{"id":2892,"date":"2016-11-14T03:05:12","date_gmt":"2016-11-14T08:05:12","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2892"},"modified":"2025-09-20T19:17:44","modified_gmt":"2025-09-21T01:17:44","slug":"inconclusive-data-in-ia-experts-fill-the-void-to-avoid-horror-vacui","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/11\/14\/2892\/inconclusive-data-in-ia-experts-fill-the-void-to-avoid-horror-vacui\/","title":{"rendered":"Inconclusive Data in IA: Experts Fill the Void To Avoid Horror Vacui"},"content":{"rendered":"

\"ia-blog-header\"<\/a><\/p>\n

Often we come across a study which raises more questions than it answers.\u00a0 Sometimes we read a study publication again and again, and still we cannot figure out what the take-away learning is, as results are simply inconclusive or discordant. Occasionally we encounter studies with results that are so counterintuitive that even the authors have had difficulty putting it all together.\u00a0 Then the interpretation becomes strangely warped, inventive or even more likely biased.<\/p>\n

Such was the case with the study on the value of combination treatment for invasive aspergillosis published by Marr et al. last year\u00a0[1]<\/a>. \u00a0It was an issue that still screams for clarification as the literature on echinocandin activity against aspergillosis is confusing to say the least.\u00a0 The subject matter is important enough to deserve a definitive answer in a well-designed study.<\/p>\n

The primary efficacy variable in this well executed, placebo controlled, double blind multicenter study was all-cause mortality by Week 6 in the modified ITT population.\u00a0 Patients in the mITT population had proven or probable IA as was determined by blinded DRC case review. The study had a somewhat unusual design wherein voriconazole was given for 6 weeks but partnered with anidulafungin only for the first 2 weeks.<\/p>\n

Patient Enrollment Dynamics: 93 study sites, 24 countries, 459 patients enrolled, 277 patients valid for efficacy, study duration: 3 years – an amazing feat!<\/span><\/p>\n<\/div>\n

It took the MSG 3 years and 93 study sites in 24 countries to collect 459 patients of which only 277 qualified for mITT analysis. Indeed, the study had to be extended for enrollment to accrue the required number of 250 mITT patients. This was clearly a herculean effort, certainly more difficult than anticipated.\u00a0 It must have cost Pfizer, the sponsor of the study, a pretty penny.\u00a0 Not to have worried, they would also reap the benefits as both drugs were from Pfizer.<\/p>\n

As it turned out, all-cause mortality for the mITT population was 27.8% with mono-therapy, and 19.5% for combination therapy (delta: -8.3; CI: -19.0, 1.5); the P-value was 0.086. Hence, one cannot\u00a0refute the Null-hypothesis of no difference between the treatment arms.<\/p>\n

A secondary endpoint was Global Response, a measure of efficacy used in former studies of IA which correlates well with mortality.\u00a0 This traditional outcome parameter allows us to create a link to prior trials. Well, in the Marr study, Global Response of success occurred with a higher frequency in patients receiving monotherapy.\u00a0 Here the Table from the publication (Figure 1):<\/p>\n

\"outcome-table\"<\/a>
Figure 1: DRC adjudicated outcomes in the mITT population<\/figcaption><\/figure>\n

Looking at the Kaplan-Meier plot (Figure 2), survival curves for mono- and combo-therapy hardly diverge before week 5\u00bd; in fact, they are almost superimposable. Are we supposed to think that anidulafungin, 4 weeks after dosing has ended, somehow magically boosts survival?\u00a0 Such an interpretation defies biology.<\/p>\n

The authors then do what all good investigators do: They performed a multi-variate analysis searching for factors that may have impacted outcome. Karnofsky score and the level of GM antigen at baseline were both strong predictors of mortality; hazard ratios indicate that combination therapy is better than mono-therapy when Karnofsky scores are low and entry GM antigen high.<\/p>\n

\"k-m-graph\"<\/a>
Figure 2: Kaplan-Meier plot – Mortality by Treatment Group<\/figcaption><\/figure>\n

At this stage you are to be forgiven if you can\u2019t figure out what to make of the study. Experts to the rescue: The authors kindly substitute what the data should have clarified with their belief system and tell us that 2 drugs are better than 1.\u00a0 Their conclusion stated in the abstract and article is that \u201cthe combination of voriconazole and anidulafungin was associated with a nonsignificant but clinically meaningful survival benefit\u201d, that \u201ccombination therapy led to higher survival in subgroups of patients with IA\u201c.<\/p>\n

Looking at the numbers, one is really baffled by such statements. It just seems nonsensical to conclude something not supported by the key study findings. Since when does data dredging trump prospectively defined endpoints?<\/p>\n

We don\u2019t like a toss-up situation either and do understand the frustration. The authors, siding with the sponsor, tell us:\u00a0 When in doubt, believe in antifungals and combination therapy; \u00a0more just has to be better!<\/p>\n

Well, not so, gents! We don\u2019t follow the piper here. Your belief system is not necessarily ours.<\/p>\n

Abbreviations:
\n<\/strong>IA\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 invasive aspergillosis
\nRCT\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 randomized controlled trial
\nGM\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 galactomannan
\nMSG\u00a0\u00a0\u00a0\u00a0\u00a0 Mycoses Study Group<\/p>\n

Reference:
\n<\/strong>[1]<\/a> K Marr.\u00a0 Combination Antifungal Therapy for Invasive Aspergillosis.\u00a0 Ann Intern Med. 2015;162:81<\/p>\n

[contact-form-7 id=”2030″ title=”Contact form 1″]<\/p>\n","protected":false},"excerpt":{"rendered":"

Often we come across a study which raises more questions than it answers.\u00a0 Sometimes we read a study publication again and again, and still we cannot figure out what the take-away learning is, as results are simply inconclusive or discordant. Occasionally we encounter studies with results that are so counterintuitive Continue reading Inconclusive Data in IA: Experts Fill the Void To Avoid Horror Vacui<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2898,"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":true,"_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":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[227,18],"tags":[1271,1575,1800,1799,1484,1576,1795,1583,1697,1796,1797,655,506,38,1798,938,928],"class_list":["post-2892","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_viewpoint","tag-allphase-pharma-consulting","tag-anidulafungin","tag-aspergillosis-therapy","tag-combination-antifungal-therapy","tag-echinocandin","tag-eraxis","tag-galactomannan","tag-harald-reinhart","tag-invasive-aspergillosis","tag-msg","tag-mycosis-study-group","tag-pfizer","tag-publication-bias","tag-rct","tag-subset-analyses","tag-vfend","tag-voriconazole"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/IA-blog-header.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-KE","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2625,"url":"https:\/\/allphasepharma.com\/dir\/2016\/07\/13\/2625\/aspergillus_guideline-zip\/","url_meta":{"origin":2892,"position":0},"title":"Aspergillus_Guideline.ZIP","author":"Harald","date":"July 13, 2016","format":false,"excerpt":"Now, I know we should not make light of any IDSA Guidelines, far from it. 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