Understanding COVID-19 Pandemic: Molecular Mechanisms and Potential Therapeutic Strategies. An Evidence-Based Review

Figures & data

Figure 1 Modified schematic diagram illustrates COVID-19 clinical presentation, diagnostic investigations, assessment of disease severity and consideration of care settings accordingly.²,³,^21–23

Figure 2 Modified schematic diagram illustrates the etiopathogenesis and pathophysiology of COVID-19. Data from Wiersinga et al.⁶⁴

Table 1 The Advantages and Drawbacks of the Therapeutic Strategies in COVID-19 Management

Therapeutic Modality	Category	Generic Name	Advantages	Drawbacks
Antiviral therapy	Antiviral cytokines	INFα and INFβ^Citation81	Broad antiviral activity Broad spectrum antivirals, exhibiting both direct inhibitory effects on viral replication and supporting an immune response to clear virus infection INFβ is better tolerated than INFα No signs of adverse birth outcome	Flu-like symptoms, nausea, fatigue, weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (eg, depression and suicidal ideation). The most serious drug-drug interactions with IFNs are the potential for added toxicity with concomitant use of other immunomodulators and chemotherapeutic agents
	Antiviral drugs	Ribivarin^Citation89	Existing inventory Reliable supply chain	Hepatic injury, myopathy, neuropathy, bone marrow suppression, and pancreatitis
		Remdesivir^Citation93	Short recovery time Does not alter the QTc interval Shortens the time to recovery in adults with no effect on mortality	Diarrhea, rash, renal failure, and hypotension, increased liver enzymes.
		Lopinavir Ritonavir^Citation99^–^Citation101	Ability to bind to the endopeptidase C30 of SARS-CoV-2 and downgrade the respiratory distress	Hyperlipidemia, systemic hypersensitivity syndromes, and Achilles Tendinopathy
		Nelfinavir^Citation103	Strongly inhibited replication of the SARS-CoV-2 expression of viral antigens	Nausea and diarrhoea
		Arbidol^Citation105,^Citation106	Broad-spectrum antiviral drug Blocks the viral replication process of SARS-CoV Well tolerated in children and adults	Allergic reactions, nausea, diarrhoea, dizziness and elevated serum transaminase
	Antimalarial drug	Chloroquine^Citation110,^Citation111	Potent antiviral effect Broad-spectrum antiviral drug Inexpensive drug Good patient safety report and tolerance levels Interference with ACE2 to block virus invasion; increase of endosomal pH required for virus fusion; mild immune suppression	Retinal or psychiatric symptoms
Corticosteroids	Glucocorticoids	Dexamethasone^Citation115	Potent anti-inflammatory effects against the cytokine storm Anti-allergic	Increased appetite, irritability, difficulty in sleeping (insomnia), swelling in your ankles and feet (fluid retention), heartburn, muscle weakness, impaired wound healing, increased blood sugar levels
		Hydrocortisone^Citation115,^Citation117	Antishock therapy Can be used as an alternative to dexamethasone to treat patients severely ill with COVID-19	Slow wound healing, thinning skin, increased body hair, irregular menstrual periods, changes in sexual function/muscle weakness, tired feeling, depression, anxiety, feeling irritable
Immunotherapy		CPT^Citation120,^Citation121	Safe, clinically effective, and reduces mortality, used in past epidemics	Transfusion related acute lung injury, transfusion associated circulatory overload, and allergic/anaphylactic reactions, transmission of infections, febrile nonhemolytic transfusion reactions, RBC alloimmunization, and hemolytic transfusion reactions
		Tocilizumab^Citation127^–^Citation129 Anakinra^Citation131	Potent anti-inflammatory action	Headache or dizziness, mouth ulcers, high blood pressure, hypercholesterolemia, allergic reactions, weight gain or swollen ankles, stomach irritation or abdominal pain, affects immune system and healing, neutropenia, immunosuppressive therapy may lead to reactivation of latent tuberculosis or other atypical or opportunistic infections
		Antibody cocktail^Citation146,^Citation147	Targeted killing, fast symptom-relief, speedy recovery, minimal side effects	None encountered to date
	ACE receptor binding strategy^Citation169		Denoted as novel SARS-CoV-2 receptor and plays an important role in modulating immunity, inflammation, ACE2, and cardiovascular disease	None encountered to date
	Exosomes^Citation170,^Citation171		Helps in disease detection and treatment Natural drug delivery vehicles High specificity and efficiency	Inefficient separation methods, difficulties in characterization, and lack of specific biomarkers
	Cellular therapy	MSCs^Citation172,^Citation173	Stem cells are able to suppress the activities of viruses via Chaf1a- mediated and Sumo2-mediated epigenetic regulation (termed pro-viral silencing) Beneficial effects in ARDS	Lack of clarity with regard to optimal dose and route of MSC delivery, difficulties in large-scale production and cryopreservation, and the potential for substantial variability
	RAS blockers^Citation174		Not associated with an increased risk of death, admission to ICU, mechanical ventilation requirement or progression to severe or critical pneumonia in COVID‐19-infected hypertensive patients, can be used safely in children and adults	Insufficient evidence of their potential harm and overwhelming evidence on their benefits
	Traditional Chinese medicines		Used in previous epidemics, remarkable symptomatic relief, antipyretic, faster recovery, reduced stay in hospital	Hypersensitivity pneumonitis, lung injury, fatigue with gastrointestinal discomfort
	Antioxidants	Food products rich in vitamins C and E	Can prevent or reduce the damage caused by oxidation Can reduced the risk of cardiovascular disease	Bruising under the skin, diarrhea, dizziness, joint pain
	Curcumin		Scientifically proven health benefits Potent anti-inflammatory and antioxidant and may also help improve symptoms of depression and arthritis	None encountered to date
	Natural therapies	Omega 3 fatty acids Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA)^Citation182	Anti-inflammatory	EPA and DHA can make cell membranes more susceptible to non-enzymatic oxidation mediated by reactive oxygen species, leading to the formation of potentially toxic oxidation products and increasing the oxidative stress
		Manuka honey^Citation183	Antibacterial Anti-inflammatory Promotes wound healing The higher the concentration of MGO, the stronger the antibiotic effect	None encountered to date
		Potato starch^Citation184	Prebiotic effect	None encountered to date
Phototherapy	PDT/a-PDT		There is no an accumulative dose: a lack of microbial specificity and the development of resistance mechanisms^Citation212 Good helper in the phagocytosis process, including inactivation of pathogen proliferation^Citation213 Clinical PDT protocol against pharyngotonsillitis in reducing more than 90% of the symptoms related to the disease after 24 h were observed. Hence, PDT is significant to inactivation the viral infection and reduce viral load in the respiratory tract^Citation221 MB mediated PDT could be a potential treatment modality for an early and advanced bronchopulmonary infection^Citation223 The delivery of three photosensitizers (ICG, the chlorine photodithazine, and porphyrin photogem) in a jet nebulizer device has showed to be effective to target the lung directly^Citation225 Effective, innovative, accessible, cost-effective treatment modality^Citation226 A reduction in mortality rate and severity of the course of disease, a reduction of viral load in COVID-19 patients^Citation226 Plasma inactivation of SARS-CoV-2 to ensure safe blood transfusion^Citation227	None encountered to date
	Laser-PBMT		Anti-inflammatory: attenuates cytokine storm at multiple levels and reduces the major inflammatory metabolites^Citation189^–^Citation194 Increases collagen and protein production, cell proliferation, normalized of impaired circulation, decreases edema and swelling, and improves quality and tensile strength of tissue^Citation189^–^Citation194 PBMT reduces pulmonary microvascular leakage, IL-1β, IL-6, and intracellular ROS. On this note, PBMT as a single or adjunct treatment modality can modulate the cytokine storm and ARDS via its anti-inflammatory action^Citation196^–^Citation199 Reduces inflammation and promotes lung healing^Citation199,^Citation205,^Citation206 and minimizes the scarring process^Citation189^–^Citation194 Has an immunomodulator effect in improving immune functional and modulating the cellular and molecular activities of the cytokine storm of SARS-CoV-2^Citation200,^Citation203,^Citation206 It is a safe, effective, low-cost modality without any side effects that may be combined with conventional treatment of ARDS^Citation196^–^Citation199 Minimizes the length of time needed on a ventilator, enhance the healing process, and shorten recovery time in COVID-19 patients^Citation199,^Citation200 PBMT as a single or adjunct treatment modality can modulate the cytokine storm and ARDS via its anti-inflammatory action^Citation196^–^Citation199 Antioxidant: reduces pain related to inflammation via dose-dependent reduction of prostaglandin E2, prostaglandin-endoperoxide synthase-2, IL-1, IL-6, TNFa, as well as the cellular influx of neutrophils, oxidative stress^Citation201^–^Citation203 Prevents acidosis and hypoxia in COVID-19 patients results in SpO2 improvement and lung healing in COVID-19 pneumonia^Citation199,^Citation205,^Citation206,^Citation210 PBMT combined with conventional medical therapy has a potential to prevent COVID-19 progress and improve symptoms^Citation200 PBMT combined with conventional treatment in patients with severe COVID-19 and morbid obesity is safe and effective^Citation211 and is potential to prevent COVID-19 progress and improve symptoms^Citation200	None encountered to date
	LEDs-PBMT		It has the same advantages as the laser-PBMT; however, the difference is that LEDs-PBMT delivers noncoherent light via a clustered probe of multiple wavelengths, which provide various penetration depths^Citation187,^Citation188 Itis safe, efficient and cost-effective treatment modality that can irradiate a large surface area, which can be useful in COVID-19 management.^Citation210	None encountered to date

Table 2 Shows the Clinical Trials Registered on ClinicalTrials.gov to October 20, 2020, Utilizing Antiviral Therapies for the Treatment of COVID-19

Study Identifier and Citation (Superscript)	Treatment Protocol	Study Phase; Estimated Enrolment (n)	Primary Outcome Measure(s)	Recruitment Status
NCT04492475^Citation83	Drug: IFNβ1a: rebif (R) is a purified 166 amino acid human IFNβ glycoprotein with an amino acid sequence identical to natural fibroblast derived human IFNβ. Each 0.5 mL prefilled syringe contains 44 µg of IFNβ1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP. Other: placebo: the IFNβ1a placebo contains either 0.5 mL 0.9% normal saline or 0.5 mL sterile water for injection. Drug: remdesivir: is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441,524. In addition to the active ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide	Phase III n=1038	Time to recovery (Time frame: day 1 through day 29) Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: (1) hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; (2) not hospitalized, limitation on activities and/or requiring home oxygen; (3) not hospitalized, no limitations on activities.	Recruiting
NCT04343976^Citation84	Drug: pegylated IFNλ 180 µg subcutaneous injection of pegylated IFNλ Other name: lambda	Phase II n=20	Undetectable COVID PCR at day 7 (Time frame: 1 week) Negative COVID PCR testing 7 days after first lambda dose	Enrolling by invitation
NCT04343768^Citation85	Experimental: hydroxychloroquine+lopinavir/ritonavir+IFNβ1a Experimental: hydroxychloroquine+lopinavir/ritonavir+IFNβ1b Active comparator: control group: hydroxychloroquine+lopinavir/ritonavir	Phase II n=60	Time to clinical improvement (Time frame: from date of randomization until 14 days later) Improvement of two points on a seven-category ordinal scale (recommended by the WHO: Coronavirus disease (COVID-2019) R&D. Geneva: WHO) or discharge from the hospital, whichever came first.	Completed
NCT04280705^Citation95	Placebo comparator: placebo: 200 mg of remdesivir placebo administered IV on day 1, followed by a 100 mg once-daily maintenance dose of remdesivir placebo while hospitalized for up to a 10-day total course n=286. Experimental: remdesivir: 200 mg of remdesivir administered IV on day 1, followed by a 100 mg once-daily maintenance dose of remdesivir while hospitalized for up to a 10-day total course n=286.	Phase III n=1062	Percentage of subjects reporting each severity rating on the 7-point ordinal scale (Time frame: day 15) The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: (1) death; (2) hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); (3) hospitalized, on noninvasive ventilation or high flow oxygen devices; (4) hospitalized, requiring supplemental oxygen; (5) hospitalized, not requiring supplemental oxygen; (6) not hospitalized, limitation on activities; (7) not hospitalized, no limitations on activities.	Completed
NCT04292899^Citation96	Drug: remdesivir: administered as an IV infusion (other names: GS 5734^TM, Veklury^® Drug: standard of care: standard of care treatment for COVID-19 infection	Phase III n=4891	The odds ratio for improvement on a 7-point ordinal scale on day 14 (time frame: day 14) The odds ratio represents the odds of improvement in the ordinal scale between the treatment groups. The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: (1) death (2) hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (3) hospitalized, on noninvasive ventilation or high flow oxygen devices (4) hospitalized, requiring low flow supplemental oxygen (5) hospitalized, not requiring supplemental oxygen—requiring ongoing medical care (coronavirus (COVID-19) related or otherwise) (6) hospitalized, not requiring supplemental oxygen—no longer required ongoing medical care (other than per protocol remdesivir administration (7) not hospitalized	Completed
NCT04292730^Citation97	Drug: remdesivir: administered as an IV infusion (other names- GS 5734^TM, veklury^® Drug: standard of care: standard of care treatment for COVID-19 infection	Phase III n=1113	The odds ratio for improvement on a 7-point ordinal scale on day 11 (Time frame: day 11) The odds ratio represents the odds of improvement in the ordinal scale between the treatment groups. The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: (1) death (2) hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (3) hospitalized, on noninvasive ventilation or high flow oxygen devices (4) hospitalized, requiring low flow supplemental oxygen (5) hospitalized, not requiring supplemental oxygen—requiring ongoing medical care (coronavirus (COVID-19) related or otherwise) (6) hospitalized, not requiring supplemental oxygen—no longer required ongoing medical care (other than per protocol remdesivir administration (7) not hospitalized.	Completed
NCT04409262^Citation98	Experimental: remdesivir+tocilizumab (RDV+TCZ): participants assigned to the RDV+TCZ arm will receive an RDV loading dose followed by one infusion of TCZ on day 1, and a once-daily maintenance dose of remdesivir from days 2–10. Interventions: drug: remdesivir; drug: tocilizumab Active comparator: remdesivir+placebo (RDV+placebo): participants assigned to the RDV+placebo arm will receive an RDV loading dose followed by one infusion of TCZ-placebo on day 1, and a once-daily maintenance dose of RDV from days 2–10. Interventions: drug: remdesivir; drug: placebo	Phase III n=450	Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on day 28 (Time frame: day 28)	Recruiting
NCT04381936^Citation104	Drug: lopinavir-ritonavir: lopinavir 400 mg-ritonavir 100 mg by mouth (or nasogastric tube) every 12 h for 10 days. Drug: corticosteroid: corticosteroid in the form of dexamethasone administered as an oral (liquid or tablets) or IV preparation 6 mg once daily for 10 days. In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or IV hydrocortisone 80 mg twice daily) should be used instead of dexamethasone. Corticosteroid (in children ≤44 weeks gestational age, or >44 weeks gestational age with PIMS-TS only) in the form of hydrocortisone or methylprednisolone sodium succinate (see protocol for timing and dosage) Drug: hydroxychloroquine: hydroxychloroquine by mouth for a total of 10 days (see protocol for timing and dosage). Drug: azithromycin: azithromycin 500 mg by mouth (or nasogastric tube) or IV once daily for 10 days. Biological: convalescent plasma: single unit of ABO compatible convalescent plasma (275mL±75 mL) IV per day on study days 1 (as soon as possible after randomization) and 2 (with a minimum of 12 h interval between first and second units) Drug: tocilizumab: tocilizumab by IV infusion with the dose determined by body weight (see protocol for dosage) Biological: immunoglobulin: IV immunoglobulin (IVIg) for children >44 weeks gestational age and <18 years with PIMS-TS only (see protocol for dosage) Drug: synthetic neutralizing antibodies: for participants ≥12 years only: a single dose of REGN10933+REGN10987 8 g (4 g of each monoclonal antibody) in 250 mL 0.9% saline infused IV over 60in±15 min as soon as possible after randomization (other name: REGN-COV2)	Phase: II, III n=15,000	All-cause mortality (Time frame: within 28 days after randomization) For each pairwise comparison with the “no additional treatment“ arm, the primary objective is to provide reliable estimates of the effect of study treatments on all-cause mortality.	Recruiting
NCT04260594^Citation109	Drug: arbidol Arbidol tablets: take 2 tablets/time, 3 times/day for 14–20 days Other name: the basic treatment used by the investigator was based on the condition of the patient Other: basic treatment basic treatment	Phase IV n=380	Virus negative conversion rate in the first week (Time frame: first week)	Not yet recruiting
NCT04347980^Citation113	Drug: dexamethasone and hydroxychloroquine: patients included in the hydroxychloroquine/dexamethasone group will benefit from standardized ventilatory management and administration of hydroxychloroquine in the same manner as the hydroxychloroquine group. They will receive in addition to dexamethasone at a rate of 20 mg IV for 15 min once a day for 5 days (D1 to D5) then at a rate of 10 mg per day from D6 to D10. If the patient is extubated before the tenth day, he will receive his last dose of dexamethasone before. (Other name: standard ventilatory management) Drug: hydroxychloroquine: patients included in the hydroxychloroquine group will benefit from standardized ventilatory management. Patients included in the hydroxychloroquine group will receive 200 mg⨰3/day enterally from J1 of the HCQ for 10 days. If the patient is extubated before the tenth day, he will receive his last dose of HCQ before. (Other name: standard ventilatory management)	Phase III n=122	Day-28 mortality (time frame: 28 days after randomization) Mortality rate evaluated 28 days after randomization	Recruiting
NCT04334928^Citation114	Drug: emtricitabine/tenofovir disoproxil Emtricitabine/tenofovir disoproxil, 200 mg/245 mg tablets. A dose of one tablet once a day will be administered. Drug: hydroxychloroquine Hydroxychloroquine, 200 mg tablets. A dose of one tablet once a day will be administered. Drug: placebo: emtricitabine/tenofovir disoproxil placebo Placebo: tablets similar in appearance to emtricitabine/tenofovir disoproxil Drug: placebo: hydroxychloroquine Placebo: tablets similar in appearance to hydroxychloroquine	Phase III n=4000	Number of confirmed symptomatic infections of SARS-CoV-2 (COVID-19) (time frame: 12 weeks)	Recruiting
NCT04513184^Citation118	Drug: IV dexamethasone 6 mg from day 1 to 10 after randomization Other name: ST Drug: nasal dexamethasone 0.12 mg/kg/daily for 3 days from day 1, followed by 0.06 mg/kg/daily from day 4 to 10 after randomization. Other name: nasal DXM	Phase II n=60	Time of clinical improvement (time frame: 10 days after randomization) Evaluation of the clinical status of patients after randomization, defined as a two-point improvement in the WHO 7-point ordinal scale	Recruiting
NCT04509973^Citation119	Experimental: dexamethasone 12 mg IV bolus injection of dexamethasone 12 mg once daily in addition to standard care for up to 10 days. We will allow the use of betamethasone 12 mg at sites, where dexamethasone is not available. Intervention: drug: dexamethasone Active comparator: dexamethasone 6 mg IV bolus injection of dexamethasone 6 mg once daily in addition to standard care for up to 10 days. We will allow the use of betamethasone 6 mg at sites, where dexamethasone is not available. Intervention: Drug: dexamethasone	Phase III n=1000	Days alive without life support at day 28 (time frame: day 28 after randomization) Days alive without life support (ie invasive mechanical ventilation, circulatory support or renal replacement therapy) from randomization to day 28	Recruiting
NCT04310228^Citation133	Drug: favipiravir combined with tocilizumab Favipiravir: On the first day, 1600 mg each time, twice a day; from the second to the seventh day, 600 mg each time, twice a day. Oral administration, the maximum number of days taken is not more than 7 days. Tocilizumab: the first dose is 4~8 mg/kg and the recommended dose is 400 mg. For fever patients, an additional application (the same dose as before) is given if there is still fever within 24 h after the first dose and the interval between two medications ≥12 h. IV infusion, the maximum of cumulative number is two, and the maximum single dose does not exceed 800 mg. Drug: favipiravir On the first day, 1600 mg each time, twice a day; from the second to the seventh day, 6 00 mg each time, twice a day. Oral adm inistration, the maximum number of days taken is not more than 7 days. Drug: tocilizumab The first dose is 4~8 mg/kg and the recommended dose is 400 mg. For fever patients, an additional application (the same dose as before) is given if there is still fever within 24 h after the first dose and the interval between two medications ≥12 h. IV infusion, The maximum of cumulative number is two, and the maximum single dose does not exceed 800 mg.	Phase: not applicable n=150	Clinical cure rate (time frame: 3 months) Definition of clinical cure: the viral load of the respiratory specimen was negative for two consecutive times (the interval between the two tests was greater than or equal to one day), the lung image improved, and the body temperature returned to normal for more than 3 days, and the clinical manifestation improved.	Recruiting
NCT04320615^Citation134	Drug: tocilizumab (TCZ) Participants will receive one dose of IV TCZ. One additional dose may onee given if clinical symptoms worsen or show no improvement. Drug: placebo Participants will receive one dose of IV placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.	Phase: II n=450	The primary and secondary endpoints of the study include clinical status, mortality, mechanical ventilation, and ICU variables.	Completed
NCT04317092^Citation135	Drug: tocilizumab injection Tocilizumab 8 mg/kg (up to a maximum of 800 mg per dose), with an interval of 12 h.	Phase: II n=400	Two primary outcome measures: arrest in deterioration of pulmonary function, and improvement in pulmonary function.	Recruiting
NCT04315480^Citation136	Single dose of tocilizumab 8 mg/kg	Phase: II n=38	To evaluate its role in the virus-induced cytokine storm, in blocking deterioration of lung function or even promoting a rapid improvement of clinical conditions, preventing nasotracheal intubation and/or death.	Active, not recruiting
NCT04322773^Citation137	Drug: roactemra IV single dose treatment with tocilizumab 400 mg IV Other name: tocilizumab 400 mg Drug: roactemra sc single dose treatment with tocilizumab 2⨰162 mg subcutaneously Other name: tocilizumab 2⨰162 mg Drug: kevzara sc single dose treatment with sarilumab 1⨰200 mg subcutaneously Other name: sarilumab 1⨰200 mg Other: standard medical care management as usual	Phase: II n=200	To compare the effect of either one of three IL-6 inhibitor administrations (ie IV tocilizumab, subcutaneous tocilizumab, and subcutaneous sarilumab), relative to the standard of care, in patients with severe SARS-CoV-2 pneumonia	Recruiting
NCT04331808^Citation138^–^Citation140	Drug: tocilizumab Tocilizumab 8 mg/kg D1 and if no response (no decrease of oxygen requirement) a second injection at D3.	Phase: II n=129	A significantly lower proportion of the patients in tocilizumab arm attained the primary outcome of need for ventilation or death at day 14	Active, not recruiting
NCT04315298^Citation141,^Citation142	Drug: sarilumab Single or multiple IV doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria. Other names: kevzara®/REGN88/SAR153191 Drug: placebo Single or multiple IV doses of placebo to match sarilumab administration	Phase: II, III n=1912	The first part is recruiting patients across multiple sites in the USA and will evaluate the effect of sarilumab on fever and need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including prevention of mortality and reduction in need for mechanical ventilation, supplemental oxygen, and/or hospitalization. The early results from this study seem to show that its utility may be reserved for the critically ill patients	Completed
NCT04324073^Citation143	Drug: sarilumab (an IV dose of 400 mg of sarilumab in a one-hour infusion at D1	Phase: II, III n=239	The recruited participants were COVID-19 patients with moderate, severe or critical pneumonia. The trials aim to compare the outcomes of sarilumab-treated patients with those receiving outcomes of standard of care as well as with patients being treated with other immunomodulators. More studies have since been registered or initiated for assessing sarilumab	Active, not recruiting
NCT04329650^Citation144	Drug: siltuximab A single-dose of 11 mg/kg of siltuximab will be administered by IV infusion. Drug: methylprednisolone A dose of 250 mg/24 h of methylprednisolone during 3 days followed by 30 mg/24 h during 3 days will be administered by IV infusion. If the patient is taking lopinavir/ritonavir, the dose will be 125 mg/24 h during 3 days followed by 15 mg/24 h during 3 days.	Phase: II, III n=239	Compare efficacy and safety of siltuximab vs corticosteroids in hospitalized patients with COVID19 pneumonia proportion of patients requiring ICU admission at any time within the study period	Recruiting
NCT04443881^Citation145	Drug: anakinra 149 mg/mL prefilled syringe (Kineret) Anakinra (100 mg/6 h) IV infusión during 15 days	Phase: II, III n=180	Treatment success, defined as number of patients not requiring mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia. (Time frame: day 15) Treatment success, defined as number of patients not requiring mechanical ventilation by day 15. Number of patients not requiring mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia. (Time frame: day 28) Number of patients not requiring mechanical ventilation Time to mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia. ((Time frame: up to 28 days) Time to mechanical ventilation Time to oxygen saturation normalization to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia. (Time frame: up to 28 days) Time to oxygen saturation normalization Stay in ICU and hospitalization to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia. (Time frame: up to 28 days) Stay in ICU and hospitalization	Recruiting

Table 3 Shows the Clinical Trials Registered on ClinicalTrials.gov To October 20, 2020, Utilizing Prospective Therapies for the Treatment of COVID-19

Therapy Modality	Study Identifier and Citation (Superscript)	Treatment Protocol	Study Phase; Estimated Enrolment (n)	Primary Outcome Measure(s)	Recruitment Status
Recombinant ACE2 receptors	NCT04375046^Citation149	Experimental: Experimental: rbACE2 group 0.4 mg/kg IV BID for 7 days (unblinded) + standard of care Intervention: drug: recombinant bacterial ACE2 receptors—like enzyme of B38-CAP (rbACE2) No intervention: no Intervention: control group Standard of care; no placebo	Phase I n=24	Time course of body temperature (fever) (time frame: 14 days) Compare the time course of body temperature (fever) between two groups over time. Viral load over time (time frame: 14 days) Compare viral load between two groups over time.	Not yet recruiting
	NCT04382950^Citation150	Experimental: Experimental: rbACE2 group plus aerosolized isotretinoin rbACE2 0.4 mg/kg IV BID for 7 days (unblinded) plus aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days Intervention: combination product: recombinant bacterial ACE2 receptors—like enzyme of B38-CAP (rbACE2) plus aerosolized 13 cis retinoic acid No intervention: no Intervention: control group Standard of care; no placebo	Phase I n=24	Viral load over time (time frame: 14 days) Compare viral load between two groups over time. P/F ratio over time (time frame: 14 days) PaO2/FiO2 ratio Sequential organ failure assessment score (SOFA score) over time (time frame: 14 days) SOFA, including assessment of respiratory, blood, liver, circulatory, nerve, kidney, from 0 to 4 scores in each systems, the higher scores mean a worse outcome. Pulmonary severity index (PSI) (time frame: 14 days) Image examination of chest over time (time frame: 14 days) Based on radiologist’s assessment of inflammatory exudative disease, category as follows: significant improvement, partial improvement, no improvement, increase of partial exudation, significant increase in exudation, unable to judge. Proportion of subjects who progressed to critical illness or death (time frame: at 14 days) Time from first dose to conversion to normal or mild pneumonia (time frame: 14 days) T-lymphocyte counts over time (time frame: 14 days) C-reactive protein levels over time (time frame: 14 days) Angiotensin II (Ang II) changes over time (time frame: 14 days) Angiotensin 1–7 (Ang 1–7) changes over time (time frame: 14 days) Angiotensin 1–5 (Ang 1–5) changes over time (time frame: 14 days) Renin changes over time (time frame: 14 days) Aldosterone changes over time (time frame: 14 days) Angiotensin-converting enzyme (ACE) changes over time (time frame: 14 days) Interleukin 6 (IL-6) changes over time (time frame: 14 days) Soluble tumor necrosis factor receptor type II (sTNFrII) changes over time (time frame: 14 days) Plasminogen activator inhibitor type-1 (PAI-1) changes over time (time frame: 14 days) Von Willebrand factor (VWF) changes over time (time frame: 14 days) Tumor necrosis factor-α (TNFα) changes over time (time frame: 14 days) Soluble receptor for advanced glycation end products (sRAGE) changes over time (time frame: 14 days) Surfactant protein-D (SP-D) changes over time (time frame: 14 days) Frequency of adverse events and severe adverse events(time frame: 14 days)	Not yet recruiting
Exosomes	NCT04491240^Citation151	Procedure: EXO 1 inhalation Twice a day during 10 days inhalation of 3 mL special solution contained 0.5–2⨰10^10 of nanoparticles (exosomes) of the first type. Procedure: EXO 2 inhalation Twice a day during 10 days inhalation of 3 mL special solution contained 0.5–2⨰10^10 of nanoparticles (exosomes) of the second type. Procedure: placebo inhalation Twice a day during 10 days inhalation of 3 mL special solution free of nanoparticles (exosomes)	Phase I PhaseII n=90	Number of participants with non-serious and serious adverse events during trial (time frame: 30 days after clinic discharge) Safety assessment such as adverse events will be registered. Adverse events will be monitored during all trial Number of participants with non-serious and serious adverse during inhalation procedure (time frame: after each inhalation during 10 days) Safety assessments such as adverse events during the inhalation procedures will be registered	Enrolling by invitation
	NCT04389385^Citation152	Biological: COVID-19 specific T cell derived exosomes (CSTC-Exo)	Phase I n=60	Adverse reaction (AE) and severe AE (SAE) (time frame: 28 days) Safety assessment efficacy assessment (time frame: 28 days) Time to clinical recovery (TTCR) The rate of recovery without mechanical ventilator (time frame: 28 days) Efficacy assessment	Not yet recruiting
MSCs	NCT04384445^Citation153	Zofin is an acellular, minimally manipulated product, derived from human amniotic fluid (HAF). This product contains over 300 growth factors, cytokines, and chemokines as well as other extracellular vesicles/nanoparticles derived from amniotic stem and epithelial cells. Biological: zofin Biological: zofin will be administered intravenously with 1 mL, containing 2–5⨰10^11 particles/mL in addition to the standard care. The zofin dose will be diluted in 100 mL of sterile saline at subject’s bedside. Participants in this group will receive standard of care plus zofin on day 0, day 4 and day 8. Intervention: Biological: zofin Other: placebo Other: placebo Placebo (saline) will be administered intravenously with 1 mL in addition to the standard care. The placebo dose will be diluted in 100 mL of sterile saline at subject’s bedside. Participants in this group will receive standard of care plus placebo (saline) on day 0, day 4 and day 8.	Phase I Phase II n=20	Incidence of any infusion associated adverse events (time frame: 60 days) Safety will be defined by the incidence of any infusion associated adverse events as assessed by treating physician Incidence of severe adverse events (time frame: 60 days) Safety will be defined by the incidence of severe adverse events as assessed by treating physician	Recruiting
	NCT04276987^Citation154	Experimental: MSCs-derived exosomes treatment group Conventional treatment and aerosol inhalation of MSCs-derived exosomes treatment participants will receive conventional treatment and 5 times aerosol inhalation of MSCs-derived exosomes (2.0*10E8 nano vesicles/3 mL at days 1, 2, 3, 4, and 5). Intervention: Biological: MSCs-derived exosomes	Phase I n=24	Adverse reaction (AE) and severe adverse reaction (SAE) (time frame: up to 28 days) Safety evaluation within 28 days after first treatment, including frequency of adverse reaction (AE) and severe adverse reaction (SAE) Time to clinical improvement (TTIC) (time frame: up to 28 days) Efficiency evaluation within 28 days, including time to clinical improvement (TTIC)	Completed
	NCT04457609^Citation155	Drug: oseltamivir Current standardized treatment for COVID-19 Drug: azithromycin Current standardized treatment for COVID-19 Biological: umbilical cord MSCs Adjuvant therapy on top of current standardized treatment (oseltamivir+azithromycin)	Phase I n=40	Clinical improvement: presence of dyspnea (time frame: 15 days) Assessing whether the patients still have dyspnea, one of cardinal symptoms of COVID-19, assessed from the respiratory rate Clinical improvement: presence of sputum (time frame: 15 days) Assessing whether the patients still have productive cough, one of cardinal symptoms of COVID-19, assessed from lung auscultation Clinical improvement: fever (time frame: 15 days) Assessing the presence of fever from measurement of body temperature checking, assessed on daily basis Clinical improvement: ventilation status (time frame: 15 days) Assessing whether the patients still require ventilation, one of cardinal symptoms of ARDS in COVID-19, assessed from patients’ ability during ventilation weaning phase Clinical improvement: blood pressure (time frame: 15 days) Assessing the patients’ blood pressure on daily basis Clinical improvement: heart rate (time frame: 15 days) Assessing the patients’ heart rate on daily basis Clinical improvement: respiratory rate (time frame: 15 days) Assessing the patients’ respiratory rate on daily basis Clinical improvement: oxygen saturation (time frame: 15 days) Assessing the patients’ oxygen saturation on daily basis	Recruiting
RAS blockers	NCT04331574^Citation156	Observational model: Case-only time perspective: cross-sectional Patients with certified diagnosis of COVID-19 recruited in Italian hospitals	Phase: not applicable n=2000	Numbers of COVID-19 patients enrolled that use ACE inhibitors and/or angiotensin receptor blockers (ARB) as antihypertensive agents (time frame: 3 months) Using anamnestic data collected from the health record of the hospital or of the general practitioner, we will count the number of COVID-19 patients enrolled that were treated with ACE Inhibitors or ARB. Numbers of COVID-19 patients enrolled with no symptoms, with moderate symptoms or with severe symptoms of pneumonia based on the WHO specification for ARDS that also used ACE inhibitors and/or angiotensin receptor blockers (ARB) as antihypertensive agents (time frame: 3 months) This study wants to observe whether the assumption of antihypertensive ACE inhibitors or ARB increases the severity of the clinical manifestation of COVID19	Recruiting
	NCT04329195^Citation157	Drug: 1: discontinuation of RAS blocker therapy discontinuation of RAS blocker therapy Drug: 2: continuation of RAS blocker therapy continuation of RAS blocker therapy	Phase III n=554	Time to clinical improvement from day 0 to day 28 (improvement of two points on a seven-category ordinal scale, or live discharge from the hospital, whichever comes first) (time frame: from day 0 to day 28 or hospital discharge)	Recruiting
	NCT04353596^Citation158	Drug: ACE inhibitor, angiotensin receptor blocker In patients randomized to stopping/replacing ACEI or ARB, it may be necessary to switch to another drug without direct effect on the RAS system. In patients, randomized to continuation, it may be needed to stop ACEI or ARB (eg hypotension with beginning sepsis) irrespective of the study.	Phase IV n=208	Combination of maximum sequential organ failure assessment (SOFA) score and death (time frame: 30 days) The minimal value of the SOFA score will be 0 and the maximal value 24 points. All-cause death is classified as the maximum score (24 points). In case of a subclinical disease progress without need for hospitalization, the SOFA score will be 0. Composite of admission to an ICU, the use of mechanical ventilation, or all-cause death (time frame: 30 days)	Recruiting
Traditional Chinese medicines	NCT04306497^Citation159	Drug: TCM prescriptions TCM prescriptions 1: take decocted or granule, one dose a day; TCM prescriptions 2: take decocted or granule, one dose a day.	Phase—no information n=340	The relief of main symptoms/disappearance rate of time (time frame: 9 days) Comparison of the time of relief/disappearance of three main symptoms of fever, cough and shortness of breath chest CT absorption (time frame: 9 days) with reference to the “pneumonia chest X-ray absorption evaluation scale” developed by Renyi Yin et al, the final absorption judgment will be used to evaluate the chest CT absorption of patients with pneumonia, which is divided into four levels according to the degree of absorption: complete absorption, majority absorption, partial absorption and no absorption.	Completed
	NCT04251871^Citation160	Drug: conventional medicines (oxygen therapy, alfa interferon via aerosol inhalation, and lopinavir/ritonavir) and TCMs granules Conventional medicines: oxygen therapy, antiviral therapy (alfa interferon via aerosol inhalation, and lopinavir/ritonavir, 400 mg/100 mg, p.o., bid) for 14 days. TCMs granules: 20 g, p.o., bid, for 14 days. Drug: conventional medicines (oxygen therapy, alfa interferon via aerosol inhalation, and lopinavir/ritonavir) Conventional medicines: oxygen therapy, antiviral therapy (alfa interferon via aerosol inhalation, and lopinavir/ritonavir, 400 mg/100 mg, p.o., bid) for 14 days.	Not applicable n=150	The incidents of acute respiratory distress syndrome (ARDS) development (time frame: 14 days) The incidence rate of acute respiratory distress syndrome (ARDS) development	Recruiting
Antioxidants	NCT04363216^Citation161	Drug: Ascor^® ascorbic acid 2-h infusion daily (for 6 days), escalating dose (0.3 g/kg, 0.6 g/kg, 0.9 g/kg). Other name: vitamin C	Phase II n=66	Clinical Improvement (time frame: 72) •Clinical improvement at 72-h of treatment, defined as a 50% reduction in the highest flow rate of oxygen during the 72-h period, a 50% reduction in the most frequent use of bronchodilators within a 12-h window within the 72-h period, or hospital discharge (whichever comes first).	Not yet recruiting
	NCT04323514^Citation162	Dietary supplement: vitamin C 10 g of vitamin C IV in addition to conventional therapy.	Not applicable n=500	In-hospital mortality (time frame: 72 h) Change of hospital mortality	Recruiting
	NCT04519034^Citation163	Audit 1 All vitamin D results performed since January 2020 (n= ~15,000) together with age, weight and height if available, ethnicity and other relevant laboratory markers (Ca, adjusted calcium, PTH, Mg, phosphate, liver and renal profile, COVID-19 screening, CRP, hematinics, FBC) Intervention: other: no intervention Audit 2 all COVID-19 screening results together with vitamin D, ethnicity, age, weight, height, length of stay in hospital including ICU (if applicable), type of illness, recovered or not, associated health conditions, CRP, ferritin, hematinics, vitamin A and E, procalcitonin, LDH, INR, fibrinogen, FBC, D-dimers, CK, troponin-T, cytokines, renal function and electrolytes from patients tested at GSTT NHS Trust. Intervention: other: no intervention	Phase—not applicable n=27,000	Collecting vitamin D results in patients from the South-East London area together with age, sex, ethnicity and BMI and other relevant laboratory results. (time frame: January–June 2020) All vitamin D results performed by the Nutristasis Unit at St. Thomas’ since January 2020 (n= ~15,000) together with age, weight and height if available, ethnicity and other relevant laboratory markers (Ca, adjusted calcium, PTH, Mg, phosphate, liver and renal profile, COVID-19 screening, CRP, hematinics, FBC) if they were tested within two weeks of the sample being measured for vitamin D will be acquired. The results of this audit will provide us with a snap shot of vitamin D status in patients from the South-East London area by age, sex, ethnicity and BMI (weight in kg/height^2). Correlation analysis will also be undertaken with other laboratory parameters.	Not yet recruiting
	NCT04323228^Citation164	Experimental: intervention—- the intervention groups will receive daily oral antioxidant supplement enriched in vitamins A, C, E, selenium and zinc. The composition of one capsule of the intervention-supplement includes: 1500 µg vitamin A (as β-carotene), 250 mg vitamin C, 90 mg vitamin E, 15 µg selenium, and 7.5 mg zinc. Intervention: dietary Supplement: oral supplement enriched in antioxidants Placebo comparator: placebo Placebo group will receive daily intervention in form of cellulose-containing gelatin capsules with the same color and shape. Intervention: dietary Supplement: cellulose-containing placebo capsules	Phase II Phase III n=40	Change from baseline score of nutrition risk screening-2002 (NRS-2002) at end of the trial (time frame: up to 3 months) Changes in scores of the NRS-2002 for patients with COVID-19 at the end of the study, from 0 to 7 scores, with those scores <3 means no risk of malnutrition and ≥3 means malnutrition. Change from baseline serum ferritin level at end of the trial (time frame: up to 3 months) Change in serum ferritin at the end of the trial as ferritin is considered as a COVID-19 fatality predictor. Change from baseline serum IL-6 concentration at end of the trial (time frame: up to 3 months) Change in IL-6 at the end of the trial as it represents the cytokine storm and it is considered as a COVID-19 fatality predictor Change from baseline serum C-reactive protein concentration at end of the trial (time frame: up to 3 months) Change in C-reactive protein in the serum at the end of the trial which reflects the acute phase Change from baseline serum TNFα concentration at end of the trial (time frame: up to 3 months) Change in the TNF a in the serum at the end of study as it represents severity of the cytokine storm Change from baseline serum monocyte chemoattractant protein 1 (MCP-1) at end of the trial (time frame: up to 3 months) plasma MCP-1 represents severity of the cytokine storm	Recruiting
Dietary Supplement	NCT04382040^Citation165	ArtemiC is a medical spray comprised of artemisinin (6 mg/mL), curcumin (20 mg/mL), frankincense (=Boswellia) (15 mg/mL) and vitamin C (60 mg/mL) in micellar formulation for spray administration. Drug: ArtemiC: Treatment will be sprayed orally twice a day for the first 2 days in the treatment period Drug: placebo: Treatment will be sprayed orally twice a day for the first 2 days in the treatment period	Phase II n=50	Time to clinical improvement, defined as a national early warning score 2 (NEWS2) of ≤ 2 maintained for 24 h in comparison to routine treatment (time frame: 24 hours) patient will be assessed using a scoring table for changes in clinical signs Percentage of participants with definite or probable drug related adverse events (time frame: 14 days) adverse events caused by the study drug will be assessed	Recruiting
	NCT04347382^Citation166	Experimental: Nigella sativa and honey group Drug: Nigella sativa seed Powder 80 mg/kg/day ground in a capsule up to a max of 14 days) Drug: natural honey 1 mg/kg/day orally up to a max of 14 days) along with standard medical care Interventions: Drug: honey; Drug: Nigella sativa/black cumin placebo comparator- standard medical Care: standard supportive medical care prescribed by treating physician, Lahore which includes standard symptomatic care along with use of antibacterial or antiviral (if advised by pulmonologist or infectious disease specialist) Intervention: Drug: placebos:	Phase III n=313	Days required to get a positive COVID-19 PCR to negative (time frame: up to max 14 days) RT-PCR will be done on admission day (0 day) and then after every fourth day for 14 days or till the symptoms resolved and RT-PCR gets negative. RT-PCR will only be shown as positive or negative (as per limitation of Pakistan). HRCT/X-ray findings of disease progression (time frame: up to max 14 days] HRCT will be conducted at admission day (0-day) and a total of maximum four CT-scans will be conducted after every fourth day. The minimum and score at which we label COVID-19 positive will be 5 and 25 respectively using internationally standard nomenclature as described by Fleischner Society glossary and peer-reviewed literature on viral pneumonia. Severity of symptoms progression (time frame: up to max 14 days) Clinically disease progression will be evaluated depending upon the severity of symptoms being classified as mild, moderate and severe. Duration of hospital stay (time frame: up to max 14 days) Duration of hospital stay would be categorized as the number of days the patient stayed in the ward during treatment. The date of admission and date of discharge would give us total duration of stay. 30 day mortality (time frame: 30 days) 30 days mortality rate in each arm	Completed
	NCT04323345^Citation167	Dietary supplement: natural honey: natural honey supplement 1 g/kg/day divided into 2 to 3 doses for 14 days either orally or through nasogastric tube. Other: Standard Care: supportive measures and lopinavir/ritonavir tablets or arbidol or chloroquine phosphate or hydroxychloroquine or oseltamivir with or without azithromycin.	Phase III n=1000	Rate of recovery from positive to negative swaps (time frame: 14 days) Percentage of patients turned from positive to negative swaps at day 14 Fever to normal temperature in days (time frame: 14 days) Number of days till no fever Resolution of lung inflammation in CT or X- ray(time frame: 30 days) Number of days till lungs recovery in chest X-ray or CT	Recruiting
	NCT04342689^Citation168	Drug: dietary supplement containing resistant starch: two tablespoons (~20 g) to be taken twice daily for 14 days (start with 2 tablespoons once daily for three days, followed by twice daily on days 4 through 14) (Other name: resistant starch) Dietary supplement: placebo starch: two tablespoons (~20 g) to be taken twice daily for 14 days (start with 2 tablespoons once daily for three days, followed by twice daily on days 4 through 14) (other name: nonresistant starch)	Phase III n=1500	Rates of hospitalization for a COVID-19 related complication (time frame: One month from the start of treatment) Subject hospitalized while presenting symptoms of fever, shortness of breath, myalgia, cough, or hypoxia with an admission diagnosis of hypoxic respiratory failure, pneumonia, or viral pneumonia on review of electronic health record (EHR). Death prior to hospitalization thought to be secondary to COVID-19 will also be defined as an event. All hospital admissions will be reviewed and adjudicated by a site PI.	Recruiting

Figure 3 Modified schematic diagram illustrates the cellular and molecular cascade of PBMT that reserve SARS-CoV-2 cellular and molecular activities to prevent ARDS.

Notes: Adapted with permission from Mokmeli S, Vetrici M. Low level laser therapy as a modality to attenuate cytokine storm at multiple levels, enhance recovery, and reduce the use of ventilators in COVID–19. Can J Respir Ther. 2020;56:1–7.²⁰⁰

Table 4 Shows the Clinical Trials Registered on ClinicalTrials.gov To October 20, 2020, Utilizing Phototherapy for the Treatment of COVID-19

Photo-Therapy	Study Identifier and Citation (Superscript)	Laser Treatment Protocol	Study Phase; Estimated Enrolment (n)	Primary Outcome Measure(s)	Recruitment Status
PDT + PBMT	NCT04416113	The patients will be divided into 3 equal groups. Group I will receive low level laser (diode laser 980 nm) from laser watch for 30 min, 20 J for 3 to 5 days and laser acupuncture. Group 2 will be treated with photodynamic therapy by injecting the methylene blue as a photosensitizer and irradiated with laser watch (diode laser 670 nm). Group 3 will serve as a control. Evaluation methods will include laboratory investigations and CT chest.	Phase: Not applicable n=60	Participants achieving either a major clinical response or partial clinical response (PCR) defined by WHO All patients will be subjected to thorough examination with complete personal and clinical history and will do the following before and after treatment: PCR, CBC, CRP, ESR, D dimers, liver enzymes, and ferritin, CXR. Endpoint treatment will be stopped if no improvement occurred after one week	Active— Not recruiting yet
PBMT	NCT04386694	PBMT combined with static magnetic field (sMF) (PBMT/sMF) on respiratory muscles of patients admitted to the Intensive Care Unit (ICU) with COVID-19 using invasive mechanical ventilation. The device has 4 diodes of 905 nm (1.25 mW each diode, 0.32 cm^2 each), 8 diodes of 633 nm (25 mW each diode, 0.85 cm^2 each), and 8 diodes of 850 nm (40 mW each diode, 0.56 cm^2 each). The static magnetic field is 110 mT. PBMT/sMF application time will be 60 seconds per site. The dose used in the lower thorax will be 31.50 J per site, a total of 6 sites will be irradiated, totaling a dose of 189 J. In addition, the dose used in the neck area (bilaterally) will be 31.50 J per site, a total of 1 site (bilaterally) will be irradiated, totaling a dose of 31.50 J (bilaterally). PBMT/sMF will be applied using the direct contact method with light pressure on the skin.	Phase: not applicable n=30	Time until discharge (time frame: from date of randomization until the date of discharge or date death from any cause, whichever came first, assessed up to 20 days)Number of days hospitalized in the ICU until discharge or death Survival rate, diaphragm muscle function Platelet count leukogram and erythrogram. C-reactive protein D-dimer Levels of immunoglobulin G and M, TNFα, and vitamin D Levels of positive end-expiratory pressure (PEEP), PO2, FiO2	Recruiting
	NCT04524715	PBMT: to reduce pneumonia inflammation by applying red light PBMT in respiratory system.	Phase: Not applicable n=64	Inflammation of lungs-O2 Inflammation of lungs-CRP Inflammation of lungs-IL6	Recruiting
	NCT04391712	Multi-wave locked system (MLS) laser therapy for COVID-19 positive patients with pulmonary disease. Laser treatment was delivered when patient at a prone position, using a 10 by 25 cm laser field across each lung with 7 J/cm^2 at 1500 Hz. The treatment frequency and duration: one daily for 4 days.	Phase: II n=10	Patient disposition post treatment [time frame: 7 days]. ICU on vent, ICU not requiring ventilation, discharge to rehab requiring assistance, discharge home unable to perform ADLs, discharge to home able to perform ADLs. Oxygenation (time frame; daily for 4 days). Patients O2 requirements pulse oximetry evaluation for change from pre- and post-treatment and end of protocol IL-6 levels (time frame: first four days of trial). The change in pre-treatment and 24 h post final treatment. CXR results (time frame: 7 days). Pre-treatment CXR, compared to post treatment, using RALE CXR evaluation scale. -Brescia-COVID Respiratory Severity Scale (BCRSS) (time frame: 7 days). Change in the pre- and post-treatment evaluated with BCRSS. SMART-COP score (time frame: 7 days). Change between pre- and post-treatment. PSI score: change between pre- and post-treatment. CRP levels (time frame: 7 days).	Completed (No study results posted on ClinicalTrials. gov for this study yet).

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