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:

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:

Corticosteroid

Intervention:

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

Pregnancy or breastfeeding women

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)[2]

Conclusion

Lopinavir-Ritonavir

  • One arm of RECOVERY Trial

Intervention

End Result[4]

  • 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

Result[5]

  • 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

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)[6]
    • 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[7]

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:[8]

Other Clinical Trials

Remdesivir [ClinicalTrials.gov number, NCT04280705]

Updates on Remdesivir

Adult

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

Favipiravir

  • Mechanism of action of favipiravir is selectively inhibits RNA polymerase.[12]
  • 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


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.[14]

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]

  • 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.[16]
  • 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:[17][18]

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

References

  1. "Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. | medRxiv".
  2. 2.0 2.1 2.2 "Breakthrough Drug for Covid-19 May Be Risky for Mild Cases - The New York Times".
  3. "Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report | medRxiv".
  4. "No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY — RECOVERY Trial".
  5. "No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19 — RECOVERY Trial".
  6. Potere N, Di Nisio M, Cibelli D, Scurti R, Frattari A, Porreca E; et al. (2020). "Interleukin-6 receptor blockade with subcutaneous tocilizumab in severe COVID-19 pneumonia and hyperinflammation: a case-control study". Ann Rheum Dis. doi:10.1136/annrheumdis-2020-218243. PMID 32647027 Check |pmid= value (help).
  7. Xu X, Han M, Li T, Sun W, Wang D, Fu B; et al. (2020). "Effective treatment of severe COVID-19 patients with tocilizumab". Proc Natl Acad Sci U S A. 117 (20): 10970–10975. doi:10.1073/pnas.2005615117. PMC 7245089 Check |pmc= value (help). PMID 32350134 Check |pmid= value (help).
  8. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J; et al. (2020). "Effectiveness of convalescent plasma therapy in severe COVID-19 patients". Proc Natl Acad Sci U S A. 117 (17): 9490–9496. doi:10.1073/pnas.2004168117. PMC 7196837 Check |pmc= value (help). PMID 32253318 Check |pmid= value (help).
  9. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J; et al. (2020). "Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma". JAMA. doi:10.1001/jama.2020.4783. PMC 7101507 Check |pmc= value (help). PMID 32219428 Check |pmid= value (help).
  10. Piechotta V, Chai KL, Valk SJ, Doree C, Monsef I, Wood EM; et al. (2020). "Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review". Cochrane Database Syst Rev. 7: CD013600. doi:10.1002/14651858.CD013600.pub2. PMID 32648959 Check |pmid= value (help).
  11. Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.; Mehta, Aneesh K.; Zingman, Barry S.; Kalil, Andre C.; Hohmann, Elizabeth; Chu, Helen Y.; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W.; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F.; Paredes, Roger; Sweeney, Daniel A.; Short, William R.; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-don; Ruiz-Palacios, Guillermo M.; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G.; Atmar, Robert L.; Creech, C. Buddy; Lundgren, Jens; Babiker, Abdel G.; Pett, Sarah; Neaton, James D.; Burgess, Timothy H.; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H. Clifford (2020). "Remdesivir for the Treatment of Covid-19 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2007764. ISSN 0028-4793.
  12. Furuta Y, Komeno T, Nakamura T (2017). "Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase". Proc Jpn Acad Ser B Phys Biol Sci. 93 (7): 449–463. doi:10.2183/pjab.93.027. PMC 5713175. PMID 28769016.
  13. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH (June 2020). "A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19". N. Engl. J. Med. doi:10.1056/NEJMoa2016638. PMID 32492293 Check |pmid= value (help).
  14. "World Health Organization - Draft landscape of COVID-19 candidate vaccines". WHO. 07/20/2020. Check date values in: |date= (help)
  15. Jackson, Lisa A.; Anderson, Evan J.; Rouphael, Nadine G.; Roberts, Paul C.; Makhene, Mamodikoe; Coler, Rhea N.; McCullough, Michele P.; Chappell, James D.; Denison, Mark R.; Stevens, Laura J.; Pruijssers, Andrea J.; McDermott, Adrian; Flach, Britta; Doria-Rose, Nicole A.; Corbett, Kizzmekia S.; Morabito, Kaitlyn M.; O’Dell, Sijy; Schmidt, Stephen D.; Swanson, Phillip A.; Padilla, Marcelino; Mascola, John R.; Neuzil, Kathleen M.; Bennett, Hamilton; Sun, Wellington; Peters, Etza; Makowski, Mat; Albert, Jim; Cross, Kaitlyn; Buchanan, Wendy; Pikaart-Tautges, Rhonda; Ledgerwood, Julie E.; Graham, Barney S.; Beigel, John H. (2020). "An mRNA Vaccine against SARS-CoV-2 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2022483. ISSN 0028-4793.
  16. Jackson, Lisa A.; Anderson, Evan J.; Rouphael, Nadine G.; Roberts, Paul C.; Makhene, Mamodikoe; Coler, Rhea N.; McCullough, Michele P.; Chappell, James D.; Denison, Mark R.; Stevens, Laura J.; Pruijssers, Andrea J.; McDermott, Adrian; Flach, Britta; Doria-Rose, Nicole A.; Corbett, Kizzmekia S.; Morabito, Kaitlyn M.; O’Dell, Sijy; Schmidt, Stephen D.; Swanson, Phillip A.; Padilla, Marcelino; Mascola, John R.; Neuzil, Kathleen M.; Bennett, Hamilton; Sun, Wellington; Peters, Etza; Makowski, Mat; Albert, Jim; Cross, Kaitlyn; Buchanan, Wendy; Pikaart-Tautges, Rhonda; Ledgerwood, Julie E.; Graham, Barney S.; Beigel, John H. (2020). "An mRNA Vaccine against SARS-CoV-2 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2022483. ISSN 0028-4793.
  17. Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, Zhu H, Zhao W, Han Y, Qin C (January 2019). "From SARS to MERS, Thrusting Coronaviruses into the Spotlight". Viruses. 11 (1). doi:10.3390/v11010059. PMC 6357155. PMID 30646565.
  18. Schindewolf C, Menachery VD (January 2019). "Middle East Respiratory Syndrome Vaccine Candidates: Cautious Optimism". Viruses. 11 (1). doi:10.3390/v11010074. PMC 6356267. PMID 30658390.