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] Huda A. Karman, M.D.

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

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

• Dexamethasone
• Chloroquine/Hydroxychloroquine
• Arbidol
• Remdesivir
• Favipiravir
• Infliximab
• C21
• Dornase Alpha
• Tocilizumab
• Clevudine

Ongoing Clinical Trials

The RECOVERY Trial

• University of Oxford
• A large interventional randomised controlled trial
• Open label
• To investigate whether any of the assigned treatment arms prevents death in patients with COVID-19 (COVID-19 therapy evaluation)
• Over 11,800 patients admitted to hospital with COVID-19
• Factorial Assignment where all eligible patients are randomly allocated between several treatment arms, each to be given in addition to the usual standard of care in the participating hospital:
  • Main randomisation (part A): Eligible patients will be randomly allocated between the available 5 treatment arms:
    • Corticosteroid: Low-dose Dexamethasone
    • Azithromycin
    • Tocilizumab
    • Lopinavir-Ritonavir
    • Hydroxychloroquine
      • The trial concluded that there is no beneficial effect of hydroxychloroquine or lopinavir-ritonavir in patients hospitalised with COVID-19, and these arms have been closed to recruitment.
      • On July 15, 2020, the interim results of RECOVERY trial published and showed that hydroxychloroquine use was associated with a longer hospital stay.
      • According to the interim results, patients who received hydroxychloroquine were more likely to need intensive care unit care and more prone to death.
  • Main randomisation (part B):
    • Convalescent plasma (Biological)
    • No additional treatment.
  • Subsequent randomisation: Participants with progressive COVID-19 (as evidenced by hypoxia and an inflammatory state) may undergo an optional second randomisation

• Intervention Model Description has been changed after hydroxychloroquine and lopinavir-ritonavir arms closed to the following:
  • Main randomisation (part A):
    • Corticosteroids: Low-dose Dexamethasone
    • Azithromycin.
    • No additional treatment.
  • Main randomisation (part B): Simultaneously random allocation between
    • Convalescent plasma (Biological)
    • No additional treatment
  • Subsequent randomisation for patients with progressive COVID-19 (evidence of hyper-inflammatory state):
    • No additional treatment
    • Tocilizumab.

Corticosteroid

• One arm of RECOVERY Trial
• Corticosteroid turns down the inflammatory response (overreaction) caused by Cytokine storm
• Used for patients with the severe acute respiratory syndrome (ventilated or hypoxic patients)

Intervention:

• Dexamethasone: Oral (liquid or tablets) or intravenous, 6 mg once daily for 10 days

Pregnancy or breastfeeding women

• Prednisolone: Oral, 40 mg or
• Hydrocortisone: Intravenous 80 mg twice daily

Results:

• Reduced mortality by one third, from 40% to 25% in ventilated patients (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001)
• Reduced mortality by one fifth, from 25% to 20% in patients requiring oxygen (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002)
• No reduced mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14)
• Increased mortality rate among patients who were not receiving respiratory support (no statistically significant difference)

Conclusion

• Dexamethasone reduced the 28-day mortality by one-third among hospitalized patients on mechanical ventilators and by one-fifth among hospitalized patients receiving supplemental oxygen by other means
• Dexamethasone increased the mortality rate in mildly ill patients
• Dexamethasone might have disparate effects at different stages of the disease

Lopinavir-Ritonavir

• One arm of RECOVERY Trial

Intervention

• Lopinavir 400mg-Ritonavir: 100mg, Oral (or nasogastric tube) every 12 hours for 10 days

End Result

• In June 29, the trial Steering Committee concluded that there is no beneficial effect of lopinavir-ritonavir in patients hospitalised with COVID-19 and closed randomisation to that treatment arm.

Hydroxychloroquine

• One arm of RECOVERY Trial

Intervention

• Hydroxychloroquine by mouth for a total of 10 days

Result

• In June 4th, the independent Data Monitoring Committee have concluded that there is no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19
• The committee decided to stop enrolling participants to the hydroxychloroquine arm of the RECOVERY Trial with immediate effect

Azithromycin

• One arm of RECOVERY Trial

Intervention

• Azithromycin 500mg by mouth (or nasogastric tube) or intravenously once daily for 10 days.

Tocilizumab

• One arm of RECOVERY Trial

• Intervention
  • intravenous infusion with the dose determined by body weight
    • 8 mg/kg (maximum: 800 mg/dose) as a single dose; may repeat dose in 8 to 12 hours if signs/symptoms worsen or do not improve.
    • 8 mg/kg (maximum: 800 mg/dose) every 12 hours for 2 doses.
    • 8 mg/kg as a single dose.
    • 4 to 8 mg/kg (usual dose: 400 mg/dose; maximum: 800 mg/dose) as a single dose; may repeat dose in ≥12 hours in patients who remain febrile within 24 hours of initial dose.

• Results
  • there is an improvement of oxygenation, as assessed by the ratio of partial pressure of oxygen to fraction of inspired oxygen (P/F), which increased at day 1 (+8%, IQR −9 to +25; p=0.005 for within-group and p<0.006 for between-group comparisons) and day 3 (+25%, IQR +10 to +52; p<0.001 for within-group and p<0.001 for between-group comparisons), whereas it continued to worsen in the SOC group (p<0.001)
  • A significant change of the percentage of lymphocytes and CRP levels was observed after tocilizumab treatment,but The value of IL-6 did not decrease significantly in the short term after treatment with tocilizumab

Convalescent plasma

• One arm of RECOVERY Trial

Intervention

• Single unit of ABO compatible convalescent plasma (275mls +/- 75 mls) intravenous per day on study days 1 (as soon as possible after randomisation) and 2 (with a minimum of 12 hour interval between 1st and 2nd units)

Results:

• All symptoms, especially fever, cough, shortness of breath, and chest pain, disappeared or largely improved within 1 d to 3 d upon Convalescent plasma transfusion.
• Different degrees of absorption of pulmonary lesions after Convalescent plasma transfusion.
• Lymphocytopenia, an important index for prognosis in COVID-19, tended to be improved after Convalescent plasma transfusion (median: 0.65 × 109 per L vs. 0.76 × 109 per L)
• Convalescent plasma containing neutralizing antibody was followed by an improvement in clinical status.
• uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence)

Other Clinical Trials

Remdesivir [ClinicalTrials.gov number, NCT04280705]

• In a first COVID-19 treatment EMA’s human medicines committee (CHMP) recommended remdesivir for EU authorization in a preliminary report.
• A total of 1063 patients underwent randomization in the remdesivir double-blind, placebo-controlled trial.
• Intravenous remdesivir used in adult hospitalized COVID-19 patients in a double-blind, randomized, placebo-controlled trial.
• Dosage of remdesivir 200 mg loading dose on day 1, which is followed by 100 mg daily for up to 9 additional days or a placebo for up-to 10 days in the random trail.

Updates on Remdesivir

• The U.S. Food and Drug Administration (FDA) has provided using of remdesivir as a Emergency Use Authorization (EUA) of unapproved remdesivir drug for patients who are positively tested or if the patient is suspected of COVID-19 symptoms in both adult and pediatric patient population who are having severe disease.
• The optimal duration of the treatment with remdesivir in COVID-19 patients is not clear.
• Severe disease of COVID-19 can be defined by the following:
  • Patients who are showing oxygen saturation (SpO2) ≤94% on room air or
  • Patients who needed supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO)

Adult

• Preferred regimen in adults population who are weighing more than 40kg: Remdesivir single loading dose of 200 mg on Day 1 followed by once daily maintenance doses of 100 mg from Day 2

Pediatric

• Preferred regimen in pediatric population who are weighing 3.5 kg to less than 40kg: Remdesivir injection, 100 mg, lyophilized powder which includes a single loading dose of remdesivir 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once daily from Day 2

CONCLUSIONS

• Remdesivir treatment was shown results superior to placebo in the outcome of shortening the time to recovery in adults who are hospitalized with Covid-19.
• Remdesivir treatment was also shown superior to placebo in the evidence of lower respiratory tract infection in adults who are hospitalized with Covid-19.

Favipiravir

• Mechanism of action of favipiravir is selectively inhibits RNA polymerase.
• In USA, phase 2 clinical trials are going in collaboration with Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School on with favipiravir with approximately 50 patients who are positive for COVID-19.
• In Japan, phase 3 clinical trials are going on with favipiravir on COVID-19 patients.
• In India, Phase III clinical trials with favipiravir along with umifenovir is started in May 2020.
• Recently in India favipiravir was approved by the Drug Controller General of India (DCGI) to treat mild to moderates cases of COVID-19 patients but it is strictly limited to emergency use only.

SOLIDARITY Clinical Trial

• WHO and partners have launched an in an international clinical trial to help find an effective treatment for COVID-19. It will compare four treatment options against the standard of care, to assess their relative effectiveness against COVID-19.
• On 17 June 2020, WHO announced that the hydroxychloroquine (HCQ) arm of the Solidarity Trial to find an effective COVID-19 treatment was being stopped.

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 a 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.
• NIH halts clinical trial of hydroxychloroquine.
• The US Govt NIAID & NIH stop trial evaluating hydroxychloroquine and azithromycin to prevent hospitalization & death from COVID19 because study leadership & DSMB determined that the rate of participant enrollment was inadequate to meet trial objectives.

FDA approved Phase II and III clinical trials

• Clinical study to evaluate the performance and safety of favipiravir in COVID-19 NCT04336904
• Ruxolitinib in Covid-19 Patients With Defined hyper inflammation (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

• There are more than 160 vaccines under development for preventing COVID-19 infection, 26 of them already undergoing clinical trials.

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 the development of a vaccine.
• Phylogenetic similarity between SARS-CoV and COVID-19 at the level of structural proteins S, E, M, and N is providing guidance for the 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

Phase 3 clinical trial [ClinicalTrials.gov number, NCT04280705]

• In USA a phase 3 clinical trail has begun to produce a investigational vaccine against COVID-19.
• The vaccine, is known as mRNA-1273.
• mRNA-1273 was co-developed by the following:
  • Cambridge, Massachusetts-based biotechnology company Moderna
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • A part of the National Institutes of Health (NIH)

• The clinical trail has enrolled approximately 30,000 adult volunteers who do not have COVID-19.
• Moderna is leading the trial and is providing the investigational vaccine for the trial.
• The funding for the clinical trial is provided by The Biomedical Advanced Research and Development Authority (BARDA).
• Under the name Operation Warp Speed, the vaccine efficacy trial is to be implemented.
• The NIH Coronavirus Prevention Network (CoVPN) is also gonna participate in conducting the trail.
• The mRNA-1273 investigational vaccine candidate will be tested at approximately 89 clinical research sites in the United States.
• The enrollment of volunteers are mostly from high-incidence areas and emerging hot zones.
• Moderna’s mRNA-1273 uses the mRNA (messenger RNA) delivery platform to encode for an S-2P immunogen.
• The goal of the investigational vaccine mRNA-1273 is to see weather the vaccine is safe or not and to see if the vaccine can prevent symptomatic COVID-19 after two doses.
• The volunteers who are enrolled in the clinical trail are gonna get two intramuscular injections approximately 28 days apart.
• Participants will be randomly assigned 1:1 to receive either two 100 microgram (mcg) injections of mRNA-1273 or two shots of a saline placebo.

Mechanism of action of mRNA-1273 investigational vaccine

• Once the investigational vaccine is given the mRNA-1273 signals the host cells to to express the spike protein on the surface and this might evoke a wide range of immune response to the coronavirus.

AdVac and PER.C6

• Beth Israel Deaconess Medical Center (BIDMC), Boston, and Johnson & Johnson (J&J) are currently collaborating to advance the 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.
• The Moderna prophylactic vaccine is developing an mRNA vaccine against COVID-19. This cohort study completed its second phase and ready to enter the third phase.
• On July 14, 2020, the Moderna trial showed promising results.
• According to the interim results of the trial, the vaccine successfully promoted antibody production in the body of the recipients.
• The highest dose of vaccine was more effective in antibody response promotion.
• The side effects of the vaccine were fatigue, chills, headache, and pain at the injection site.
• The study has not reported any concerns regarding the safety of the vaccine, which makes the dream of fighting against COVID-19 more real.

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 the 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 III (ISRCTN89951424) Phase I (NCT03399578, NCT03615911)	Competent immune response	Varied immune response based on the 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	Phase I/II (NCT04368988)	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 the whole virus	Requires optimum nucleocapsid assembly
Inactivated	Whole virus Formaldehyde or gamma irradiation inactivation	Phase III (NCT04456595, ChiCTR20000034780, ChiCTR2000034780), Phase I/II(NTC04383574, NTC04352608)	Preservation of the 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 viruses		Sensitivity to mutagenesis Excellent B and T cell response
RNA	LNP-encapsulated mRNA	Phase III (NCT04470427)	Safety - non infectious Reliable Scalable	Unintended immune reactions; Storage - need to be frozen or refrigerated Delivery - RNA strand must be incorporated into other molecules