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      COVID-19 hits a trial: Arguments against hastily deviating from the plan

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          Abstract

          The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to supervise trials in the usual way and precautionary measures had to be implemented to care for medication supply and general safety of study participants it is now important to consider, how the impact of the pandemic on trial outcome can be assessed, which measures are needed to decide, how to proceed with the trial and what is needed to compensate to irregularity introduced by the pandemic situation. Obviously not all trials will suffer to the same degree: some trials may be close to finalizing recruitment, others may not yet have started. Similarly not all clinical trials investigate vulnerable patient populations, but some will and may in addition have recruited to an extent that beneficial effects achieved in the initial phase of the trial may be outweighed by an increase e.g. in mortality that impacts both treatment groups. The situation is further complicated by the fact that the pandemic reached different countries in the world and even cities in one country at different points in time with different severity. Our example is a randomized and double-blind clinical trial comparing digitoxin and placebo in patients with advanced chronic heart failure. This trial has recruited roughly 1/3 of the overall 2200 patients when the disease outbreak reached Germany. We discuss how simulations and theoretical considerations can be used to address questions about the need to increase the overall sample-size to be recruited to compensate for a potential shrinkage of the treatment effect caused by the COVID-19 pandemic and what role the degree of consistency could play when comparing pre-, during- and post- COVID-19 periods of trial conduct regarding the question, whether the treatment effect can be considered consistent and with this generalizable. This is dependent on the size of the treatment effect and the impact of the pandemic. We argue, that in case of doubt, it may be wise to proceed with the original study plan.

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          Rationale and design of the DIGIT‐HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double‐blind, placebo‐controlled study

          Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT‐HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double‐blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all‐cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all‐cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT‐HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all‐cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.
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            Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction in heart failure.

            The importance of heart rate in the pathophysiology of heart failure with reduced LVEF has recently attracted attention. In particular, the findings of the Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial (SHIFT) have put special emphasis on heart rate reduction with ivabradine for improvement in clinical outcomes. Of course, there is a much older drug that reduces heart rate, i.e. digoxin. In this short commentary, we retrospectively analyse the Digitalis Investigation Group (DIG) Trial looking at the primary composite endpoint used in SHIFT (i.e. cardiovascular death or hospital admission for worsening heart failure) and compare the effect of digoxin on this endpoint with that of ivabradine. A remarkably similar risk reduction in the composite outcome and in its components appears evident among patients receiving the active treatment in both studies (although ivabradine was added to a beta-blocker, whereas digoxin was not). This raises the question of whether the Cardiological community dismissed digoxin too readily and if we should reappraise its potential role in the treatment of heart failure.
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              Bundesamt, Sterbefallzahlen im April 2020 8% über dem Durchschnitt der Vorjahre

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                Author and article information

                Journal
                Contemp Clin Trials
                Contemp Clin Trials
                Contemporary Clinical Trials
                The Authors. Published by Elsevier Inc.
                1551-7144
                1559-2030
                19 September 2020
                November 2020
                19 September 2020
                : 98
                : 106155
                Affiliations
                Institut für Biometrie, Medizinische Hochschule Hannover, Germany
                Author notes
                [* ]Corresponding author at: Institut für Biometrie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
                Article
                S1551-7144(20)30233-0 106155
                10.1016/j.cct.2020.106155
                7831554
                32961360
                df2cb669-263d-400c-be50-01d9b7370eec
                © 2020 The Authors

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 2 August 2020
                : 13 September 2020
                : 15 September 2020
                Categories
                Article

                Medicine
                clinical trial,covid-19,consistency,trial adaptation,impact of the pandemic on trial conduct

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