{"id":16381,"date":"2011-11-28T21:07:33","date_gmt":"2011-11-29T02:07:33","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=16381"},"modified":"2011-11-28T23:13:13","modified_gmt":"2011-11-29T04:13:13","slug":"in-the-shadows","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2011\/11\/28\/in-the-shadows\/","title":{"rendered":"in the shadows…"},"content":{"rendered":"
After the post about Quintiles [an invisible empire II…<\/font><\/a><\/strong><\/u>], I recalled Amir Kalali’s<\/strong><\/font> name from somewhere else – the Latuda [Lurasidone] Trial I was writing about a few months back [ought to know by now…<\/font><\/em><\/a><\/em><\/strong><\/u>]. Over the Thanksgiving holiday while off visiting, I read it again for signs of Quintiles’ presence. Not much shows in the article itself. But this morning, I left Raleigh for the eight hour trek back to Georgia, and there it was! a big building in the Research Triangle Park sitting by the Interstate that said Q<\/font>uintiles<\/font><\/strong> on top. It was easier to find Quintiles on I-40 without even trying than it was to find them in the article. So I thought I’d look more closely:<\/div>\n
\n
Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study.<\/font><\/strong><\/u><\/a>
by Meltzer HY<\/font><\/strong>, Cucchiaro J<\/font><\/strong>, Silva R<\/font><\/strong>, Ogasa M<\/font><\/strong>, Phillips D<\/font><\/strong>, Xu J<\/font><\/strong>, Kalali AH<\/font><\/strong>, Schweizer E<\/font><\/strong>, Pikalov A<\/font><\/strong>, and Loebel A.<\/font><\/strong><\/sup>
American Journal of Psychiatry.<\/font><\/strong> 2011 168[9]:957-67.<\/div>\n

<\/p>\n

Objective<\/font><\/strong><\/u>: The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia.
Method<\/font><\/strong><\/u>: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (as the key secondary efficacy measure).
Results<\/font><\/strong><\/u>: Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing ≥7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group.
Conclusions<\/font><\/strong><\/u>: Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg\/day of lurasidone compared with 40 mg\/day.<\/sup><\/div>\n

<\/p>\n

 <\/div>\n<\/blockquote>\n
I assumed that this study was done by Quintiles because Amir Kalali<\/strong><\/font> was named as an author. However, the word "Quintiles" doesn’t appear in the on-line data supplement<\/font><\/strong>, on clinicaltrials.gov<\/font><\/strong><\/a><\/u>, or in the FDA documents<\/font><\/strong><\/u><\/a>. "Quintiles" is mentioned in the full text of the article<\/font><\/strong> in the acknowledgements and as Amir Kalali<\/strong><\/font>‘s employer only – but nowhere else. The article has a CRO footprint – a multinational<\/em> study [US, India, Philippines, Columbia, Lithuania]. Dr. H. Y. Meltzer<\/font><\/strong> of Vanderbilt seems to be the only non-industry author. Dr. E Schweizer <\/font><\/strong>appears to be a paid medical writer ["Dr. Schweizer has received payment for consulting or medical writing services from Alkermes, Orexigen Therapeutics, Pfizer, Sunovion<\/font><\/strong> Pharmaceuticals, and Titan Pharmaceuticals and owns stock in Pfizer<\/em>"] [Paladin Consulting Group, Hoboken, N.J.<\/font><\/strong>].<\/div>\n

So first, about the multinational scope of the trial. This from clinicaltrials.gov<\/font><\/strong><\/a><\/u><\/font><\/strong>, FDA documents<\/font><\/strong><\/u><\/a>, and the full text of the article<\/font><\/strong>: <\/p>\n\n\n\n\n\n\n\n\n\n\n
Country<\/font><\/strong><\/td>\nSubjects<\/font><\/strong><\/td>\nLUR40mg<\/sub><\/font><\/strong><\/td>\nLUR120mg<\/sub><\/font><\/strong><\/td>\nZYP15mg<\/sub><\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
US<\/font><\/strong><\/td>\n284
<\/em><\/font><\/td>\n		p=0.046<\/font><\/strong>
<\/em> <\/td>\n		p=0.183<\/font><\/em><\/td>\np<0.001<\/font><\/strong><\/em><\/td>\n<\/tr>\n
Lithuania<\/font><\/strong><\/td>\n29<\/em><\/font><\/td>\np=0.906<\/font><\/em><\/td>\np=0.188<\/font><\/em><\/td>\np=0.034<\/font><\/strong><\/em><\/td>\n<\/tr>\n
Columbia<\/font><\/strong><\/td>\n48<\/em><\/font><\/td>\np=0.005<\/font><\/strong><\/em><\/td>\np=0.017<\/font><\/strong><\/em><\/td>\np=0.017<\/font><\/strong><\/em><\/td>\n<\/tr>\n
Philippines<\/font><\/strong><\/td>\n26<\/em><\/font><\/td>\np=0.246<\/font><\/em><\/td>\np=0.911<\/font><\/em><\/td>\np=0.061<\/font><\/em><\/td>\n<\/tr>\n
India<\/font><\/strong><\/td>\n88<\/em><\/font><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
MMRM Analysis
<\/font><\/strong> <\/td>\n		475<\/font><\/em> <\/td>\np<0.001
<\/font><\/strong><\/em> <\/td>\n		p=0.011<\/font><\/strong><\/em><\/td>\np<0.001<\/font><\/strong><\/em><\/td>\n<\/tr>\n<\/table>\n
Statistically Significant Values in BOLD<\/strong><\/sup><\/div>\n

My reading of this data is that Lurasidone barely made significance in the US, and without the stellar results in Columbia, it would’ve been a wash overall. Multinational Clinical Trials are a hallmark of the Clinical Research Organizations [CROs]. For one thing, they’re faster [and, I suspect, cheaper]. You can read their position on globalization<\/font><\/em><\/u><\/a> at the Association of Clinical Research Organizations<\/font><\/strong> [ACRO] web site. Also notice the unexpected level of significance in the MMRM Analysis [correction method for drop-outs].<\/p>\n

Next, I wanted to see how close I could get to the raw PANSS totalscores. In the Online Data Supplement<\/font><\/strong>, there was a table of uncorrected mean changes in PANSS scores per time interval, per group:<\/p>\n\n\n\n\n\n\n\n\n\n\n\n
Change in PANSS Score
<\/font><\/strong><\/td>\n<\/tr>\n
Day<\/font><\/strong><\/td>\nLUR40mg<\/sub><\/font><\/strong><\/td>\nLUR120mg<\/sub><\/font><\/strong><\/td>\nZYP15mg<\/sub><\/font><\/strong><\/td>\nPlacebo<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
4<\/font><\/strong><\/td>\n-5.1<\/font><\/td>\n-5.4<\/font><\/td>\n-6.1<\/font><\/td>\n-4.8<\/font><\/td>\n<\/tr>\n
7<\/font><\/strong><\/td>\n-10.4<\/font><\/td>\n-8.7<\/font><\/td>\n-11.0<\/font><\/td>\n-7.2
<\/font> <\/td>\n<\/tr>\n
14<\/font><\/strong><\/td>\n-15.4<\/font><\/td>\n-13.8<\/font><\/td>\n-16.3<\/font><\/td>\n-11.6<\/font><\/td>\n<\/tr>\n
21<\/font><\/strong><\/td>\n-18.5<\/font><\/td>\n-20.9
<\/font> <\/td>\n		-21.7<\/font><\/td>\n-15.6<\/font><\/td>\n<\/tr>\n
28<\/font><\/strong><\/td>\n-22.8<\/font><\/td>\n-25.1<\/font><\/td>\n-25.8<\/font><\/td>\n-18.9<\/font><\/td>\n<\/tr>\n
35<\/font><\/strong><\/td>\n-26.8<\/font><\/td>\n-28.6<\/font><\/td>\n-29.1<\/font><\/td>\n-22.5<\/font><\/td>\n<\/tr>\n
42<\/font><\/strong><\/td>\n-30.5<\/font><\/td>\n-27.3<\/font><\/td>\n-30.8<\/font><\/td>\n-23.6<\/font><\/td>\n<\/tr>\n<\/table>\n

The article itself has the mean baseline PANSS scores<\/font><\/strong>. So applying the reported mean changes in the PANSS from this table to those baseline PANSS scores –<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
Estimated Total Mean PANSS Scores
<\/font><\/strong><\/td>\n<\/tr>\n
Day<\/font><\/strong><\/td>\nLUR40mg<\/sub><\/font><\/strong><\/td>\nLUR120mg<\/sub><\/font><\/strong><\/td>\nZYP15mg<\/sub><\/font><\/strong> <\/td>\nPlacebo<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
0<\/font><\/strong><\/td>\n96.6<\/font><\/td>\n97.9<\/font><\/td>\n96.3<\/font><\/td>\n95.8<\/font><\/td>\n<\/tr>\n
4<\/font><\/strong><\/td>\n91.5<\/font><\/td>\n92.5<\/font><\/td>\n90.2<\/font><\/td>\n91.0<\/font><\/td>\n<\/tr>\n
7<\/font><\/strong><\/td>\n86.2<\/font><\/td>\n89.2<\/font><\/td>\n85.3<\/font><\/td>\n88.6
<\/font> <\/td>\n<\/tr>\n
14<\/font><\/strong><\/td>\n81.2<\/font><\/td>\n84.1<\/font><\/td>\n80.0<\/font><\/td>\n84.2<\/font><\/td>\n<\/tr>\n
21<\/font><\/strong><\/td>\n78.1<\/font><\/td>\n77.0
<\/font> <\/td>\n		74.6<\/font><\/td>\n80.2<\/font><\/td>\n<\/tr>\n
28<\/font><\/strong><\/td>\n73.8<\/font><\/td>\n72.8<\/font><\/td>\n70.5<\/font><\/td>\n76.9<\/font><\/td>\n<\/tr>\n
35<\/font><\/strong><\/td>\n69.8<\/font><\/td>\n69.3<\/font><\/td>\n67.2<\/font><\/td>\n73.3
<\/font> <\/td>\n<\/tr>\n
42<\/font><\/strong><\/td>\n66.1<\/font><\/td>\n70.6<\/font><\/td>\n65.5<\/font><\/td>\n72.2<\/font><\/td>\n<\/tr>\n<\/table>\n

– gives us a graph that is as close to the observed<\/u> mean PANSS Total Scores as I can get without access to the raw data itself:<\/p>\n

<\/p>\n

This American Journal of Psychiatry <\/font><\/strong>article is from Study D1050231, one of five considered by the FDA for in the approval process for Lurasidone [Latuda]. This next table summarizes the results of all [5] things considered [the D1050049 comparator was Haldol 10mg\/day, the D1050231 comparator was Zyprexa 15mg\/day] [synopsized from Drugs@FDA<\/font><\/strong><\/u><\/a>]: <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
LS Mean Difference from Placebo<\/font><\/strong><\/td>\n<\/tr>\n
Study #<\/font><\/strong><\/td>\n <\/td>\nLUR20mg<\/sub><\/font><\/strong><\/td>\nLUR40mg<\/sub><\/font><\/strong><\/td>\nLUR80mg<\/sub><\/font><\/strong><\/td>\nLUR120mg<\/sub><\/font><\/strong><\/td>\nComparator<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1050006  US<\/font><\/strong><\/sup>
   2001   n=149<\/sup>
   66% drop out <\/sup><\/td>\n		BPRSd (LOCF)<\/font><\/strong><\/td>\n <\/td>\n-5.6<\/font><\/strong><\/td>\n <\/td>\n-6.7<\/font><\/strong><\/td>\n <\/td>\n<\/tr>\n
BPRSd (MMRM)<\/td>\n-7.3<\/font><\/strong><\/td>\n-9.2<\/font><\/strong><\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-9.6<\/td>\n-11.0<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1050049  US<\/font><\/strong><\/sup>
   2003   n=356<\/sup>
   43% drop out <\/sup><\/td>\n		BPRSd (LOCF)<\/font><\/strong><\/td>\n-5.0<\/td>\n-5.2<\/td>\n-8.0<\/td>\n-9.8<\/td>\n-7.9<\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-7.1<\/td>\n-7.2<\/td>\n-13.6<\/td>\n-16.0<\/td>\n-12.3<\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1050196 US<\/font><\/strong><\/sup>
   2004   n=180<\/sup>
   45% drop out <\/sup><\/td>\n		BPRSd (LOCF)<\/font><\/strong><\/td>\n <\/td>\n-4.7<\/font><\/strong><\/td>\n <\/td>\n <\/td>\n <\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-8.6<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1050229<\/font><\/strong><\/sup>
   2008   n=496<\/sup>
   34% drop out <\/sup><\/td>\n		PANSS (MMRM<\/font><\/strong>)<\/td>\n <\/td>\n-2.1<\/td>\n-6.4<\/font><\/strong><\/td>\n-3.5<\/td>\n <\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-2.7<\/font><\/strong><\/td>\n-6.1<\/font><\/strong><\/td>\n-3.5<\/td>\n<\/tr>\n
US Sites<\/td>\n+0.6<\/td>\n-2.0<\/td>\n+0.2<\/td>\n<\/tr>\n
Non-US Sites<\/td>\n-6.5<\/td>\n-10.8<\/font><\/strong><\/td>\n-8.6<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1050231<\/font><\/strong><\/sup>
   2009   n=475<\/sup>
   38% drop out <\/sup><\/td>\n		PANSS (MMRM)<\/font><\/strong><\/td>\n <\/td>\n-9.7<\/font><\/strong><\/td>\n <\/td>\n-7.5<\/font><\/strong><\/td>\n-12.6<\/font><\/strong><\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-7.9<\/font><\/strong><\/td>\n-4.8<\/td>\n-11.4<\/font><\/strong><\/td>\n<\/tr>\n
US Sites<\/td>\n-5.7<\/td>\n-4.8<\/td>\n-11.4<\/td>\n<\/tr>\n
Non-US Sites<\/td>\n -10.5<\/font><\/strong> <\/td>\n-3.8<\/td>\n-9.6<\/font><\/strong><\/td>\n<\/tr>\n<\/table>\n
1° Efficacy Variable in BOLD<\/font><\/strong>, Statistically Significant [p<<\/u>0.05<\/em>] Values in RED<\/font><\/strong><\/sup><\/div>\n

<\/p>\n

Just a few comments from the FDA evaluation<\/font><\/strong><\/u><\/a>:<\/div>\n