Randomized trials in the news

Healthcare policymakers around the world often have a particular interest in how a new drug fares against existing treatment options, taking into account cost-effectiveness, the possible effects on quality of life, and other factors that paint a picture of overall benefit and the cost of the drug to society and individuals.

Policymakers also have to account for the lack of diversity in clinical trials when making decisions about healthcare guidelines and funding. Historically, clinical trials have typically been carried out using white male patients, resulting in the approval of a range of drugs and interventions that have subsequently appeared to be less effective or riskier in people of different sex or ethnicity.

Research in non-human animals or a limited section of the population is, in most cases, insufficient for recommending the widespread use of a drug or treatment within the general population. The approval of some drugs based on animal research has led to significant harm in humans, as non-human animals are generally a poor model for predicting the human response to a drug or treatment.

A true placebo can be difficult to achieve and disguise. In some cases, giving a placebo is unethical. A trial using a placebo might not be fair on participants.

In these circumstances, the researchers would give an already-available treatment to a comparison group. The participants would not be sacrificing their standard care for the sake of a dummy treatment. Researchers may use a different trial design if no existing treatment is available. Independent ethical review boards make decisions about whether trial designs are fair on the participants. The researcher assigns participants to experimental and placebo groups randomly, removing any selection bias from the sample.

Selection bias can skew results in a way that benefits a researcher or the body funding the study at the expense of scientific integrity. A placebo is a treatment that resembles the experimental drug.

When a placebo is not ethical to use, for example in instances of trials for the treatment of a life-threatening disease for which the participant cannot stop their course of treatment, the researchers will use a treatment that is standardly available to test the differences.

A drug or treatment generally have to pass an RCT before the FDA approves it as safe and effective for wider distribution. Following preliminary clinical trials, a new anti-stroke drug shows promise for improved treatment, rendering patients less prone to adverse effects.

Clinical trials are essential for safely and effectively testing out news treatments and medicines for wide distribution. This article explains what….

The placebo effect is a phenomenon in which the body starts to heal even if it only thinks it is receiving treatment. The effect is mysterious…. The past 12 months have seen discoveries, breakthroughs, and innovations in medical research. MNT take you on a journey through 's highlights.

What is a randomized controlled trial? Medically reviewed by Daniel Murrell, M. Reasons for randomization The controlled element Ethical considerations Takeaway Randomized controlled trials are the most reliable method available for testing new treatments. In a traditional randomized clinical trial design, patients who are ineligible for randomization are excluded from study participation.

However, these patients often constitute an important subgroup of the disease population. By extending existing trial infrastructure, efforts to evaluate such patients in parallel cohort arms provided an efficient means of generating multicenter prospective data in patients for whom there were significant gaps in medical knowledge, laying the foundation for potential future trials involving these VTE subgroups of interest.

Since keeping a patient on anticoagulant medication involves a continuous tradeoff between the risk of bleeding related to anticoagulation and the risk of developing more blood clots each of which potentially can be life-threatening , Goldenberg and colleagues including University of Colorado-based biostatistician-leader John Kittelson, Ph. The JAMA publication reports the findings of the randomized controlled trial involving over patients across 42 of the 51 centers that participated in the overall study , while the results of the parallel cohorts involving more than additional patients will be the subject of subsequent publications.

Goldenberg and his team are applying for NIH funding to follow up on how the Kids-DOTT findings are disseminated and adopted into practice globally, and to monitor the degree to which the favorable outcomes measured in Kids-DOTT continue to be observed in subsequent real-world experience. The immediate legacy of Kids-DOTT will go beyond its practice-changing findings, as it signals that it is a very auspicious time to be a part of pediatric thrombosis. Agents used in these trials include antiplatelet agents, unfractionated heparin UFH and heparin derivatives, parenteral direct thrombin inhibitors DTIs , direct oral anticoagulants DOACs , fibrinolytic agents, sulodexide a mixture of heparin sulfate and dermatan sulfate 39 , dociparstat a heparin derivative with anti-inflammatory properties , and nafamostat a synthetic serine protease inhibitor with anticoagulant activity.

A succinct discussion of the design features of these trials is provided in the following sections according to the clinical setting. Additional details are provided in Supplemental Tables 2 and 3. In each section, the discussion begins with parenteral anticoagulants, followed by fibrinolytic therapy, oral anticoagulants, antiplatelet agents, and investigational agents with antithrombotic properties. This sequence is arbitrary and does not indicate treatment preference. Figure 3 illustrates how RCTs of various agents can fill the knowledge gaps about antithrombotic therapy in COVID in various settings of illness severity.

Categorizing the RCTs evaluating different agents in various settings, including those treated entirely as outpatients, patients in the non-ICU hospital wards, critically ill patients in the ICU, and post-hospital discharge. Others: dociparstat, nafamostat, and sulodexide.

Abbreviations as in Figure 2. Eleven RCTs of antithrombotic therapy in outpatients with COVID have been registered in clinical trials databases and are studying enoxaparin, DOACs, aspirin, and sulodexide compared with no treatment 6 of 11 or with placebo 5 of These trials are mostly 8 of 11 open-label, with the number of participants ranging from to 7, patients, and they include patients with a hyperinflammatory or procoagulant profile including elevated levels of C-reactive protein [1 of 11] or D-dimer [2 of 11] and exclude patients at high risk of bleeding e.

The most common primary efficacy outcomes in the outpatient trials include the need for hospitalization, incidence of thromboembolic events, mortality, or composite outcomes inclusive of these factors. Bleeding events 5 of 11 constitute the most commonly assessed safety endpoints in the trials with an outpatient setting.

LMWHs at standard prophylactic dose , DOACs at both low intensity and high intensity , aspirin, and sulodexide are the agents under investigation in the outpatient setting.

Low-intensity apixaban 2. This single-center study of participants assessed the efficacy of sulodexide compared with placebo on day rates of hospitalization and need for use of supplemental oxygen.

Use of sulodexide was associated with reduced hospital admissions relative risk: 0. The study has limitations, including frequent Many of the outpatient antithrombotic therapy trials for COVID are large, and the follow-up windows are sufficient to capture the intended primary outcomes.

An issue with some of these trials is an open-label design, which is a pragmatic feature facilitating the design and enrollment but potentially limits the internal validity, especially for outcomes that may be less bias resistant. In addition, the available data do not clarify whether dose adjustments are made for renal or liver dysfunction. Most trials 44 of 50 are open-label.

The antithrombotic agents under investigation include heparin both systemic and inhaled , DOACs, aspirin, P2Y 12 inhibitors, dipyridamole, dociparstat, nafamostat, and a combination of these drugs. The planned sample sizes range between 34 and 20, patients. Most trials exclude pregnant women 41 of 50 and patients with active bleeding or history of intracranial or gastrointestinal bleeding 39 of In most trials, the time frame for the primary outcome assessment is 28 to 30 days, although a few studies are designed to assess the primary outcomes at earlier or longer durations.

These RCTs are focused on primary efficacy outcomes, including all-cause mortality, VTE, arterial thrombosis, requirement for respiratory support, or a composite of these outcomes.

Twenty-eight ongoing studies are being conducted to examine the efficacy of heparin-based regimens on primary outcomes such as all-cause mortality, venous and arterial thrombosis, re-hospitalization, the need for invasive mechanical ventilation, or composite outcomes inclusive of these factors in hospitalized patients with COVID Bleeding events is the most common 17 of 28 primary safety endpoint used in these trials.

The majority of these RCTs have chosen a standard-dose prophylactic anticoagulation regimen as the comparator. Conversely, a total of 18 RCTs with 19, patients will evaluate the efficacy of therapeutic anticoagulation in non-ICU hospitalized patients The different intensities of heparin derivatives are summarized in Supplemental Table 3.

Patients with definite acute coronary syndromes are excluded from this RCT. The effect of dual pathway inhibition using the combination of low-dose rivaroxaban and aspirin is being evaluated in the adaptive ACTCOVID19 inpatient study. REMAP-CAP A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia is a large global RCT with a multifactorial adaptive design that is planning to randomize 7, patients to receive multiple therapeutic interventions, including an anticoagulant arm and an antiplatelet agent arm evaluating aspirin and the P2Y 12 inhibitors clopidogrel, ticagrelor, or prasugrel CAM-Covid evaluates the impact of a higher dose of aspirin mg 4 times a day along with colchicine and montelukast on inflammatory markers such as high-sensitivity C-reactive protein in 34 patients.

High-mobility group box protein 1 HMGB1 is a protein involved in the pathogenesis of inflammation. Dociparstat, a heparin derivative with presumed anticoagulant and anti-inflammatory properties, inhibits HMGB1 and may reduce the formation of NETs and the risk of thrombosis. Nafamostat is a synthetic serine protease inhibitor with antiviral, anti-inflammatory, and anticoagulant activity previously used for anticoagulation during hemodialysis The primary efficacy outcome in 5 of these 7 trials is time to recovery.

The strengths of many of the antithrombotic trials among inpatients with COVID include relatively large sample sizes and ample follow-up for detection of events.

There is also variability across the trials in methods for identification and ascertainment of thrombotic outcomes. Lack of blinding and blinded outcome adjudication are practical limitations for some of these trials.

The sample size of these studies range from 15 to 20, patients. These trials are studying the role of systemic anticoagulants intermediate- to full-therapeutic-dose of heparin and direct thrombin inhibitors , inhaled UFH, fibrinolytic agents tenecteplase and alteplase , antiplatelet agents aspirin, clopidogrel, and dipyridamole , and nafamostat. Bleeding complications are the most widely used primary safety outcome among these studies. Preliminary analyses indicate that intermediate-dose compared with standard-dose anticoagulation did not reduce a composite of venous or arterial thrombosis or death.

The full results are imminent. Finally, 11 RCTs are evaluating the potential role of therapeutic-dose versus standard prophylactic dose anticoagulation in 5, patients.

More details are forthcoming Conversely, in January , the same study groups paused enrollment into the strata of moderately ill hospitalized patients with COVID not requiring ICU level of care, in whom a preliminary analysis showed a reduction in the need for ventilatory support or other organ-supportive interventions with therapeutic-dose enoxaparin Data supporting these decisions have not yet been finalized or peer reviewed, and they are anxiously awaited.

The study did not have sufficient power to compare all-cause mortality between the study groups. Bleeding may have been underestimated due to barriers in performing imaging testing, including computed tomography scanning to identify a source, in critically ill patients Most of these trials include patients with severe disease severe acute respiratory distress syndrome, elevated troponin levels, and elevated D-dimer levels.

Patients receiving therapeutic anticoagulation, and those with thrombocytopenia or a history of intracranial or gastrointestinal bleeding, are excluded from fibrinolytic therapy trials. The role of antiplatelet agents is under investigation in critically ill patients in 4 trials.

The primary efficacy outcome is the incidence of VTE or arterial thrombosis incidence 28 days after enrollment. In many cases, patients are unconscious, and obtaining informed consent requires discussion with health care proxies. This situation is further complicated because visitors are prohibited. The strengths of the aforementioned studies in the ICU include the diversity of studied antithrombotic agents and sample size in many RCTs.

There are also a number of notable limitations to these trials. The most important limitation is the small sample size in several studies, raising the possibility of a type II error. The small sample size will mostly influence trials of thrombolytic therapy and nonheparin anticoagulants.

In addition, there are 7 RCTs with a projected total of 1, participants that will continue the already assigned antithrombotic therapy after discharge in patients who were randomized in the general medical wards or in the ICU. Most of the ongoing RCTs are excluding patients at increased risk of bleeding, or with acute and chronic hepatic failure.

Specific dose adjustment for obesity is considered for 10 of 34 trials of systemic heparin compounds. Pregnant women are excluded from 25 of 34 trials of systemic heparin compounds. Although patient selection in these studies is based on practical considerations, it is unlikely that high-quality evidence will soon be available for antithrombotic therapy in such vulnerable subgroups Figure 4 , Supplemental Figure 2.

With limited high-quality data on the horizon for these vulnerable and high-risk subgroups, decision-making for optimal management in these patients will continue to be challenging. Categorizing the RCTs evaluating different agents in vulnerable populations, including patients with advanced kidney disease, end-stage kidney disease ESKD , patients with liver failure, and obese patients.

Further details are illustrated in Supplemental Figure 1. Until the results accrue, participation in these RCTs is encouraged. Efficacy outcomes vary based on the location of enrollment i. As for safety outcomes, many of the trials are systematically assessing major bleeding by using the International Society on Thrombosis and Haemostasis criteria or the Bleeding Academic Research Consortium definitions 61 , Although observational evidence suggests low rates of major bleeding 33 , 63 , observational studies have the potential for under-reported outcomes, and therefore RCTs with systematic and prospective capture of both thrombotic and bleeding events will help determine the true risk—benefit ratio for treatments.

Heparin-based regimens are the most frequently studied antithrombotic agents in patients with coronavirus disease Trials of fibrinolytic therapy are reserved for patients admitted to the intensive care unit ICU. Although results from the individual trials may inform interim practice, some challenges persist. The large number of antithrombotic agents under investigation, the variable dosing regimens tested, and variability in trial conduct as well as methods of outcome detection and adjudication may complicate the identification of the optimal regimens.

A prospective meta-analysis of RCTs, ideally with individual participant data, will help to assess the effects of distinct agents across the spectrum of disease severity and may address the clinical and statistical heterogeneity of the upcoming results. Efforts to harmonize endpoints have been advocated, with creation of common data elements for VTE, for example, to aid in pooling trial results 64 , In addition, there are few head-to-head comparisons for many of the experimental therapies, such as intermediate-dose regimens compared with fully therapeutic heparin-based regimens.

Network meta-analytic techniques might generate insights into the comparative tradeoffs of these regimens Additional biomarker and clinical risk prediction substudies can also further elucidate subgroups with more favorable net benefit profiles from distinct regimens. Moreover, the remaining knowledge gaps summarized in Table 1 should be kept in mind so that the design of additional studies could be considered. PMA needed to understand the relative efficacy of antiplatelet agents, standard prophylactic dose of enoxaparin compared with DOACs.

Anti-inflammatory properties and activity against thromboinflammation have been attributed to several antithrombotic regimens, including heparin derivatives and antiplatelet agents 30 , 67 , 68 , with the potential to reduce large-vessel thrombosis and improve outcomes. Another evolving concept is the role of microthrombosis and pulmonary intravascular coagulopathy 7 , 8 , 69 in the pathophysiology of respiratory failure in COVID Therapeutic drug monitoring of the investigational agents is also important.

Even when an agent is selected e. Some experts recommend measuring anti—factor Xa levels in those receiving intravenous UFH, because the high levels of factor VIII observed among critically ill patients with COVID may interfere with activated partial thromboplastin time assays. The necessity and optimal method for dosing and monitoring of heparins and LMWHs, in particular for patients with kidney disease or obesity, have yet to be elucidated and are even understudied outside COVID Ideally, future strategy trials should test the merits and limitations of these monitoring tests.

Notable challenges such as barriers to follow-up and site monitoring persist. However, the desire to provide an evidence-based response has been one of the key drivers of positive changes during the pandemic These changes include multispecialty study teams, harmonization of multicenter protocols, expedited multi-institutional agreement execution and institutional review board and governmental agency approvals, accelerated informed consent, and enrollment with digital contact-free technology, expeditious outcomes ascertainment, remote monitoring, and dissemination of the findings via fast-track publications, pre-prints, and social media accounts from scientific societies or investigators Table 2 75 , 76 , Although traditional RCTs have provided a great deal of knowledge for modern medicine, they are confined to testing a limited number of interventions.

Because COVID has multiorgan involvement and broad manifestations including inflammation, acute respiratory distress syndrome, thrombosis, and others , adaptive platform trials, which allow for testing multiple interventions in a single disease based on a decisive algorithm, have gained attention This type of trial has a perpetual and multiarm, multistage design REMAP-CAP is testing several interventions, including steroids, antiviral agents, biologic agents, simvastatin, and antiplatelet therapy.

Notwithstanding the good will of investigators, the constant pressure to provide a rapid pandemic response may pose challenges as well. In some cases, multiple small single-center RCTs underpowered for their clinical points or using surrogate endpoints with short follow-up have been designed 74 , 82 and may compete against larger multicenter, and potentially more definitive, studies. The large numbers of these trials alone, in addition to the intense pressure to present broadly and publish these findings, suggests at least some potential for type I error with amplification of these results through rapid dissemination of the results.

Additional methodological aspects deserve attention. Interpretation of these trial results may be limited by underutilization of placebo perhaps except for the outcome of mortality 57 , Some experts consider that the pressures of working during a global pandemic make the use of placebo more aspirational than realistic. Nevertheless, when feasible, placebo control improves the internal validity of a trial.

Furthermore, appropriate endpoint assessment, including blinded adjudication when feasible, and pre-specified analysis methods will remain of importance Institutional Review Boards and independent ethics committees may experience the burden of numerous protocol submissions and amendments during the pandemic. Burnout of health care systems during the pandemic, and the risks to the research teams are unique challenges that should also be considered when designing and executing study protocols Investigators should attempt to foresee some of the challenges to minimize the need for protocol amendments 83 , 84 , Moreover, the informed consent process has become adapted to facilitate discussions by telephone or video conference, followed by verbal confirmation, and documentation of consent using approved software programs and electronic signature, where acceptable 83 , Monitoring of efficacy and safety outcomes is also critical.

Execution of online Clinical Event Committee and Data and Safety Monitoring Board meetings for assessing the adverse events is a fast, safe, and efficient alternative to face-to-face meetings. If done with appropriate planning to adhere to standards of high-quality Clinical Event Committee and Data and Safety Monitoring Board meetings, such approaches may be considered even when society transitions out of the pandemic 84 , Peer review and dissemination of the studies have had unique challenges and advancements as well.

Journal editors and reviewers have been pressured for rapid release of the results of completed studies. This has activated the fast-track peer review process more than ever. The process of peer review remains an imperfect, yet essential, step in the evaluation and reporting of results Pre-print servers include full drafts of research studies shared publicly before peer review.

Pre-prints have the potential benefit of early dissemination and opportunity for feedback and discussion, and could be of substantial benefit during the pandemic. With a pre-print, key researchers in the field can discover findings sooner, indicate critical errors, or suggest new studies or data that strengthen the argument The limitations of pre-prints should be also communicated transparently, so that similar weight is not placed on pre-print and peer-reviewed literature by the lay people, the press, health care workers, or policy makers.

Indeed, many retracted papers were from pre-print servers