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      Noninferiority trials

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          Abstract

          Noninferiority trials are intended to show that the effect of a new treatment is not worse than that of an active control by more than a specified margin. These trials have a number of inherent weaknesses that superiority trials do not: no internal demonstration of assay sensitivity, no single conservative analysis approach, lack of protection from bias by blinding, and difficulty in specifying the noninferiority margin. Noninferiority trials may sometimes be necessary when a placebo group can not be ethically included, but it should be recognized that the results of such trials are not as credible as those from a superiority trial.

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          Trials to assess equivalence: the importance of rigorous methods.

          B. Jones, P Jarvis, J. Lewis … (1996)
          The aim of an equivalence trial is to show the therapeutic equivalence of two treatments, usually a new drug under development and an existing drug for the same disease used as a standard active comparator. Unfortunately the principles that govern the design, conduct, and analysis of equivalence trials are not as well understood as they should be. Consequently such trials often include too few patients or have intrinsic design biases which tend towards the conclusion of no difference. In addition the application of hypothesis testing in analysing and interpreting data from such trials sometimes compounds the drawing of inappropriate conclusions, and the inclusion and exclusion of patients from analysis may be poorly managed. The design of equivalence trials should mirror that of earlier successful trials of the active comparator as closely as possible. Patient losses and other deviations from the protocol should be minimised; analysis strategies to deal with unavoidable problems should not centre on an "intention to treat" analysis but should seek to show the similarity of results from a range of approaches. Analysis should be based on confidence intervals, and this also carries implications for the estimation of the required numbers of patients at the design stage.
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            Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.

            E Paolasso, John Heikkila, Azan Binbrek … (1999)
            Bolus fibrinolytic therapy facilitates early efficient institution of reperfusion therapy. Tenecteplase is a genetically engineered variant of alteplase with slower plasma clearance, better fibrin specificity, and high resistance to plasminogen-activator inhibitor-1. We did a double-blind, randomised, controlled trial to assess the efficacy and safety of tenecteplase compared with alteplase. In 1021 hospitals, we randomly assigned 16,949 patients with acute myocardial infarction of less than 6 h duration rapid infusion of alteplase (< or = 100 mg) or single-bolus injection of tenecteplase (30-50 mg according to bodyweight). All patients received aspirin and heparin (target activated partial thromboplastin time 50-75 s). The primary outcome was equivalence in all-cause mortality at 30 days. Covariate-adjusted 30-day mortality rates were almost identical for the two groups--6.18% for tenecteplase and 6.15% for alteplase. The 95% one-sided upper boundaries of the absolute and relative differences in 30-day mortality were 0.61% and 10.00%, respectively, which met the prespecified criteria of equivalence (1% absolute or 14% relative difference in 30-day mortality, whichever difference proved smaller). Rates of intracranial haemorrhage were similar (0.93% for tenecteplase and 0.94% for alteplase), but fewer non-cerebral bleeding complications (26.43 vs 28.95%, p=0.0003) and less need for blood transfusion (4.25 vs 5.49%, p=0.0002) were seen with tenecteplase. The rate of death or non-fatal stroke at 30 days was 7.11% with tenecteplase and 7.04% with alteplase (relative risk 1.01 [95% CI 0.91-1.13]). Tenecteplase and alteplase were equivalent for 30-day mortality. The ease of administration of tenecteplase may facilitate more rapid treatment in and out of hospital.
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              A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators.

              P. Probst, H Emanuelsson, D. Ardissino … (1997)
              Reteplase (recombinant plasminogen activator), a mutant of alteplase tissue plasminogen activator, has a longer half-life than its parent molecule and produced superior angiographic results in pilot studies of acute myocardial infarction. In this large clinical trial, we compared the efficacy and safety of these two thrombolytic agents. A total of 15,059 patients from 807 hospitals in 20 countries who presented within 6 hours after the onset of symptoms with ST-segment elevation or bundle-branch block were randomly assigned in a 2:1 ratio to receive reteplase, in two bolus doses or 10 MU each given 30 minutes apart, or an accelerated infusion of alteplase, up to 100 mg infused over a period of 90 minutes. The primary hypothesis was that mortality at 30 days would be significantly lower with reteplase. The mortality rate at 30 days was 7.47 percent for reteplase and 7.24 percent for alteplase (adjusted P=0.54; odds ratio, 1.03; 95 percent confidence interval, 0.91 to 1.18). The 95 percent confidence interval for the absolute difference in mortality rates was -1.1 to 0.66 percent. Stroke occurred in 1.64 percent of patients treated with reteplase and in 1.79 percent of those treated with alteplase (P= 0.50). The respective rates of the combined end point of death or nonfatal, disabling stroke were 7.89 percent and 7.91 percent (P=0.97; odds ratio, 1.0; 95 percent confidence interval, 0.88 to 1.13). As compared with an accelerated infusion of alteplase, reteplase, although easier to administer, did not provide any additional survival benefit in the treatment of acute myocardial infarction. Other results, particularly for the combined end point of death or nonfatal, disabling stroke, were remarkably similar for the two plasminogen activators.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Control Trials Cardiovasc Med
                Title: Current Controlled Trials in Cardiovascular Medicine
                Publisher: BioMed Central
                ISSN (Print): 1468-6708
                ISSN (Electronic): 1468-6694
                Publication date (Print): 2000
                Publication date (Electronic): 31 July 2000
                Volume: 1
                Issue: 1
                Pages: 19-21
                Affiliations
                [1 ]Merck Research Laboratories, West Point, Pennsylvania, USA
                Article
                Publisher ID: cvm-1-1-019
                DOI: 10.1186/cvm-1-1-019
                PMC ID: 59590
                PubMed ID: 11714400
                SO-VID: 6497ffc6-832d-4273-bfae-71deaf135f12
                Copyright © Copyright © 2000 Current Controlled Trials Ltd
                History
                Date received : 14 April 2000
                Date revision requested : 3 July 2000
                Date revision received : 10 July 2000
                Date accepted : 10 July 2000
                Categories
                Subject: Commentary

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: intention-to-treat,blinding,assay sensitivity,equivalence,clinical trials
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: intention-to-treat, blinding, assay sensitivity, equivalence, clinical trials

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