Clinical Trial Data
During the lengthy processes of vaccine and antiviral development targeted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to consider currently available medications that may be able to save lives in the interim by reducing the risk of multiorgan damage from the progression of COVID-19. Several agents are under investigation for use in severely and critically ill patients with COVID-19.
Remdesivir is a nucleoside analogue prodrug that has shown inhibitory effects on animal and human coronaviruses, including SARS-CoV-2 in vitro and in animal models. A randomized, double-blind, placebo-controlled study found that patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio [HR] = 1.52; 95% confidence interval [CI], 0.95–2.43). The trial enrolled 237 hospitalized patients with confirmed SARS-CoV-2 infection, an interval from symptom onset to enrollment of ≤12 days, radiologically confirmed pneumonia, and oxygen saturation of ≤94% on room air or ratio of arterial oxygen partial pressure to fractional inspired oxygen of ≤300 mg Hg.1
Preliminary results from the Adaptive COVID-19 Treatment Trial (ACTT), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, found that patients who received remdesivir had a 31% faster time to recovery than those who received placebo. The trial enrolled 1,063 patients with advanced COVID-19 with lung involvement. The median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for patients who received placebo. Results also suggest a survival benefit, with a mortality rate of 8.0% for the remdesivir group and 11.6% for the placebo group (P= .059).2
Novel therapies, particularly anti-cytokine approaches targeting interleukin (IL)-6, IL-1, interferon (IFN)-γ, and IL-18, have shown efficacy in treating cytokine storm syndrome (CSS). Early reports from a single-arm study of 21 patients in China have demonstrated favorable outcomes of IL-6 blockade with tocilizumab in severely ill COVID-19 patients, including rapidly reduced fevers and decreased need for supplemental oxygen in 75% of patients. All 21 patients in the group met the criteria for severe or critical COVID-19. Severe patients had to meet one of the following criteria: shortness of breath, respiratory rate >30/min; oxygen saturation <93% while resting; or PaO2/FiO2 ≤300 mm Hg. Critical patients had to meet one of the following criteria: respiratory failure requiring mechanical ventilation; shock; and/or admission to the intensive care unit (ICU) with other organ failure. All 21 patients had a fever that was reduced to a normal temperature on the first day of treatment with tocilizumab. Within 5 days of initiating tocilizumab, 75% (15/20) of the patients reduced their oxygen intake, and one patient no longer required oxygen. Imaging examination by computed tomography (CT) scan showed that 90.5% (19/21) of the patients had resorption of pulmonary lesions. Laboratory examination showed that the proportion of peripheral blood lymphocytes and C-reactive protein (CRP) returned to normal in the majority of patients. All of the patients were discharged, most within 2 weeks of tocilizumab therapy.3,4 Tocilizumab therapy has been formally included in the diagnosis and treatment program for COVID-19 of the National Health Commission of China as of March 3, 2020.4
A randomized, controlled, open-label trial found no statistically significant benefit with lopinavir-ritonavir beyond standard care in hospitalized patients with severe COVID-19. The trial enrolled 199 patients with confirmed SARS-CoV-2 infection and an SpO2 of ≤94% on room air or a PaO2:FiO2 of ≤300 mm Hg. Patients were randomized to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice daily plus standard care or standard care alone. Treatment with lopinavir-ritonavir was associated with a numerical difference from standard care in the time to clinical improvement (HR = 1.31; 95% CI, 0.95–1.80) and a reduction in mortality at 28 days (19.2% vs 25.0%; difference, –5.8 percentage points; 95% CI, –17.2 to 5.7). Although antiviral drugs are most effective when they are administered early in an infection, the patients in this trial underwent randomization a median of 13 days after disease onset.6 Further trials are needed to determine if initiating therapy earlier may be more effective, since systemic hyperinflammation rather than viral pathogenicity dominates in later stages of SARS-CoV-2 infection.
Preliminary findings from the phase IIb, randomized CloroCovid-19 trial suggest that higher doses of chloroquine (CQ) for the treatment of severe COVID-19 are associated with QTc interval prolongation and increased mortality, particularly among patients also receiving azithromycin and oseltamivir. The trial randomized 81 patients to high-dose CQ (i.e., 600 mg CQ twice daily for 10 days) or low-dose CQ (i.e., 450 mg twice daily on day 1 and once daily for 4 days). The high-dose group was older (54.7 vs 47.4 years) and included more patients with heart disease (17.9% vs 0%). All patients received azithromycin, and the frequency of oseltamivir use was 86.8% and 92.5% in the low- and high-dose groups, respectively. QTc prolongation was more common in the high-dose group (18.9% vs 11.1%). Mortality until day 13 was higher in the high-dose group compared with the low-dose group (39.0% vs 15.0%). The overall mortality rate in this trial was 27.2% (95% CI, 17.9–38.2%), which overlapped with the 95% CI of the metanalysis of 2 major studies (95% CI, 14.5–19.2%) that included similar patients not receiving CQ. No difference in mortality rates was observed in a subgroup analysis of critically ill patients.7
In an observational study of 1,376 hospitalized patients with COVID-19 in New York City, hydroxychloroquine administration was not associated with a lower risk of intubation or death (HR, 1.04; 95% CI, 0.82-1.32). Hydroxychloroquine was administered to 58.9% of patients in the study; 45.8% of patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median PaO2:FiO2, 223 vs. 360).8
Clinical trials are underway to investigate the efficacy and safety of Janus kinase (JAK) inhibitors in managing COVID-19. The JAK family of enzymes are responsible for signal transduction in the immune system, and JAK inhibitors play a major role in inhibiting and blocking cytokine release.9 Baricitinib, a JAK inhibitor, may be a candidate for the management of COVID-19 by reducing cytokine release. Baricitinib also acts as a numb-associated kinase (NAK) inhibitor with high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis. Inhibition of AAK1 may inhibit viral infection of cells with SARS-CoV-2.10 A baricitinib arm will be added to the Adaptive COVID-19 Treatment Trial by the National Institute of Allergy and Infectious Diseases (NIAID).11
The efficacy and safety of tofacitinib, an oral JAK inhibitor, will be evaluated in an independent phase 2 investigator-initiated study for use in patients with COVID-19-associated interstitial pneumonia. Interest in tofacitinib in the management of COVID-19 is based on the hypothesis that JAK inhibition could mitigate systemic and alveolar inflammation in patients with COVID-19-related pneumonia. Tofacitinib may inhibit essential cytokine signaling involved in immune-mediated inflammatory responses that lead to lung damage and ARDS in patients with COVID-19-related pneumonia.12
Vaccine development is a priority with COVID-19 given the high rate of transmission of this novel virus and the lack of herd immunity amongst the population.13 Vaccines are the most effective strategy for preventing infectious disease since they are cost-effective, limit morbidity and mortality, and reduce hospitalization rates. The development of an effective and safe vaccine generally takes up to 15 to 20 years.14 However, it is expected that a vaccine for SARS-CoV-2 will be developed by 2021.
Over the past two decades, three human coronaviruses (SARS, MERS, and COVID-19) emerged worldwide, causing considerable threat to global public health. However, there is still no approved vaccines for human coronaviruses. Previous efforts to develop safe vaccines for genetically similar viruses, including SARS and MERS coronaviruses, proved challenging as potential candidate vaccines induced significant lung immunopathology in animal models following viral challenge.16,17
Trials on emerging vaccines are underway:
- A phase 1/2 trial for the BNT162 vaccine began dosing participants in the U.S. in May 2020. There are four vaccine candidates in the BNT162 program that represent different mRNA formats and target antigens. mRNA-based vaccines contain mRNA molecules encoding viral antigens, which are translated by the host’s cellular machinery after vaccination. mRNA vaccines have advantages over conventional vaccines as they do not integrate into the host genome, can be developed rapidly, and provoke improved immune responses through the production of multimeric antigens.18 In the BNT162 vaccine program, the mRNA is combined with a lipid nanoparticle formulation. Two of the candidate vaccines contain sequences for the larger spike protein and the other 2 include the smaller optimized receptor binding domain (RBD) from the spike protein. The RBD-based candidates contain the piece of the spike that is thought to be most important for eliciting antibodies that can inactivate the virus. The dose level escalation portion of the phase 1/2 trial in the U.S. will enroll up to 360 healthy subjects in two age cohorts (18-55 and 65-85 years). Older adults will only be immunized with a given dose level of a vaccine candidate once testing of the candidate in younger adults has shown evidence of safety and immunogenicity.19,20
- A phase I trial of the mRNA-1273 vaccine began in March 2020 with 45 healthy adult volunteers. The investigational vaccine is a viral mRNA molecule that directs the body’s cells to express viral proteins and elicit an immune response. The mRNA-1273 vaccine has shown promise in animal models.21
- The ChAdOx1 nCoV-19 vaccine is under investigation at the University of Oxford. This vaccine uses a viral vector based on a weakened version of the common cold (adenovirus) that contains the genetic material of the SARS-CoV-2 spike protein. After vaccination, the surface spike is produced, which primes the immune system to recognize the spike and attack the SARS-CoV-2 virus if it infects the body in the future. The ChAdOx1 vaccine has been given to 320 people to date and has shown to be safe and well tolerated. The most common adverse events to date are temperature, flu-like symptoms, headache, or sore arm.22
- Another phase I clinical trial is expected to begin in September 2020. The vaccine candidate was developed using patented technology based on the production of adenovirus vectors as gene carriers.23,24
- Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. 2020;April 29: Epub ahead of print.
- National Institutes of Health (NIH). NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. Available at niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19.
- Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci. 2020;April 29: Epub ahead of print.
- Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18:164.
- Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nature Rev Immunol. 2020;20:271-272.
- Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe epCOVID-19. N Engl J Med. 2020;382:1787-1799.
- Silva Borba MG, Almeida Val FF, Souza Sampaio V, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection: a randomized clinical trial. JAMA Netw Open. 2020;3:e208857.
- Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020;May 7: Epub ahead of print.
- Kontzias A, Kotlyar A, Laurence A, et al. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol. 2012;12:464-470.
- Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20:400-402.
- Lilly Press Release. Lilly Begins Clinical Testing of Therapies for COVID-19. April 10, 2020. Available at https://investor.lilly.com/node/43041/pdf.
- Pfizer press release. Pfizer advances battle against COVID-19 on multiple fronts. April 9, 2020. Available at pfizer.com/news/press-release/press-release-detail/pfizer_advances_battle_against_covid_19_on_multiple_fronts.
- Horton R. Offline: COVID-19 – a reckoning. 2020;395(10228):935.
- Davis MM, Butchart AT, Coleman MS, et al. The expanding vaccine development pipeline, 1995-2008. Vaccine. 2010;28:1353-1356.
- Jackson NAC, Kester KE, Casimiro D, et al. The promise of mRNA vaccines: a biotech and industrial perspective. Npj Vaccines. 2020;5:11.
- Agrawal AS, Tao X, Algaissi A, et al. Immunization with inactivated Middle East respiratory syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus. Hum Vaccin Immunother.2016;12(9):2351–2356.
- Tseng CT, Sbrana E, Iwata-Yoshikawa N, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One. 2012;12(9): 2351–2356.
- Ahn DG, Shin HJ, Kim MH, et al. Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19). J Microbiol Biotechnol. 2020;30(3):313-324.
- Pfizer Press Release. Pfizer and BioNTech Dose First Participants in the U.S. as Part of Global COVID-19 mRNA Vaccine Development Program. Available at https://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_biontech_dose_first_participants_in_the_u_s_as_part_of_global_covid_19_mrna_vaccine_development_program.
- Associated Press. BioNTech and Pfizer announce regulatory approval from German authority Paul-Ehrlick-Institut to commence first clinical trial of COVID-19 vaccine candidates. April 22, 2020. Available at: https://apnews.com/96b5fbdfeaf0b06af59349ee7c7a4dc2.
- National Institutes of Health (NIH). NIH clinical trial of investigational vaccine for COVID-19 begins. Available at https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins.
- AstraZeneca Press Release. AstraZeneca and Oxford University announce landmark agreement for COVID-19 vaccine. Available at https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-oxford-university-announce-landmark-agreement-for-covid-19-vaccine.html.
- Patented vaccine capabilities and technologies. Available at: https://www.janssen.com/infectious-diseases-and-vaccines/patented-technologies.
- Johnson and Johnson. Johnson & Johnson Announces a Lead Vaccine Candidate for COVID-19; Landmark New Partnership with U.S. Department of Health & Human Services; and Commitment to Supply One Billion Vaccines Worldwide for Emergency Pandemic Use. March 30, 2020. Available at: https://www.jnj.com/johnson-johnson-announces-a-lead-vaccine-candidate-for-covid-19-landmark-new-partnership-with-u-s-department-of-health-human-services-and-commitment-to-supply-one-billion-vaccines-worldwide-for-emergency-pandemic-use.