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Clinical trials for COVID-19 – update #4

After almost 5 months since the epidemic of SARS-CoV-2 began, more than 3 million people have fallen ill and approximately 230,000 people have died. Every day of multiple groups of scientists perform clinical trials in the hope of finding an effective drug or vaccine against the virus.

Drugs

Remdesivir

The recent publication of an open-label, non-randomised study of remdesivir, a potential drug in the treatment of COVID-19, originally developed by Gilead Sciences; in a heterogeneous patient population has added to the confusion.

Remdesivir is a prodrug. Its active analogs enter and accumulate in cells, inhibiting viral RNA dependent RNA polymerase (RdRp), which is an important part of viral replication mechanism. Because of this, remdesivir stops viral replication. It is worth noting that coronaviruses have a “proofreading” enzyme (exoribonuclease) that corrects replication errors in RNA sequence, potentially limiting the effects of the analogs of remdesivir, but remdesivir can evade this proofreading. There is not well known, the mechanism, why remdesivir is able to evade the proofreading. In animal studies, remdesivir protected rhesus monkeys from the MERS-CoV infection and reduced the severity of lung damage when given after exposure to MERS-CoV, of which is remarkably similar to SARS-CoV-2. A preprint of a randomised, well masked, controlled trial in 12 rhesus monkeys infected with SARS-CoV-2, reported that the course of remdesivir administered from 12 hours after inoculation, attenuated respiratory symptoms and lung damage.

In recent days, the World Health Organisation website accidentally announced a short report of a Chinese phase I clinical trial, where 237 patients with laboratory-confirmed COVID-19 underwent randomisation (158 took remdesivir, 79 were in the control group). According to the summary of the Chinese study, remdesivir was “not associated with a difference in time to clinical improvement” compared to a standard of care control. After one month, it appeared that 13.9% of the remdesivir patients had died compared to 12,8% of patients in the control arm. The difference was not statistically significant. The study was terminated prematurely because it was difficult to enroll patients in China where the number of COVID-19 cases was decreasing. It was also noted that approximately 65% of patients in remdesivir arm had experienced side effects. At present, there are 11 other clinical trials utilizing remdesivir which are recruiting or ongoing. Before any recommendations related to remdesivir are made, the results from these clinical trials should be evaluated.

Hydroxychloroquine and chloroquine

On 24th April 2020, the FDA announced a report cautioning against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 outside of a hospital setting or a clinical trial due to the risk of heart rhythm problems. Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT interval prolongation, which is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between the beats; and a dangerously rapid heart rate called ventricular tachycardia. These risks may increase when these medicines are combined with other medicines known to prolong the QT interval including the antibiotic azithromycin.

The FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT-prolonging medicines. Both chloroquine and hydroxychloroquine continue to be tested in clinical trials for COVID-19. In many countries, these drugs had their use authorized during the COVID-19 pandemic for the treatment of the virus in hospitalized patients. Alongside this, in many countries, both drugs were also authorized for use in the prevention of COVID-19.

Further reports from ongoing studies should show the real efficacy and safety data informing the approach to the use of hydroxychloroquine or chloroquine in COVID-19 patients.

Vaccines

ChAdOx1

In recent weeks, scientists from Oxford University in the United Kingdom have begun testing a  vaccine against SARS-CoV-2 called ChAdOx1 on human volunteers. Around 1102 healthy participants (aged 18-55 years) will take part in this study across multiple study sites in Oxford, Southampton, London and Bristol. Half of them will take the vaccine, and the other half will receive a widely available meningitis vaccine (MenACWY). The MenACWY is a licensed vaccine against group A, C, W and Y meningococcus which has been given routinely to teenagers in the UK since 2015.

The study aims to assess whether healthy individuals can be protected from COVID-19 with this new vaccine based on an adenovirus host, which may be the case of the vaccine can generate a strong immune response within the human body against the virus. The study will also provide significant information on the safety aspects of the vaccine.

Furthermore, scientists are going to vaccine 800 volunteers in the UK over the next month. If the trial will be successful, in the UK, they will approach scientists and the government in Kenya for permission to evaluate it there.

BNT162

A phase I/II of the clinical trial of the BNT162 vaccine against SARS-CoV-2 which being developed by BioNTech SE and Pfizer has been granted approval in Germany. This is the first clinical trial of a SARS-CoV-2 vaccine candidate to start in Germany and is a part of a global development program.

BNT162 is a vaccine candidate based upon mRNA. BioNTech has four vaccine candidates and these are the first candidates from their COVID-19-focused project “Lightspeed”, each representing different mRNA formats and target antigens. Two of the four vaccine candidates include a nucleoside modified mRNA, one includes uridine containing mRNA, and the last one utilizes self-amplifying mRNA. Each mRNA format is combined with a lipid nanoparticle (LNP) formulation.

This part of the clinical trial will include approximately 200 healthy volunteers between the ages 18 and 55 and will target dosages of between 1ug and 100ug aiming to determine the optimal dose for further studies, as well as evaluate the safety and immunogenicity of the vaccine.

Pfizer and BioNTech also announced they will also conduct trials for BNT162 in the United States upon regulatory approval.

References

  1. “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.” Case Medical Research, 2020, doi:10.31525/ct1-nct04292730.
  2. https://www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show-no-benefit-for-coronavirus-patients/
  3. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
  4. https://www.ox.ac.uk/news/2020-04-23-oxford-covid-19-vaccine-begins-human-trial-stage
  5. https://www.europeanpharmaceuticalreview.com/news/117624/germany-to-begin-first-clinical-trial-of-covid-19-vaccine-candidate/
  6. https://www.precisionvaccinations.com/vaccines/bnt162-sars-cov-2-vaccine
  7. https://www.who.int/
  8. https://bing.com/covid/
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