Clinical Trial Evaluating Safety and Efficacy of Ivermectin and Nitazoxanide Combination as Adjuvant Therapy in COVID-19 Newly Diagnosed Egyptian Patients: A Tanta University Hope

Selected Drugs

Ivermectin has anti-parasitic effect along with anti-viral activity against a broad range of viruses in vitro. Ivermectin was identified as an inhibitor of interaction between the human immunodeficiency virus-1 (HIV-1) integrase protein (IN) and the importin (IMP) α/β1 heterodimer responsible for IN nuclear import. Ivermectin has since been confirmed to inhibit HIV-1 replication. Importantly, Ivermectin has been demonstrated to limit infection by RNA viruses such as West Nile Virus and influenza. This broad-spectrum activity is believed to be due to the reliance by many different RNA viruses on IMPα/β1 during infection. Ivermectin has similarly been shown to be effective against the DNA virus pseudorabies virus (PRV) both in vitro and in vivo. Finally, Ivermectin was the focus of a phase III clinical trial in Thailand against DENV infection, in which a single daily oral dose was observed to be safe and resulted in a significant reduction in serum levels of viral NS1 protein, but no change in viremia or clinical benefit was observed.

The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV). Studies on SARS-CoV proteins have revealed a potential role for IMPα/β1 during infection in signal-dependent nucleocytoplasmic shutting of the SARS-CoV nucleocapsid protein that may impact host cell division. In addition, the SARS-CoV accessory protein ORF6 has been shown to antagonize the antiviral activity of the STAT1 transcription factor by sequestering IMPα/β1 on the rough ER/Golgi membrane.

Taken together, these reports suggested that Ivermectin's nuclear transport inhibitory activity may be effective against SARS-CoV-2. Interestingly, it has been postulated that the FDA-approved drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro whereas a single treatment was able to provoke approximately 5000-fold reduction in viral load within 48h. Ivermectin has an established safety profile for human use. Recent reviews and meta-analysis indicate that high dose Ivermectin has comparable safety as the standard low-dose treatment, although there is not enough evidence to make conclusion about the safety profile in pregnancy. In clinical setting, Ivermectin was the focus of a phase III clinical trial on patients with dengue viral infection in Thailand, in which a single daily dose (200 - 400 µg/kg once daily for 2 days in one arm and 200-400 µg/kg once daily for 3 days in the other arm) was found to be safe but did not produce any clinical benefit. In previous clinical study, one dose of Ivermectin 200 μg/kg or four doses of Ivermectin 200 μg/kg (given on days 1, 2, 15, and 16) for the treatment of non-disseminated strongyloidiasis were implicated. The author proposed that, multiple doses of Ivermectin did not show higher efficacy and was tolerated less than a single dose. A single dose should, therefore, be preferred for the treatment of non-disseminated strongyloidiasis.

Nitazoxanide is originally developed as an antiprotozoal agent and has a broad-spectrum antiviral activity undergoing development for the treatment of influenza and other viral respiratory infections. In addition to its antiviral activity, Nitazoxanide inhibits the production of pro-inflammatory cytokines TNFα, IL-2, IL-4, IL-5, IL-6, IL-8 and IL-10 in peripheral blood mononuclear cells. Nitazoxanide could improve outcomes in patients infected with MERS-CoV by suppressing overproduction of pro-inflammatory cytokines, including IL-6. Nitazoxanide has been tested in clinical setting for the treatment of acute uncomplicated influenza, where the subjects received either 600 or 300 mg of Nitazoxanide or placebo orally twice daily for five days and were followed for 28 days. Subjects who received Nitazoxanide 600 mg twice daily experienced shorter times to alleviation of symptoms compared with subjects who received 300 mg Nitazoxanide twice daily, which in turn, was shorter than placebo.