COVID-19 Drugs: University Of Liverpool Phase 1a Clinical Trial Of Using Nitazoxanide To Treat COVID-19 Shows Potential. Phase 1b/2a Initiated

COVID-19 Drugs: The phase 1a clinical trial led by researchers from the University of Liverpool-UK using the antiparasitic drug Nitazoxanide has shown potential in terms of treating the COVID-19 disease. The research team also comprised clinicians and scientist from University of Southampton-UK, University of Cambridge-UK, the Liverpool School of Tropical Medicine-UK and the Liverpool University Hospitals NHS Foundation Trust. An important aspect of the study was that most patients who were involved in the trial were infected with the Delta variant hence showing that the drug had potential against the never emerging SARS-CoV-2 coronavirus variants.

 
There has been a dire need to explore drug repurposing to find potential existing drugs that could help in the treatment for COVID-19 as the pandemic had wreak havoc globally over the last 20 months with more than 227 million people having been affected so far and more than 4.7 people who have died from COVID-19.The pandemic shows no signs of slowing down despite massive vaccination campaigns globally and in fact more catastrophic surges are expected in coming weeks.
 
To date, repurposing approved drugs has led to the identification of immunomodulatory treatments for severe COVID-19.
 
However finding repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses.
 
Nitazoxanide is a US FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase 1 trial in healthy adult participants was undertaken with high dose nitazoxanide.
 
Study participants received 1500mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose and schedule. Intensive pharmacokinetic sampling was undertaken day 1 and 5 with Cmin sampling on day 3 and 7.
 
A total of fourteen healthy participants were enrolled between 18th February and 11th May 2021. All 14 doses were completed by 10/14 participants.
 
The trial found that Nitazoxanide was safe and well tolerated with no significant adverse events. Moderate gastrointestinal disturbance (loose stools) occurred in 8 participants (57.1%), with urine and sclera discolouration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on first dose and maintained throughout.
 
The study found that Nitazoxanide administered at 1500mg BID with food was safe and well tolerated and a phase 1b/2a study is now being initiated in COVID-19 patients.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.09.10.21263376v1
 
The decision to start looking at Nitazoxanide as a possible candidate for drug repurposing to treat COVID-19 started after a few studies showed its potenti al to inhibit the SARS-CoV-2 coronavirus in vitro studies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678434/
 
A Mexican study using Nitazoxanide among healthcare workers showed that it prevented COVID-19 disease progression and lowered the risk of mortality. https://www.spandidos-publications.com/10.3892/wasj.2021.94?text=fulltext
 
An earlier Brazilian randomized clinical trial showed that Nitazoxanide has efficacy to treat COVID-19 not only because of its antiviral properties but also its anti-inflammatory capabilities as well. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00261-3/fulltext
 
Another Brazilian study showed that Nitazoxanide used in individuals with mild COVID-19 prevented disease progression and lead to faster viral clearance.
https://erj.ersjournals.com/content/58/1/2003725
 
There has also been numerous other studies showing its efficacy as one of the many  potential COVID-19 Drugs.
https://www.medrxiv.org/content/10.1101/2021.03.03.21252509v1
 
Studies are also underway exploring it use as a prophylaxis. https://www.authorea.com/users/321465/articles/450723-dose-prediction-for-repurposing-nitazoxanide-in-sars-cov-2-treatment-or-chemoprophylaxis
 
In the current COVID-19 pandemic, there have been many instances of drugs being repurposed for use against the disease. These include trialed and approved drugs such as remdesivir and tocilizumab, to potentially dangerous and ineffective drugs such as ivermectin. However most drugs being explored as a potential antiviral to treat has so far failed with the exception of fluvoxamine.
 
To date, the most common drugs that are used to treat COVID-19 include steroids and interleukin-6 (IL-6) blockers.
 
Nitazoxanide, sold under the brand name Alinia among others, is a broad-spectrum antiparasitic and broad-spectrum antiviral medication that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. 
 
Nitazoxanide is effective in the treatment of cryptosporidiosis and giardiasis and has also demonstrated effectiveness against anaerobic bacteria, protozoa, and several viruses. Some trials have shown antiviral properties of nitazoxanide; however, this activity was observed at small doses that could increase the risk of SARS-CoV-2 in developing resistance against this drug.
 
Nitazoxanide is effective against the influenza virus due to its impact on post-translational modification and maturation of hemagglutinin.
 
Interestingly a recent study reported a similar mechanism involving the SARS-CoV-2 spike protein, which is an essential component of SARS-CoV-2 for its entry into host cells. To this end, researchers hypothesize that nitazoxanide may help to stimulate the immune system for a more rigorous response against COVID-19.
https://www.biorxiv.org/content/10.1101/2021.04.12.439201v1
 
Numerous similar drugs have been reported to block the SARS-CoV-2 spike protein-mediated syncytia formation. This process involves the formation of a mass of fused cells with several nuclei that can cause extensive lung damage.
 
However as nitazoxanide is already approved by the United States Food and Drug Administration (FDA), along with the fact that it is cheap and available globally, this drug shows great promise as a potential treatment approach to COVID-19.
 
The current study reports results from a Phase I trial where only healthy volunteers between the ages of 18 and 75 were included. Moreover, no pregnant or breastfeeding individuals, nor any individuals who were currently taking any medications or suffering from any clinically significant allergy, were included in the current study.
 
The study included 14 individuals who received 1500 mg of nitazoxanide twice a day with food for one week.
 
The study team evaluated the safety of the volunteers by assessing the presence of any side effects, as well as their tolerability of the drug. The researchers were also interested in determining the optimal dose and best schedule to administer nitazoxanide.
 
For the study, on days 1 and 5, volunteers were dosed in an inpatient unit; however, for the remainder of the study, the participants could medicate themselves at home. All volunteers were administered polymerase chain reaction (PCR) tests to exclude the possibility of COVID-19.
 
The study team monitored the volunteers’ general physical health, serum chemistry, and hematology at the screening phase two days before the drug was administered, the first day of the study, as well as 120 hours post-dose. Urinalysis was also performed at more frequent intervals.
 
However due to suspected QTcB prolongation, which is a drug-induced heart problem, in one patient, (Not related directly to nitazoxanide) dosing was suspended early for 4 volunteers. Eight of the other volunteers completed six full days of dosing, with two completing the full treatment course.
 
Unfortunately the trial was paused following the prolongation until consultation with the Safety Review Committee and United Kingdom medicines regulator. In other patients, the most common complaints were mild gastrointestinal distress and the discoloration of the outer layer of the eyeball and bodily fluids. It was agreed that these were relatively minor adverse events, and escalation to a second phase of the trial could subsequently begin in South Africa.
 
Importantly the pharmacokinetic data gathered during the study was also promising, as the dose appeared high enough to show effectivity against COVID-19 if nitazoxanide proves effective. While the predicted drug accumulation did not present itself, concentrations hit the target on the first dose and remained high throughout the trial.
 
The study team highlights the urgent need for effective antiviral therapeutics for COVID-19, not just to reduce the progression of the disease to a state requiring hospitalization, but also to reduce viral transmission. The pharmacokinetic data gathered through serum and urinalysis suggests that the 1,500 mg dose has the maximum potential to demonstrate any potential activity of nitazoxanide against COVID-19 in vivo in future trials.
 
There are to date almost 17 more ongoing clinical trials globally in various countries exploring the usage of nitazoxanide to treat COVID-19. It some cases its being combined with certain phytochemicals in clinical trials.
 
Note: Please do not attempt to use nitazoxanide to treat COVID-19 at home and if you suspect you have COVID-19, go see a licensed doctor first.
 
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