A Lancaster University statistician who worked on the first published large randomized clinical trial for a potential treatment for the COVID-19 virus said it was encouraging to see the scientific community coalescing to combat COVID-19. With no treatments and growing deaths, researchers are scouring the planet to explore existing drugs for efficacy and safety. Lancaster University’s Professor Thomas Jaki participated clinical trials in Wuhan that investigated whether anti-viral drugs to treat HIV (lopinavir-ritonavir) would relieve COVID-19 symptoms. The University of Lancaster statistician suggested the results were encouraging from the first Wuhan study during the beginning of the pandemic. However, the data and opinions are not all aligned as the final conclusion of that Wuhan study was disappointing; but the number of trials assessing lopinavir-ritonavir is on the rise.
The First Wuhan Study
The study, published in the New England Journal of Medicine, included 199 patients with SARS-CoV-2 at Jin Yin-Tan Hospital treated either with standard of care or lopinavir-ritonavir treatment. Patients were randomly selected to receive lopinavir-ritonavir or placebo. According to the University of Lancaster statistician, those patients that received lopinavir-ritonavir appeared to improve faster. And according to Jaki, those who actually received lopinavir-ritonavir experienced faster time to clinical improvement than those patients only receiving standard of care alone. At least in the studies observed to date, the safety levels have been acceptable.
Official Study Conclusion: No Benefit
However, the actual study authors reported a different finding, noting that no benefit was observed with lopinavir-ritonavir treatment beyond standard of care. They suggested that more clinical trials are set up for patients with severe COVID-19 cases so as to help confirm or exclude the possibility of a treatment benefit.
Analyst Suggests Look Closer at the Data
As reported by Angus Liu at FiercePharma, Umer Raffat, an analyst from Evercore ISI, noted that the study timing wasn’t optimal. Most of the patients already had the symptoms too long and little was known about the actual virus. He raised Roche’s Tamiflu as an example—actual administration of the drug needs to be started in less than two days from symptom onset. In this early case of Wuhan, nothing at all was known about SARS-CoV-2 and hence, at the time, the time of viral load peak was uncertain. The pharmaceutical analyst suggested the investigators should have focused on “identifying the time point up until which an antiviral may work.”
In fact, Liu pointed out that Raffat sees a clear mortality benefit of Kaletra (lopinavir-ritonavir) over the placebo: “the death rate in Kaletra patients was 15.0% at day 28, versus 27.1% among placebo patients, provided therapy started within 12 days of symptoms starting.” However, factoring in fully analysis of modified intention-to-treat patients and the difference slims to 16.7% versus 25%. Raffat suggested that the study sponsors share the data so that he could “see a further sub-cut of this data…perhaps for patients that initiated less than eight days from symptom onset.”
The RECOVERY Trial Ramps up in Record Time
Others prominent investigators saw potential in the Wuhan study and hence included the design of the RECOVERY Trial. The rapid ramp up of the RECOVERY Trial, reported on by TrialSite News, is led by University of Oxford, the UK’s venerable research institution. The investigators there are fully aware that there is no known declared treatment for COVID-19 but that there is a range of potential targets and hence the study is designed to methodically assess these candidates, including:
- Lopinavir-Ritonavir (commonly used to treat HIV)
- Low dose Dexamethasone (steroid used to reduce inflammation)
- Hydroxychloroquine (anti-malarial)
- Inhaled interferon beta a (antiviral)
The University of Oxford investigators will regularly review the generated data to prepare an effective treatment and hence, quickly, adjust to help as many patients as possible. Peter Horby, the chief investigator, also worked on the Wuhan study previously discussed above. Due to the global pandemic, the RECOVERY trial was launched with incredible velocity—the time from initial agreement between the Department of Health and Social Care to the first patient recruited occurred in a record-breaking nine days—condensing a process that would have usually taken between six and nine months.
Classified as an Urgent Public Health Research Study, the RECOVERY trial is one of a group of initiative receiving £10.5 million as part of the £20 million rapid research response funded by UK Research and Innovation and by the Department of Health and Social Care through the National Institute for Health Research (NIHR).
The St. Michael’s Hospital Clinical Trial
Recently, St. Michael’s Hospital in Toronto announced the launch of the COVID-19 Ring-based Prevention Trial with Lopinavir/Ritonavir (CORIPREV-LR). Led by principal investigator Darrell Tan, this Phase III study will enroll 1,220 participants and run from March 30, 2020 to March 31, 2022.
The study team has identified lopinavir/ritonavir as a good candidate as a potential post-exposure prophylaxis (PEP) against COVID-19. Due to the drug’s good safety profile and global availability, the Canadian sponsor designed a cluster randomized controlled trial of oral lopinavir/ritonavir as PEP against COVID-19 that, the sponsor targets, will address the immediate need for preventive interventions, generate key data on COVID-19 transmission, and serve as a research platform for future vaccines and preventive agents.
More on Lopinavir-Ritonavir
Currently there are at least twenty-one (21) clinical trials involving hospitalized COVID-19 patients and lopinavir-ritonavir, totaling nearly 25,000 patients. But what is lopinavir-ritonavir?
According to the National Institutes of Health (NIH) website, the drug’s trade name is Kaletra. Approved to treat HIV infection in adults and children 14 years and up, it is always used in combination with other HIV medicines.
This combination (high dose of lopinavir and los dose of ritonavir) is generally recommended for use with other antivirals. Additionally, it has bee used as a treatment after a needlestick injury or other potential exposure. Side effects can run from the mild up to the severe. See the FDA label for more details.
The drug has been approved for use in the United States since 2000. Additionally, it is on the World Health Organization’s List of Essential Medicines.