COVID-19 future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Sabawoon Mirwais, M.B.B.S, M.D.[3]

Overview

The investigational therapies for COVID-19 is an area of vast research due to its global health impact. Many world-renowned research scientists and pharmaceutical companies have joined hands to address the health impact of COVID-19 on the human race. Investigational therapies include both preventative and treatment based strategies.

Future or Investigational Therapies

Antivirals

The following pharmacological therapies are currently under investigation as potentials to treat COVID-19:

• Chloroquine/Hydroxycholoroquine
• Arbidol
• Remdesivir
• Favipiravir

Ongoing Clinical Trials

Chloroquine/Hydroxycholoroquine

• A a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis found that after high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure.
  • The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]).
  • Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
    

FDA approved Phase II and III clinical trial

• Clinical Study To Evaluate The Performance And Safety Of Favipiravir in COVID-19 NCT04336904
• Ruxolitinib in Covid-19 Patients With Defined Hyperinflammation (RuxCoFlam) NCT04338958
• Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment NCT04292730
• Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19) (CORON-ACT) NCT04335071
• A Study of Quintuple Therapy to Treat COVID-19 Infection (HAZDpaC Hydroxychloroquine, azithromycin, vitamin C, Vitamin D, zinc) [Phase II] NCT04334512
• An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID-19
• A Multi-center, Randomized, Parallel-Controlled Clinical Trial of the Application of A Hydrogen-Oxygen Generator With Nebulizer in the Improvement of Symptoms in Patients Infected With COVID-19
• A Randomized, Double-blind, Placebo-controlled, Multi-site, Phase III Study to Evaluate the Safety and Efficacy of CD24Fc in COVID-19 Treatment
• Use of cSVF For Residual Lung Damage COPD/Fibrotic Lung Disease After Symptomatic COVID-19 Infection For Residual Pulmonary Injury or Post-Adult Respiratory Distress Syndrome Following Viral Infection
• A Pragmatic Adaptive Open Label, Randomized Phase II/III Multicenter Study of IFX-1 in Patients With Severe COVID-19 Pneumonia
• Chloroquine Phosphate Against Infection by the Novel Coronavirus SARS-CoV-2: The HOPE Open-Label, Non Randomized Clinical Trial
• A Phase 2, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Leronlimab for Mild to Moderate Coronavirus Disease 2019 (COVID-19)
• A Phase 1b, Randomized, Double-blinded, Placebo-controlled Study of Hydroxychloroquine in Outpatient Adults With COVID-19

Vaccine

Immune Targets

• The B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins are currently under investigation as immune targets for development of vaccine.
• Phylogenetic similarity between SARS-CoV and COVID-19 at the level of structural proteins S, E, M, and N is providing guidance for development of a possible vaccine.

Current Clinical Trials

The following countries are currently working on the development of a vaccine for COVID-19 (SARS-CoV2)

USA

• Beth Israel Deaconess Medical Center (BIDMC), Boston and Johnson & Johnson (J&J) are currently collaborating to advance COVID-19 vaccine. A Phase I trial is expected to launch during the last quarter of 2020. AdVac and PER.C6 technologies are being used for rapid production.
• National Institute for Allergy and Infectious Diseases (NIAID) has announced that a phase 1 trial has begun for COVID-19 immunization in Washington state.
• The trial includes 45 young, healthy volunteers with different doses of immunization shots co-developed by NIH and Moderna Inc.

Israel

• Researchers at Israel’s Institute for Biological Research are expected to announce in the coming days that they have completed development of a vaccine for COVID-19

China

• China was the first country to release the genetic sequence of the virus on open scientific databases so that research institutes and commercial companies could try to develop treatments and vaccines without needing to obtain samples.
• China has announced the first animal tests.

Australia

• Following successful in vitro experiments, animal testing has begun in University of Queensland in Australia

Prior Work

The following table depicts major vaccine products that have been developed against SARS-CoV and MERS-CoV:

Vaccine Base	Antigen	Clinical Testing	Pros	Cons
DNA	Spike protein S1	Phase I, II (NCT03721718)	Reduced production time Easy design and manipulation Stimulates B and T cells responses	Requires efficient intradermal gene gun delivery to antigen-presenting cells Weaker immune response compared to live vaccine
Viral Vector	Spike protein S1; Chimpanzee adenovirus vector, Modified Vaccinia Ankara	Phase I (NCT03399578, NCT03615911)	Competent immune response	Varied immune response based of mode of delivery Th2 bias
Conjugated subunit	Spike protein S1 Receptor binding domain Nucleocapsid Membrane protein Envelope protein Delta Inulin Adjuvant and/or fusion with Fc		Stimulates humoral and cellular responses Increased safety Ease of production	Reduced cost-effectiveness may hinder production Adjuvants required
Virion	Spike protein S1 Receptor binding domain Membrane protein Envelope protein Prepared in baculovirus		Multi-unit Preservation of whole virus	Requires optimum nucleocapsid assembly
Inactivated	Whole virus Formaldehyde or gamma irradiation inactivation		Preservation of whole virus Reduced production time Competent neutralizing antibody production Enhanced Protection while ameliorating lung eosinophilic immunopathology	Hypersensitivity reaction Th2-bias
Live attenuated	Mutant MERS-CoV and SARS-CoV or recombination with other live attenuated virus		Sensitivity to mutagenesis Excellent B and T cell response

Randomized Clinical Trials

Medication:

Hydroxychloroquine

• 215 studies worldwide
• 55 studies in the USA
• Placebo: Vitamin D, Pacebo: Calcium citrate, Vit C, Mannitol, glucose tablets, Folic Acid, Ascorbic Acid
• Combination/comparison:
  • Drug: Vitamin D, Zinc sulfate, Azythromycin, Doxycycline,Indomethacin, Zithromax Oral Product, Ivermectin, Camostat Mesilate, Bromhexine, Nitazoxanide, Lopinavir/ritonavir, Sirolimus, Telmisartan, Active Comparator (Ciclesonide inhalor), Favipiravir, diltiazem and niclosamide, Clevudine, Lopinavir/ritonavir, Favipiravir, Interferon-β 1a, Bromhexine, Baricitinib, Nitazoxanide,

Purpose of study:

• Primary prevention
• Post-exposure prophylaxis
• Treatment
  • Clinical improvement
  • Viral load clearance from Nasopharyngeal sample

Design/Strategy:

• Phase 2 vs 3 vs 4
• 2 arm study vs 4 arm study
• Dose-based (200 vs 400 vs 600 mg)
• Frequenc-based ( Once vs twice vs trice per day)
• Duration-based (5 vs 10 vs 14 ... days)

Completed Studies

	Name of the study	Location	Randomized	Controlled	Objective	Severity	Endpoint

Ongoing Studies

	Randomized	Controlled	Endpoint	Objective	Severity

Country	Intervention	Objective	Design&Date	Strategy	Outcome
Renmin Hospital of Wuhan University, China	Hydroxychloroquine (HCQ) (Preprint article)	Treatment efficacy evaluation	February 4 to February 28, 2020 62 patients with confirmed COVID-19 diagnosis Participants were randomized in a parallel-group trial Males: 46.8%; Female: 53.2%; Mean age: 44.7 years. age and sex were adjusted between the control group and the HCQ group 31 patients treatment group	A 5-day HCQ (400 mg/d) treatment The HCQ effect was evaluated at baseline and 5 days after treatment by assessing the following: Time to clinical recovery (TTCR), clinical characteristics, and radiological results	TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group (80.6%, 25 of 31of patients with improved pneumonia in the HCQ treatment group compared with the control group (54.8%, 17 of 31) 4 patients progressed to severe illness that occurred in the control group 2 patients with mild adverse reactions in the HCQ treatment group Conclusion: The use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia in patients with COVID-19
Méditerranée Infection University Hospital Institute in Marseille, France	Hydroxychloroquine and azithromycin	Treatment efficacy evaluation	Early March to March 16th 36 out of 42 patients meeting the inclusion criteria 6 lost to follow up 20 hydroxychloroquine-treated patients 16 control patients Patients were included in a single-arm protocol Inclusion criteria: Age >12 years PCR documented SARS-CoV-2 carriage in nasopharyngeal sample at admission regardless of the clinical status Control was untreated patients from another center and cases refusing the protocol Endpoint: presence and absence of virus at Day6-post inclusion	600mg of HCQ daily 200 mg, three times per day for ten days Viral load in nasopharyngeal swabs was tested daily in a hospital setting Azithromycin: Added depending on the clinical presentation 500mg on day1 followed by 250mg per day, the next four days To prevent bacterial super-infection under daily electrocardiogram control	There was a statistically significant difference between treated patients and controls at days 3-4-5 and 6 (negative PCR) At day 6, 70% of HCQ-treated patients were virologically cured comparing with 12.5% in the control group (p= 0.001) HCQ vs HCQ-Azithromycin combination There was a statistically significant difference between treated patients and controls at days 3-4-5 and 6 (negative PCR) At day 6, 100% of patients treated with HCQ and azithromycin combination were virologically cured comparing with 57.1% in patients treated with HCQ only, and 12.5% in the control group (p < 0.001) Conclusion: HCQ is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin
Marqués de Valdecilla University Hospital, Cantabria, Spain	HDQ	Chemoprophylaxis	Start scheduled for the second week of May 2020 Prospective, single center, double blind, randomised, controlled trial (RCT) 450 Adult health-care professionals (18-65 years) Working in areas of high exposure and high risk of transmission of SARS-COV-2	Oral Hydroxychloroquine 200mg, once-daily, for two months (HC group) or placebo (P group) Intervention: (n = 225): One 200 mg hydroxychloroquine sulfate coated tablet once daily for two months. Comparator (control group) (n = 225): One hydroxychloroquine placebo tablet (identical to that of the drug) once daily for two months In addition to the protective measures appropriate to the level of exposure established by the hospital. A serological evaluation every 15 days with PCR in case of seroconversion, symptoms or risk exposure.
Eight hospitals in Spain	Melatonin	Prophylaxis	Recruitement (May 21-31) 450 participants 225 in the experimental arm 225 in the placebo arm.	Experimental: Melatonin (Circadin®, 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo, orally before bedtime for 12 weeks.