{"id":268,"date":"2019-10-09T21:44:49","date_gmt":"2019-10-09T16:14:49","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=268"},"modified":"2019-10-09T21:44:49","modified_gmt":"2019-10-09T16:14:49","slug":"clinical-trial-designs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/clinical-trial-designs\/","title":{"rendered":"Clinical Trial Designs"},"content":{"rendered":"\n<p><strong>Clinical Trial Design<\/strong><\/p>\n\n\n\n<p><strong>Clinical\ntrials &#8211; <\/strong>Any\nresearch study that prospectively assigns human participants or groups of\nhumans to one or more health-related interventions to evaluate the effects on\nhealth outcomes<strong><\/strong><\/p>\n\n\n\n<ul><li>Interventional trials<\/li><\/ul>\n\n\n\n<p>Intervention\ncould be \u00e0 Drugs, cells, and other biological products, surgical procedures,\nradiologic procedures, devices, behavioral treatments, process-of-care changes,\npreventive care, etc. <\/p>\n\n\n\n<p><strong>Clinical Trial Design<\/strong><\/p>\n\n\n\n<ul><li>Single-arm studies<\/li><li>Parallel group designs<\/li><li>Cross over designs<\/li><li>Enrichment designs<\/li><li>Add on designs<\/li><li>Randomized withdrawal designs<\/li><li>Factorial design<\/li><\/ul>\n\n\n\n<p><strong><em>Traditional\ndesigns<\/em><\/strong><strong><\/strong><\/p>\n\n\n\n<ul><li><strong>&nbsp;<\/strong>involve fixing sample size before the trial commences &amp; performing\nonly single efficacy analysis after the trial has occurred<\/li><\/ul>\n\n\n\n<p><strong><em>Flexible\ndesigns <\/em><\/strong><strong><\/strong><\/p>\n\n\n\n<ul><li><strong>&nbsp;<\/strong>entail actively monitoring efficacy during the trial (either continuously\n\/ at intervals) &amp; altering study based on efficacy data<\/li><\/ul>\n\n\n\n<p><strong><br>\nChoice of experimental design has two main objectives:<\/strong><\/p>\n\n\n\n<ul><li>Minimize bias, with the aim of obtaining bias-free comparisons<ul><li>Minimize the variability of observations<em>, with the aim of obtaining powerful <\/em>statistical tests &amp; precise estimates<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><\/p>\n\n\n\n<ol><li> <strong>Single-arm studies<\/strong> <ul><li>include an only single group of patients with each patient in the group receiving a single intervention<\/li><li><strong>No placebo or comparison<\/strong> interventions<\/li><li>not a parallel-group study<\/li><li><strong>the anticipated effect<\/strong> of the intervention is <strong>large, dramatic, &amp; obvious<\/strong><\/li><li><strong>the intervention has not been studied previously<\/strong><\/li><li>the study <strong>population is homogeneous<\/strong><\/li><li><strong><em>Appropriate patients are very rare<\/em><\/strong><\/li><\/ul><\/li><\/ol>\n\n\n\n<p><strong>Multiple arms &#8211; Parallel group design<\/strong><\/p>\n\n\n\n<p><\/p>\n\n\n\n<ul><li>A complete randomized design <\/li><li>simplest group comparison parallel-group design &#8211; the two-group parallel design which compares two treatments<\/li><li>(e.g., a treatment group vs. a control group). <\/li><li>Each treatment group &#8211;\u00a0 approximately the same number of patients<\/li><\/ul>\n\n\n\n<ul><li><strong>use of three-group parallel design:<\/strong> with an active control &amp; placebo control &#8211; distinguishes an ineffective drug from an ineffective design<\/li><li>An effective design: evaluation of <em>assay sensitivity &#8211; shows the superiority of active <\/em>control over placebo<\/li><\/ul>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"428\" height=\"173\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-82.png?w=428\" alt=\"\" class=\"wp-image-269\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-82.png 428w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-82-300x121.png 300w\" sizes=\"(max-width: 428px) 100vw, 428px\" \/><\/figure><\/div>\n\n\n\n<ul><li><strong>Run-in (or lead-in) period<\/strong><strong><\/strong><ul><li>Placebo<\/li><\/ul><ul><li>No\nactive treatment<\/li><\/ul><ul><li>Dietary\ncontrol, or active maintenance therapy <\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>Advantage<\/strong><\/p>\n\n\n\n<ul><li>washout period to <strong>remove effects of previous therapy<\/strong><strong><\/strong><\/li><li>to <strong>obtain baseline data<\/strong> and to <strong>evaluate\nif patient fulfills study entry criteria<\/strong><\/li><li>training period<\/li><li>helps in <strong>identifying placebo responders<\/strong><strong><\/strong><\/li><li>information regarding <strong>patient compliance<\/strong><strong><\/strong><\/li><\/ul>\n\n\n\n<p><strong><em>When is run in period unsuitable?<\/em><\/strong><\/p>\n\n\n\n<ul><li>For patients requiring\nimmediate treatment<\/li><\/ul>\n\n\n\n<ul><li><strong>Crossover designs<\/strong><ul><li>A\ncrossover design &#8211; a <strong>modified randomized\nblock design<\/strong><\/li><\/ul><ul><li>Each block receives more than one\ntreatment at different dosing periods<\/li><\/ul><ul><li>A block can be a patient or a group\nof patients<\/li><\/ul><ul><li>&nbsp;Patients in each block receive different\nsequences of treatments<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>Two periods two sequence cross-over design<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"466\" height=\"207\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-83.png?w=466\" alt=\"\" class=\"wp-image-270\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-83.png 466w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-83-300x133.png 300w\" sizes=\"(max-width: 466px) 100vw, 466px\" \/><\/figure>\n\n\n\n<p><strong>Crossover design \u2013 advantages<\/strong><\/p>\n\n\n\n<ul><li>It <strong>allows a within-patient comparison between treatments<\/strong> since <strong>each patient serves as his or her own\ncontrol<\/strong><\/li><li>It <strong>removes the inter-patient variability<\/strong> from the comparison between\ntreatments<\/li><li>&nbsp;With proper randomization of patients to the\ntreatment sequences, it <strong>provides the\nbest-unbiased estimates for the differences between treatments<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Washout period<\/strong><\/p>\n\n\n\n<ul><li>The washout period is defined as\nthe <strong><em>rest period between two treatment periods<\/em><\/strong><em> <\/em>for which the effect of one\ntreatment administered at one dosing period does not carry over to the next. <\/li><li>The washout period <strong><em>must be long enough <\/em>for the\ntreatment effect to wear off<\/strong> so that there is no carryover effect from one\ntreatment period to the next. <\/li><\/ul>\n\n\n\n<p><strong>Crossover\ndesigns may be used if\u2026..<\/strong><\/p>\n\n\n\n<ul><li><strong>Chronic (relatively stable) disease<\/strong> are under study <\/li><li><strong>Drugs<\/strong> with a relatively <strong>short half-life<\/strong> are being investigated<\/li><li><strong>Relatively short treatment periods<\/strong> are considered<\/li><li><strong>Baseline and washout periods are feasible<\/strong><\/li><\/ul>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"351\" height=\"212\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-84.png?w=351\" alt=\"\" class=\"wp-image-271\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-84.png 351w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-84-300x181.png 300w\" sizes=\"(max-width: 351px) 100vw, 351px\" \/><\/figure><\/div>\n\n\n\n<ul><li><strong>Enrichment\ndesigns<\/strong><ul><li><strong>Therapeutic\nagents&nbsp; &#8211; effective in a specific\npopulation<\/strong> of patients <\/li><\/ul><ul><li><strong>Identify the patients<\/strong>\nin whom the <strong>test agent is likely to be\nbeneficial<\/strong> in the early phase of the trial<\/li><\/ul><ul><li><strong>Enrichment\nphase &#8211; <\/strong>The <strong>phase of\nmanipulation of dose levels<\/strong> for identification of patients with drug\nefficacy <\/li><\/ul><ul><li>then <strong>randomized to receive either the efficacious dose<\/strong> of the test agent\nor the matching placebo<\/li><\/ul><ul><li>An enrichment design usually\nconsists of at least two phases<\/li><\/ul><\/li><\/ul>\n\n\n\n<p>The first phase &#8211; enrichment phase<\/p>\n\n\n\n<ul><li>open-label study with a titration design <ol><li>to identify patients with a clinical response<\/li><\/ol><\/li><\/ul>\n\n\n\n<p>The second phase<\/p>\n\n\n\n<ol><li>Randomized and double-blind,\npossibly with a concurrent placebo control<\/li><li><strong>Add-On Design<\/strong><\/li><li>In\nan add-on design, a placebo-controlled trial of a study intervention takes\nplace while patients stay on established effective treatments <\/li><li>In\nother words, the <strong>trial occurs <em>\u201con top\u201d <\/em>of patients receiving\nregular treatment <\/strong><\/li><li><strong>No one ever goes completely\nuntreated<\/strong><\/li><li><strong>Placebo patients basically are on\nestablished effective treatments<\/strong><\/li><li>Unless\nthe study intervention counteracts the effects of the established treatment,\npatients on the study intervention will be on multiple treatments that could\ntreat the condition<\/li><li><strong>Allows you to study intervention\ninteractions<\/strong><\/li><\/ol>\n\n\n\n<p> <strong>Disadvantages of add-on design<\/strong><\/p>\n\n\n\n<ul><li>Treatment interactions may occur<\/li><li>Being on simultaneous treatments\ncan be dangerous<\/li><li><strong>If\na patient improves, Is it due to the study intervention or the established\neffective treatment? <\/strong><\/li><li>The \u201c placebo \u201d arm may help but\ndoes not always fully answer this question<\/li><\/ul>\n\n\n\n<ul><li><strong>Randomized withdrawal design<\/strong><ul><li><strong><em>A new drug or <\/em>placebo is added by random assignment to the conventional treatment given at an effective dose, and conventional treatment is then withdrawn gradually, usually by tapering. <\/strong><\/li><\/ul><ul><li>The objective &#8211; to compare the ability to maintain the patient\u2019s baseline status between the new drug and placebo.<\/li><\/ul><ul><li>Treat all patients with the study intervention in the first period <\/li><\/ul><ul><li>Randomize patients to either placebo or continued study intervention treatment for the second period<\/li><\/ul><ul><li>Patients remain on the study intervention or placebo until the treatment fails (e.g., symptoms return)<\/li><\/ul><\/li><\/ul>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"545\" height=\"213\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-85.png?w=545\" alt=\"\" class=\"wp-image-272\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-85.png 545w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-85-300x117.png 300w\" sizes=\"(max-width: 545px) 100vw, 545px\" \/><\/figure><\/div>\n\n\n\n<p><strong>Advantage \u2013 <\/strong><\/p>\n\n\n\n<ul><li>When <strong>long term placebo use is not ethical<\/strong> or practical<\/li><li>Can <strong>evaluate progressive diseases<\/strong><\/li><li>Amount of time&nbsp; patient receives less effective\ntreatment&nbsp; is shorter<\/li><\/ul>\n\n\n\n<p><strong>Disadvantages<\/strong><\/p>\n\n\n\n<ul><li>Carryover effects <\/li><li><strong>Taking\npatients off treatment abruptly&nbsp; may be\ndangerous<\/strong><\/li><li>Change in the natural course of\ndiseases can confound results<\/li><\/ul>\n\n\n\n<ul><li><strong>Factorial designs<\/strong><ul><li>Factorial designs <strong>involve testing two or more different interventions on the same group at the same time<\/strong> (i.e., in one period)<\/li><\/ul><ul><li><strong>Different groups receive different combinations of the available interventions<\/strong><\/li><\/ul><ul><li>By testing multiple interventions against controls simultaneously, <strong>factorial designs minimize the number of patients used<\/strong><\/li><\/ul><\/li><\/ul>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"490\" height=\"237\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-86.png?w=490\" alt=\"\" class=\"wp-image-273\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-86.png 490w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2019\/10\/image-86-300x145.png 300w\" sizes=\"(max-width: 490px) 100vw, 490px\" \/><\/figure><\/div>\n\n\n\n<p><strong>A factorial design can represent:<\/strong><\/p>\n\n\n\n<ul><li>Two or more independent studies<\/li><li>A single study looking at\ninterventions alone and in combination<\/li><li>Factorial designs can <em>address more than one question <\/em>in\none study in an elegant manner and significantly reduce the required sample\nsize<\/li><li>The main drawback to the factorial\ndesign is the <em>potential for\ninteraction<\/em> among different interventions<\/li><\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Clinical Trial Design Clinical trials &#8211; Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes Interventional trials Intervention could be \u00e0 Drugs, cells, and other biological products, surgical procedures, radiologic procedures, devices, behavioral treatments, process-of-care changes, preventive care, etc.[&#8230;]\n","protected":false},"author":3,"featured_media":269,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/268"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=268"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/268\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media\/269"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=268"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=268"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=268"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}