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\begin{document}

\title{COVID-19 Clinical trials: quality matters more than quantity}



\author[1]{Sergio Bonini}%
\author[2]{Giuseppe Maltese}%
\affil[1]{National Research Council}%
\affil[2]{Epsom and Saint Helier University Hospitals NHS Trust Sally Howell Library}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\textbf{COVID-19 Clinical trials: quality matters more than quantity}

\textbf{Sergio Bonini \textsuperscript{1}, Giuseppe
Maltese\textsuperscript{2}}

\textsuperscript{1}Institute of Translational Pharmacology, Italian
National Research Council, Rome, Italy; \textsuperscript{2}Epsom and St
Helier University Hospitals, Surrey, United Kingdom.

Introduction

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 April 28,
PubMed listed 7442 papers published in 2020 (almost eight every working
hour), but this number is increasing as 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\textsuperscript{1,2},
modes of transmission, incubation period, clinical features, incidence
and lethality of the disease\textsuperscript{3,4}.

Following initial discordant strategies in different
countries\textsuperscript{I}, there has also been general agreement on
the efficacy of the lockdown in China and the strict public health
measures firstly 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 governments appear to be fully justified and
supported by accurate modelling on their potential effect on the
mitigation or suppression of the infection\textsuperscript{5}.

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
on the clinical trials exploring potential treatment for COVID-19.

The leading role of allergists and clinical immunologists in the fight
against SARS CoV-2

There is no doubt that allergists and clinical immunologists should be
on the front line in the fight against SARS CoV-2, for different
reasons. First, the host immune response is the main mechanism to block
the viral infection and attenuate or prevent
symptoms\textsuperscript{6}. 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\textsuperscript{5}. Third, beyond plasma-based therapy and
vaccines, several candidate drugs against SARS CoV-2 are part of the
current therapeutic armamentarium of the clinical immunologist and
require the expertise of our specialty\textsuperscript{7}.

So far, 26 clinical trials explore the efficacy of Tocilizumab, an
anti-IL-6R (sIL-6R and mIL-6R) monoclonal approved for rheumatoid
arthritis, giant cell arteritis and the CAR-T induced Cytokine Release
Syndrome \textsuperscript{II-V}. Some other monoclonal antibodies
targeting IL-1, IL-17A, growth factors, complement factors are listed in
Table I.

Beside monoclonal antibodies, several other immunosuppressants and
immunomodulators are under investigation. Interferon beta 1a -- both
intravenously and in an inhaled formulation -, interferon alfa 2a and
peginterferon lamda 1A are object of 31 clinical studies. Immunoglobulin
and convalescent plasma-based therapy are investigated in 35 trials.

Fifteen registered studies\textsuperscript{V} are evaluating the use of
systemic corticosteroids in COVID-19. Despite concern about possible
detrimental effects\textsuperscript{8,9}, 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\textsuperscript{10,11}.

Other non-steroid anti-inflammatory drugs and the effect of cytokine
filtration devices are also under investigation, particularly in
COVID-19 subjects with pneumonia and a severe inflammatory
disease\textsuperscript{7}.

More studies on anti-TNF drugs have also been
recommended\textsuperscript{12}. Among cell-based therapies, 24 studies
plan to investigate the immunomodulatory role of mesenchymal stem
cells\textsuperscript{7}. In an in-silico molecular modelling screening
of 2000 FDA approved drugs for potential inhibitory effect on SARS CoV-2
main protease enzyme (Mpro), the top hits bound to the central site of
Mpro substrate-binding pocket include antiviral drugs such as Darunavir,
Nelfinavir and Saquinavir. Interestingly, the top hits bound to the
terminal site of Mpro substrate-binding pocket included Montelukast and
Fexofenadine\textsuperscript{13}. Independently from the practical
impact of the above observation, this strategy appears promising in
repositioning available drugs , until novel targeted treatments for
COVID-19 are available.

However, despite this intense clinical research and 177 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\textsuperscript{14.} 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)\textsuperscript{15}. However, 53 additional
studies are investigating the efficacy of Lopinavir/Ritonavir in various
severity stages of the disease\textsuperscript{V}.

Following the more promising results of a cohort study of patients
treated with Redemsivir on a compassionate-use\textsuperscript{16}, both
FDA and EMA have permitted the use of this drug in COVID-19. While a
randomized double-blind placebo-controlled trial could not confirm a
significant benefit of Redemsivir in a cohort of 236 patients --
possibly because of the failure to recruit its target of 453
patients\textsuperscript{17} -, Anthony Fauci anticipated that a larger
multi-center trial in over 1000 subjects showed a high significant
(\textless{}0.001) effect on the primary outcome of the study (i.e. time
to recovery, which was reduced from 15 to 11 days)\textsuperscript{VI}.
Eleven more trials on Redemsivir are still ongoing\textsuperscript{V}. 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\textsuperscript{18}.

COVID-19 registries and drugs pipeline

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\textsuperscript{II} (ICTRP) includes 1524 studies,
whose details are not easily accessible. The registry, due to the heavy
traffic generated by the COVID-19 outbreak is temporarily not accessible
from outside the WHO.

US NIH Clinicaltrials.gov\textsuperscript{III} lists 997 trials,
including 617 interventional studies; only 14 of these trials have been
completed, and the results have not been published yet.

EudraCT\textsuperscript{IV} includes 131 clinical trials, which are
still ongoing.

Cytel, Bill\& Melinda Gates' registry\textsuperscript{V} lists 665
clinical trials, 322 from China and 102 dealing with traditional Chinese
medicinal products. Most interventional studies evaluate the effects of
hydroxychloroquine or chloroquine (147 studies), lopinavir/ritonavir (53
studies), plasma based therapy (35), and tocilizumab (26 studies). Only
7 of the 12 studies already completed with results (11 from China and 1
from France) have a randomized study design.

The conclusion of the registry for the two drugs more frequently
investigated is that current data do not support the use of
hydroxychloroquine/chloroquine for prophylaxis and treatment of COVID-19
and do not provide strong evidence about the efficacy of
lopinavir/ritonavir in SARS CoV-2 infection.

In other registries the number of clinical trials ranges from
1480\textsuperscript{VII} to 598\textsuperscript{IX}.

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\textsuperscript{18}.
This approach will make easier 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)\textsuperscript{19} in line with the new EU Clinical Trial
Regulation\textsuperscript{20}. Data sharing is also recommended by
several international institutions\textsuperscript{21} and by the
International Committee of Medical Journal Editors\textsuperscript{22}.
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\textsuperscript{IX}.

The need for a standardized approach in COVID-19 clinical research

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)\textsuperscript{X} and the Core~Outcome Measures in
Effectiveness Trials (COMET) initiative\textsuperscript{XI}.

In fact, the major criticism emerging from a review of the ongoing
trials is the heterogeneity of protocols. Following the decision of both
FDA and EMA, respectively, to allow the use of chloroquine or
hydroxichloroquine and remdesivir in COVID-19\textsuperscript{23,XII},
several small trials have started using these drugs on a compassionate
basis. The EMA has expressed concern for these small studies and the
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 put in place to prioritize
large multi-country randomized trials and multi-arm clinical trials
investigating different agents simultaneously\textsuperscript{XIII}.

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\textsuperscript{24}. 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-centres
trials are highly advisable provided that standard operational
procedures are set out. Adaptive designs might be considered and the
setting should be specified. Rules for informed consent must adapted to
the chosen population. Centralized Ethics Committees or IRBs 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 and COS-STAP statement\textsuperscript{25}.

Age, gender, ethnicity, previous diseases and undergoing treatments have
been reported to influence the incidence of
COVID\textsuperscript{3,26-28}. 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; Fig.1)\textsuperscript{29}.

Several research groups are working on a variety of preventive and
therapeutic interventions. However, despite the accelerated development
pathways adopted by many regulatory bodies\textsuperscript{XIV}, the
marketing authorization pathway for new drugs is a long process, with a
high attrition rate. Therefore, there has been considerable interest in
repurposing existing drugs -- such as antiviral and immunosuppressant
agents - for use in COVID-19\textsuperscript{22}. Studies with these
drugs should keep in consideration the putative mechanisms of action of
the investigational drug in relation to the different phases of
COVID-19. Antiviral agents, for example, should be used during the early
viral phase of the disease while immunosuppressant may be promising
candidate drugs in the severe inflammatory phase (while they might
dampen the immune response if used early on\textsuperscript{14}).
Combination or sequential treatment might also be considered.

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 the
WHO\textsuperscript{XV}. 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 by a 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 end-points 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\textsuperscript{30}.

Conclusions

Hopefully, the unprecedent 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 effects of
COVID-on ongoing trials for other diseases. 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.

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Resources

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\emph{II. https://www.who.int/ictrp/en/}

\emph{III.
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\emph{IV.http://clinicaltrialregister.eu/ctr-search/search?query=COVID-19}

\emph{V. https://www.covid19-trials.com/}

\emph{VI.https://www.nature.com/articles/d41591-020-00016-y}

\emph{VII. covid19.trialstracker.net/index.html}

\emph{VIII.cellstrials.org}

\emph{IX. www.vivli.org}

\emph{X. https://www.spirit-statement.org/}

\emph{XI. http://www.cometinitiative.org/Resources}

\emph{XII.}
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\emph{XIII.}
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\emph{XIV.}
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\emph{XV.
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments}

XVI.\emph{https://laegemiddelstyrelsen.dk/da/nyheder/temaer/ny-coronavirus-covid-19/\textasciitilde{}/media/5B83D25935DF43A38FF823E24604AC36.ash}

\emph{XVII. https://covid19treatmentguidelines.nih.gov/introduction/}

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