key: cord-0811727-g5if9g2w
authors: Elalfy, Hatem; Besheer, Tarek; El‐Mesery, Ahmed; El‐Gilany, Abdel‐Hady; Soliman, Mahmoud Abdel‐Aziz; Alhawarey, Ahmed; Alegezy, Mohamed; Elhadidy, Tamer; Hewidy, Asem A.; Zaghloul, Hossam; Neamatallah, Mustafa Ahmed Mohamed; Raafat, Douaa; El‐Emshaty, Wafaa M.; Abo El Kheir, Nermin Y.; El‐Bendary, Mahmoud
title: Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID‐19
date: 2021-03-11
journal: J Med Virol
DOI: 10.1002/jmv.26880
sha: 1dc2485d292a427771f34297711caf5b1bfc73b3
doc_id: 811727
cord_uid: g5if9g2w

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non‐randomized controlled trial included 62 patients on the triple combination treatment versus 51 age‐ and sex‐matched patients on routine supportive treatment. all of them confirmed cases by positive reverse‐transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS‐COV2 from the nasopharynx in a shorter time than symptomatic therapy.

The coronavirus disease 2019 pandemic caused by the novel Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in Wuhan, China, in December 2019, and spread worldwide 1 The mortality rate of COVID-19 is one of the most important ways of measuring the disease's burden. Johns

Hopkins resource data reveals the deaths per 100.000 population ranged from 10.1% to 3.5% in different localities, as updated on 20 October 2020. 2 The urgent need for a safe and effective treatment has encouraged researchers to initiate clinical trials evaluating the efficacy of many drugs targeting viral proteins, viral entry pathway or the immune regulatory pathways. 3 the following mentioned drugs were approved as safe and effective in other indications, now we redirect its use in combinations toward COVID-19.

Nitazoxanide is an oral antiparasitic drug having activity against many protozoa and helminths. Recent studies suggested a potential antiviral activity for nitazoxanide and immune-modulatory effect suppressing the proinflammatory cytokines including interleukin-6 and tumor necrosis factor-α. [4] [5] [6] [7] In vitro studies suggested that nitazoxanide has activity against SARS-COV-2 replication but there is no clear evidence about its usefulness in the clinical setting. 2, 8 Ribavirin is a guanosine analogue having a broad-spectrum antiviral effect against RNA and DNA viruses. The mechanism of ribavirin action is not completely clear, but possible mechanisms include inhibition of mRNA capping and induction of mutations during viral replication. These mechanisms can limit viral replication and reduce the viral load. 9,10 Indirect antiviral activity of ribavirin mediated via immune regulatory pathways was also noted by many authors. [11] [12] [13] [14] Previous clinical experience with ribavirin in the treatment of SARS-COV and Middle-East respiratory syndrome coronavirus has proved its efficacy against coronaviruses and encouraged researchers to evaluate ribavirin as a potentially effective antiviral in treatment of SARS-COV-2 infection. [15] [16] [17] [18] [19] [20] [21] [22] The Chinese governmental treatment plan recommended Ribavirin for SARS-COV-2 pneumonia and then many clinical trials started evaluating the drug in SARS-COV-2 infection. 23, 24 Ivermectin is a broad-spectrum antiparasitic drug belonging to the Ivermectin family having proved antiparasitic, antibacterial, and antiviral activity 25, 26 Ivermectin has a broad range of antiviral activity against many RNA and DNA viruses in vitro. The in vivo antiviral potential of the drug was proved only against two RNA viruses, the West Nile virus, the Newcastle disease virus, and two DNA viruses the pseudorabies virus and parvoviruses. [27] [28] [29] [30] A recent study reported an in vitro inhibition of SARS-COV-2 replication by Ivermectin, and so the drug is now a potential candidate for SARS-COV-2 treatment. 31 Zinc ions (Zn) play a pivotal role in the development and maturation of both the innate and acquired antiviral immune response and its deficiency is associated with immune dysregulation. 32 Zinc ions may also directly inhibit SARS-CoV-2 replication. Many authors hypothesized that zinc supplementation may have a potentially beneficial effect for treatment of SARS-CoV-2 infection. 33, 34 2 | STUDY RATIONALE This is the first non-randomized controlled trial on the triple combination of Ivermectin, nitazoxanide, and ribavirin compared to routine supportive treatment in the treatment of patients with COVID-19. We hypothesized that treatment with a combination of multiple antiviral drugs with therapeutic minimum doses may be more effective than single-drug treatments as this treatment regimen is safe with minor and self-limiting gastrointestinal adverse events of diarrhea and vomiting.

This trial aims to compare the rate and time of viral clearance in subjects receiving the combination of nitazoxanide, ribavirin, and ivermectin plus zinc versus those receiving supportive treatment.

This study was carried out at the outpatients' clinic of COVID-19 at 

Non-randomized phase I clinical trial. 

Patients were self-allocated to the treatment groups; the first 3 days of the week for the intervention arm while the other 3 days for symptomatic treatment. Patients were informed about the drugs included in each arm of the study and informed consent was signed from each case.

A questionnaire was constructed to collect: *Sociodemographic data, for example, age, sex, residence, occupation. 

Supportive symptomatic treatment (controlled or named white arm):

in the form of paracetamol tablets (three times/day), zinc supplements (twice/day), good nutrition and hydration, and azithromycin capsules once may be added on a case by case basis.

Combined drugs as antivirals (intervention or named yellow arm): in the form of nitazoxanide 500 mg rapid release formula/6 h, ribavirin 1200 mg (400 mg divided doses); ivermectin in dose according to the following weight schedules: less than 60 kg or 60-90 kg 3 tables (200-300 μg/kg) (6 mg each table), 90-120 kg 4 tables (300-400 μg/kg), more than 120 kg 5 tables (30 mg fixed dose); all ivermectin doses taken singly after meals (due to long half live 12 to 54 h) were taken every 72 h till the end of 2 weeks according to each case; plus zinc supplement 30 mg twice daily.

Patients adherence: The best way to assess adherence is to discuss medication-taking behaviors directly with the patient. The project clinical team revised the remaining pills before swabs plus followed up with the patients by telephone contact. 

Data were analyzed using statistical package for social sciences version 23. Quantitative variables were presented as mean and standard deviation and an unpaired t test was used for group comparison.

Categorical variables were presented as number and percent. χ 2 test or Fisher's exact test was used for the comparison between the two groups, as appropriate. p ≤ .05 was considered statistically significant.

Sociodemographic data described in Table 1 shows that both groups are matched by their age, sex, residence, and CT lung findings.

However, patients on supportive treatment are more likely to be health care workers, unknown exposure, early moderate severity, and have low mean oxygen saturation than the other group. Patients flow charts in Figure 1 summarize the patients' selection criteria in both arms of the study.

Clinical symptomatology data shown in Table 2 reveals that no symptoms, abdominal pain, and nausea were significantly higher among the group of the combined antiviral than the supportive treatment. However, dyspnea is significantly higher among the supportive treatment group than the combined antiviral. Table 3 shows that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in supportive treatment and combined antiviral groups, respectively.

Basic biochemical data in Table 4 shows more leukocytopenias and lymphopenias in the combined antiviral group while the liver biochemical profile had no difference and renal functions in all included patients were normal.

Drugs' side effect data in Table 5 Many studies proved that Ribavirin was effective against COVID-19 when used in combination with interferon-α or lopinavir-ritonavir. 36, 37 In contrast; when used as a single agent in vitro studies it showed decreased potency compared to its comparative therapeutic agents. 38, 39 This suggests that ribavirin when used alone has limited therapeutic efficacy against COVID-19.

Moreover; dose-dependent adverse drug reactions, including hematologic and liver toxicity, were reported. 3 In in vitro studies (Vero E6 cells), nitazoxanide inhibited SARS-CoV-2 at a low micromolar concentration. 2 Nitazoxanide was suggested as a protocol for early cases of COVID-19 in combination with azithromycin. 40 

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Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19

The peer review history for this article is available at https://publons. 

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