Continuous low dose subcutaneous lidocaine for treatment of the symptoms of COVID*19.   A randomised controlled open*label phase III study.

The COVID-19 pandemic has become a major challenge for countries and global
institutions to control. Patients are admitted to the general ward and ICU with
respiratory symptoms, exceeding the maximum hospital capacity within a few
weeks. The major complication of a COVID-19 infection is respiratory failure
and acute respiratory distresssyndrome (ARDS). Invading viral pathogens in the
airways cause cellular stress. This causes a massive exocytosis of ATP,
resulting in high extracellular ATP concentrations. Initially, this stimulates
purinergic P2Y2 and P2X4 receptors, resulting in a short period of surfactant
exocytosis, but as ATP levels continue to rise,the P2X4 and P2Y2 receptors are
insensitive to preventing normal release of surfactants. At some point, the
extracellular levels of ATP exceed the lower threshold for the activation of
the P2X7 extracellular ATP receptors (P2X7Rs) located on the cell surface of
the innate immune cells. This causes a pro-inflammatory response ofinnate
immunity, followed by a massive release of inflammatory mediators and cytokine
storm. The resulting vascular leakage and pulmonary edema cause the
disaggregation and inactivation of lung surfactant, a key element in the
pathogenesis of ARDS, ending in alveolar collapse and decreased gas exchange.
The conversion of extracellular ATP by ectonucleotidases to adenosine activates
the different adenosine receptors (i.e. adenosine receptor A1 - AdoRA1,
AdoRA2A, AdoRA2b and AdoR3). This leads to secondary immune suppression, which
is the basis of the compensatory anti-inflammatory response syndrome (CARS),
sometimes followed by pulmonary fibrosis.Here we propose to target the P2X7R in
COVID-19 ARDS patients with lidocaine. Lidocaine is widely known and is used as
a safe analgesic. It deactivates fast voltage-dependent Na + channels and
limits the transmission of neurons. However, it has also been described as a
powerful and selective P2X7R inhibitor. Both after pharmacological inhibition
and in P2X7R knockout mice, survival in ARDS is increased in preclinical
models. We hypothesize that lidocaine has an anti-inflammatory effect that can
be used to prevent progression to ARDS and to treat ARDS in COVID-19 patients.
Finally, the anti-nociceptive agent lidocaine has a clear advantage over other
immunosuppressants, as it primarily targets hyperactivity of the innate immune
system through inhibition of the P2X7 receptor. Corticosteroids, for example,
result in a broad immunosuppression that decreases the ability to fight the
viral infection, while humanized monoclonal antibodies (i.e., tocilizumab and
anakinra) are feared for their serious side effects.

To determine the effect of lidocaine on the main symptoms of COVID-19.

Phase III open-label randomized controlled trial to demonstrate the clinical
efficacy of continuous low dose subcutaneous lidocaine to alleviate key
symptoms in patients with COVID-19 requiring hospitalization.

The IMP used in this study is lidocaine. Lidocaine will be administered as a
subcutaneous loading dose of 1 mg/kg, followed by a continuous subcutaneous
lidocaine infusion of 1 mg/kg/hr. Treatment duration will be 21 days or (if
applicable) until discharge, whichever comes first.
Patients randomized to the control arm will receive standard of care.

The subject will receive a drug that is not yet known to be effective in
combating symptoms of COVID-19. However, there are currently few alternatives.
There are risks that can potentially occur:reportedly, a metallic taste in the
mouth may occur after a local injection of lidocaine. Type I (anaphylactic
reaction) and type IV hypersensitivity to lidocaine are very rare. Other
adverse effects of lidocaine (central nervous system, cardiac, respiratory and
allergic effects) are caused only by plasma concentrations above 5 µg / ml
(0.021 mmol / L). Examples of deaths involving lidocaine overdose and an
anaphylactic reaction are shown in Table 5 (Section 6.3.2 in the protocol). It
should be borne in mind that even after administration of the recommended doses
by the appropriate route, the plasma concentrations of lidocaine can be
unpredictable when the elimination of lidocaine by the liver and kidneys, as
mentioned above, is impaired. Because side effects only occur with high blood
concentrations, we do not expect to experience a serious side effect of
lidocaine in this study. Minor side effects (metallic taste in the mouth,
dizziness, etc.) can be reversed by discontinuing treatment with lidocaine or
by administering a lower dose.Furthermore, the daily tax is low. The subject
must complete a questionnaire daily for a maximum of 21 days or discharge
(whichever comes sooner).