatives.\u00a0 One would think only severely constipated patients were selected in the screening process.\u00a0 Nonetheless, some 30% obviously had spontaneous improvement in bowel function whilubiprostle receiving only placebo.<\/p>\n

Actually this does not come as a total surprise.\u00a0 Other well-controlled OIC trials have come up with similar data.\u00a0 For instance, patients on placebo in Alvimopan (Entereg\u00ae) studies showed a positive response in approx. 40%.[iii]\u00a0 While endpoints and FDA stipulated criteria for \u2018responders\u2019 have changed very dramatically in recent years, high placebo responses have remained a consistent finding in OIC drug trials.\u00a0 Only in the lubiprostone (Amitiza\u00ae) 12-wk studies a\u00a0lower placebo response rates of approx. 19% was found.<\/p>\n

What does this mean?\u00a0 Clearly it shows that we are unable to select true non-responders with any kind of predictive accuracy.\u00a0 Even rigorous enrollment criteria are unable to identify those patients that would only respond to an MOR antagonist.\u00a0 Should we raise the bar further when selecting patients?\u00a0 Should we require complete normalization of bowel function as an endpoint?\u00a0 I think a sensitivity analysis that better defines true non-responders and a better understanding of the natural course of OIC and its presentation over time would help reduce the number of placebo responders.\u00a0 This is a testable hypothesis.<\/p>\n

We have certainly made enrollment very difficult by implementing criteria that are not of much value.\u00a0 This looks like an effort driven by what makes sense conceptually but turns out to be just burdensome.<\/p>\n

Case in point, the Phase 3 trial program for naloxegol.<\/p>\n

#2 – A huge effort to find the \u2018right\u2019 patients:<\/span><\/h4>\n

Why did it take 257 study sites and 19 months to find 1352 ITT-evaluable OIC patients?\u00a0 This amounts to a yield of only 5 patients per center, on average, during the entire trial.\u00a0 Admittedly, 2 out of 3 patients screened did not meet entry criteria after the run-in period and therefore did not get randomized. \u00a0As discussed above that screening effort did not buy much reduction in background noise but surely created much work for the sponsor and CRO.<\/p>\n

Still for a condition as common as OIC any screening process should be easy and fast, right?<\/p>\n

I guess this is a wrong assumption, too.\u00a0 Logical assumptions can be so misleading in the real world.<\/p>\n

————————————————————————————-<\/p>\n

UPDATED 8\/14\/2014:
\n– Naloxegol\u2019s PDUFA date was\u00a0originally\u00a0set for June 11, 2014, but is now Sept. 16, 2014
\n– Naloxegol brand name = \u00a0Movantik\u00a0\u00ae<\/p>\n

 <\/p>\n

Abbreviations<\/strong><\/p>\n

ITT\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 intent-to-treat population
\nOIC\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 opioid-induced constipation
\nSBM\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 spontaneous bowel movement<\/p>\n

 <\/p>\n

\u00a0References<\/strong><\/p>\n

[i]\u00a0 Chey, NEJM 2014; Online First, June 4, 2014
\n[ii] Webster, Pain 2013; 154: 1542
\n[iii] Ford, Am J Gastroenterol 2013; 108:1566<\/p>\n","protected":false},"excerpt":{"rendered":"

An interesting report has just been published showing that Naloxegol is beneficial in OIC [i].\u00a0 Naloxegol is a \u00b5 opioid receptor (MOR) antagonist which \u2013 by virtue of pegylation \u2013 acts peripherally and not centrally.\u00a0 Hence, the analgesic effects of opioid therapy are unaffected while the very bothersome side effect Continue reading Trial Pains Secondary to Placebo Effect?<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":261,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[18],"tags":[97,106,104,98,99,105,109,461,94,100,107,101,108,102,96,95,103],"class_list":["post-259","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_viewpoint","tag-alvimopan","tag-amitiza","tag-enrollment-dynamics","tag-entereg","tag-fda-guidance","tag-lubiprostone","tag-mor-antagonist","tag-movantik","tag-naloxegol","tag-oic","tag-opioid-side-effect","tag-opioid-induced-constipation","tag-peripheral-opioid-antagonist","tag-phase-3","tag-placebo-effect","tag-sbm","tag-study-size"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/06\/Rodin.jpe","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-4b","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":722,"url":"https:\/\/allphasepharma.com\/dir\/2014\/08\/15\/722\/some-curious-tidbits\/","url_meta":{"origin":259,"position":0},"title":"Some Curious Tidbits","author":"Harald","date":"August 15, 2014","format":false,"excerpt":"Were you aware\u00a0that... there is also an amphotericin A which has antifungal properties? \u00a0It has a broader spectrum but is much less potent than Amphotericin B and therefore not being used. 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