key: cord-0940996-5wsfr0oz
authors: Bonini, Sergio; Maltese, Giuseppe
title: COVID‐19Clinical trials: quality matters more than quantity
date: 2020-05-20
journal: Allergy
DOI: 10.1111/all.14409
sha: 98426a2fb62b331eabe2b75d378abb2015db3454
doc_id: 940996
cord_uid: 5wsfr0oz

Despite the ferment aroused in the scientific community by the COVID‐19 outbreak and the over 11,000 papers listed in PubMed, published evidence on safe and effective drugs has not progressed yet at the same speed of the pandemic. However, clinical research is rapidly progressing, as shown by the hundreds of registered clinical trials on candidate drugs for COVID‐19. Unfortunately, information on protocols of individual studies differs from registry to registry. Furthermore, study designs, criteria for stratification of patients and choice of outcomes are quite heterogeneous. All this makes data sharing and secondary analysis difficult.At last, small single centre studies and the use of drugs on a compassionate basis should be replaced by highly powered, multi‐centre, multi‐arm clinical trials, in orderto provide the required evidence of safety and efficacy of novel or repurposed candidate drugs. Hopefully, the efforts of clinical researchers in the fight against the SARS Cov‐2 will result into the identification of effective treatments. To make this possible, clinical research should be oriented by guidelines for more harmonized high‐quality studies and by a united commitment of the scientific community to share personal knowledge and data. Allergists and clinical immunologists should have a leading role in this unprecedent challenge.

Covid-19 has aroused an unprecedented scientific ferment to tackle this deadly pandemic. The most important scientific journals, including Allergy, have created a specific section on COVID-19. As of May 12, day of submission, a PubMed search for COVID-19 shows11,336papers published in 2020 (almost 10 every working hour).However, this number increasesas rapidly as the number of worldwide infected people and deaths reported daily by the WHO and the national authorities. Through this emerging literature, much has been learned on the mechanisms of SARS CoV-2 infection 1,2 , modes of transmission, incubation period, clinical features, incidence and lethality of the disease 3,4 .

Following initial discordantstrategies in different countries 5 , there has also been general agreement on the efficacy of the lockdown in China and the strict public health measuresfirstly implemented in Europe by the Italian government to suppress COVID-19 diffusion (isolation of areas with a high number of positive cases, closure of non-essential public places, schools and universities, cancellation of congresses and mass gathering events). Recommendations made by governmentsfor a lockdown -although implemented at different times -appear to be fully justified and supported by accurate modelling on their potential effect on the mitigation or suppression of the infection 6 .

On the other hand, the search for an effective therapy of COVID-19 is still a work in progress, which demands a harmonized approach of the scientific community. This article aims to provide a critical overview of the clinical trials exploring candidate drugs for potential treatment for COVID-19. The several ongoing clinical trials on SARS-CoV-2 vaccines do not fall within the scope of this article.

There is no doubt that allergists and clinical immunologists should be on the front line in the fight against SARS CoV-2, since their expertise is required for a better understanding of COVID-19pathophysiology and its management.First, the host immune response is the main mechanism to block the viral infection and attenuate or prevent symptoms 7 . Second, there is a wide consensus that the progression of the disease to the most severe life-threatening forms is associated with an intense inflammatory process and a cytokine storm 7 . Third, beyond plasma-based therapy and vaccines, several candidate drugs against SARS CoV-2

This article is protected by copyright. All rights reserved are part of the current therapeutic armamentarium of the clinical immunologist and require the expertise of our specialty 8 .

In fact, 39 clinical trials explore the efficacy of Tocilizumab, an anti-IL-6R (sIL-6R and mIL-6R) monoclonal antibody widely used by allergists and clinical immunologists for the treatment of rheumatoid arthritis, giant cell arteritis and the CAR-T induced Cytokine Release Syndrome 9 . Some other candidate monoclonal antibodies for COVID-19 clinical trials -targeting IL-1, IL-17A, growth factors, complement factors -, are listed in Table I . Twenty-three registered studies 9 are evaluating the use of systemic corticosteroids in COVID- 19 . Despite concern about possible detrimental effects 10, 11 , there is yet no evidence for or against their use in COVID-19 patients. There is rational to speculate that their safety and efficacy may be different in the early viral phase compared to the late inflammatory phase. Conversely, there is no evidence to withdraw an ongoing treatment with inhaled steroids in subjects with asthma and rhinitis 12, 13 .

Other immunomodulatory/immunosuppressive drugs and the effect of cytokine filtration devices are also under investigation, particularly in COVID-19 subjects with pneumonia and a severe inflammatory

More studies on anti-TNF drugs have been recommended 14 . Among cell-based therapies, 24 studies plan to investigate the immunomodulatory role of mesenchymal stem cells 8 .

However, despite this intense clinical research and236 papers (including 4 systematic reviews) on COVID-19 treatment listed by PubMed, evidence available for safe and effective drugs has not progressed at the same speed of the pandemic 15 .In fact, to our knowledge only very few clinical trials have been published.

The randomized, open-label trial with Lopinavir/Ritonavir in 199 patients with severe COVID-19 failed to meet the primary end-point (time to clinical improvement) 16 . However, 70additional studies are investigating the efficacy of Lopinavir/Ritonavir in various severity stages of the disease 9 .

Following the more promising results of a cohort study of patients treated with Remdesivir on a compassionate-use 17 , both FDA and EMA have permitted the use of this drug in COVID-19 clinical trials.

While a randomized double-blind placebo-controlled trial could not confirm a significant benefit of Remdesivir in a cohort of 236 patients -possibly because of the failure to recruit its target of 453 patients 18 -, it has been recently anticipated that a larger multi-centre trial in over 1000 subjects showed a high significant (<0.001) effect on the primary outcome of the study (i.e. time to recovery, which was

This article is protected by copyright. All rights reserved reduced from 15 to 11 days) 19 .Eleven more trials on Remdesivirare still ongoing 9 . A few additional published studies with hydroxichloroquine vs best supportive care, favipiravir vs umifenovir, and lopinavir/ritonavir vs umifenovir are reported by Thorlund and co-workers 20 .

However, clinical research is rapidly expanding and hundreds of clinical trials have been registered including, beside immunologic drugs, anti-viral drugs, protein-kinase inhibitors, anti-inflammatory drugs, or drugs aimed at facing the most severe symptoms of COVID-19, such as anti-coagulants, anti-infective drugs, drugs for the cardiovascular, respiratory and nervous systems ( Table 2 ).

The WHO registry 21 (ICTRP) included, at April 29,1524 studies, whose details are not easily accessible. The Only8studies are already completed with results (7 from Chinaand 1 from France) but only one has have a randomizeddouble-blind study design.

The comparative review of registries allows some critical considerations.

There is a substantial discrepancy in the number of studies reported in different registries and it is quite difficult to identify duplicates among registries or studies listed in some registries but not in others.

Furthermore, the available information for individual studies differs from registry to registry and is not easily extractable. At last, protocols of studies are not accessible in most registries. Thus, it is highly appreciable the initiative of tracking and collating clinical trials in a single registry, also using artificial intelligence-based methods for data search and aggregator services 20 .This approachwill alloweasier data sharing among investigators and analysis of pooled data.

Data sharing and secondary analysis represent valuable tools to advance knowledge and help regulatory decisions. Transparency policies have been recently adopted in Europe by the European Medicines Agency (EMA) 24 

This article is protected by copyright. All rights reserved several international institutions 26 and by the International Committee of Medical Journal Editors 27 . Data sharing appears fundamental in health emergencies, such as COVID-19 outbreak, to implement rapid and effective responses. Several platforms are available for data storage and analysis also offering protocol assistance and free anonymization of data from subjects with COVID-19 28 .

However, in order to make feasible secondary analysis of individual studies, these should follow guidelines for standard protocols and minimal requirements for outcome measures such as the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) 29 and the Core Outcome Measures in Effectiveness Trials (COMET) initiative 30 .

In fact, the major criticism emerging from a review of the ongoing trials is theheterogeneity of protocols.

Following the decision of both FDA and EMA,respectively, to allow the use of chloroquine or hydroxichloroquine and remdesivirfor clinical trials inCOVID-19 31, 32 ,several small trials have started using these drugs on a compassionate basis. The EMA hasexpressed concern for these small studies andthe compassionate use programmes across Europe, as they are unlikely to produce the required level of evidence of efficacy and safety of investigational drugs. On the contrary, the EMA strongly recommends that a more coordinated approach and efforts are putin place to prioritize large multi-country randomized trials and multi-arm clinical trials investigating different agents simultaneously 33 .In order to generate robust evidence on efficacy and safety of drugs and vaccines for COVID-19,EMA offersfree scientific advice on the best methods and designs to be usedin clinical trials 34 .

Unarguably, high quality clinical trials cannot be easily performed in the setting of an outbreak, when investigators are often asked to make patients' care a priority. Nonetheless, even if adapted to this challenging context, high quality research is still needed 35 . Accordingly, a more standardized approach to clinical research on COVID-19 should be warranted, including a rigorous but realistic study design, a well characterized study population stratified on the basis of age and severity of the disease, a rationale behind the use of the investigational drug and the choice of comparator, and optimal minimal primary outcome(s).

With regard to the study design, while masking might be difficult in studies of COVID-19, randomization should be mandatory. Multi-centre trials are highly advisable provided that standard operational procedures are set out. Adaptive designs might beconsidered and the setting should be specified. Rules for informed consent must adapted to the chosen population. Centralized Ethics Committees or IRBs

This article is protected by copyright. All rights reserved might favour a more rapid start of the trial. Investigators should be encouraged to publish the study protocol to be drafted according to the SPIRIT 29 and COS-STAP statement 36 .

Age, gender, ethnicity, previous diseases and undergoing treatments of the selected population have been reported to influence the incidence of COVID 3, 4, [37] [38] [39] . Demographic and history data should be obtained, possibly through a standard questionnaire, along with other patients' characteristics such as social status and environmental exposure.

While waiting for a consensus on criteria for the diagnosis of COVID-19 and a classification of the disease, patients should be stratified on the basis of the study setting, severity, and the predominant pathophysiological abnormality in different phases of the disease (viral, pulmonary, inflammatory; Standard of care seems to be a more realistic comparator than placebo, in view of the emergency nature of the epidemic.

Collaborative trials and multi-arm studies comparing different drugs should also be considered.A commendable example of this kind of approach is represented by the Solidarity clinical trial launched by

This article is protected by copyright. All rights reserved the WHO 43 .The Solidarity trial is a randomized multi-countries open label trial which compares the efficacy of four treatment options (Remdesivir, Lopinavir/Ritonavir, Interferon beta-1a and Chloroquine or Hydroxychloroquine) against standard of care in hospitalized adult patients with COVID-19. Underlying conditions are recorded and severity of illness at entry is determined bya reduced set of end-points that can be recorded even in overwhelmed hospitals. Clinically relevant outcomes undergo an interim analysis by an independent Global Data and Safety monitoring Committee. The simplicity of the trial is balanced by the thousands of patients that are expected to be recruited in more than 70 countries. Preliminary results of this trial are expected by June 2020.

In more rigorous study designs, primary outcome measures should be chosen in relation to the phase of the disease and the drug under investigation. While SARS CoV-2 RNA clearance and the effects on the progression of the disease may represent significant outcome measures for antivirals in the mild forms of the disease, hard end-points such survival/death are advisable in the most severe forms.However, a core outcome standard set is urgently needed to define a minimal set of outcome measures relevant to patients, investigators and regulators 44 .

Hopefully, the efforts of clinical researchers in the fight against the SARS Cov-2 will result into the identification of effective treatments. This would largely counterbalance the delaying effectsof COVID-on ongoing trials for other diseases 45 .However, these efforts might be negatively affected in the absence of guidelines for a more harmonized clinical research and a united commitment of the scientific community to share personal knowledge and data. Allergists and clinical immunologists should have a leading role in this unprecedent challenge.

Conflict of Interest statement: The authors have nothing to disclose.

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Legenda: ICU = Intensive Care Unit

SatO 2 = Oxigen saturation

PaO2/FiO2 = ratio of arterial oxygen partial pressure (PaO2, in mmHg) to fractional inspired oxygen (FiO2, expressed as a fraction)

Chain Reaction

Flow Nasal Cannula

NIPPV = Non-Invasive Positive Pressure Ventilation

LMWH = Low molecular-weight heparins

LFTs = Liver Function Tests; CAP = Community acquired