Modified intention to treat analysis shows not significant difference from the per-protocol analysis (Table S3).
Taking an endpoint of Ct level>35 as negative result and comparing the two groups, the ivermectin group showed that 43% (20/46) reached this point at day 6 vs. 33% (13/39) of the placebo group, however it did not reach statistical significance (P= 0.34).
During the study period four patients were referred to hospitals, with three of them being in the placebo arm. The first placebo-treated patient was hospitalized for 11 days with prolonged respiratory symptoms and needed oxygen even after his discharge from hospital. The second was hospitalized for one day due to respiratory complaints. The third one was referred to hospital due to headache and dizziness and was diagnosed with sinusitis after evaluation (brain CT and MRI). In addition, one asymptomatic patient became symptomatic, which occurred in the placebo group. In the ivermectin arm, one patient was referred to hospital due to shortness of breath at the day of recruitment. He continued the ivermectin and a day later was sent back to the hotel in good condition.
Culture Positivity rate
A convenient number of 16 samples were cultured on the day of recruitment (day zero). Ct levels ranged from 14-28 (mean 21.5±4.1), and among them 13/16 (81.2%) turned out to be positive. Culture viability was tested further by available samples with Ct ≤ 30 on days two, four and six after intervention (see details Table S2–supplement). Altogether 52 samples were cultured; viable culture in the placebo group were positive in 14 out of 29 cultures (48.2%) while among the ivermectin group, only 3/23 (13.0%) were found positive (P=0.008).
In a composite calculation, taking into account Ct values >30 together with non-viable culture, the negative results of the ivermectin group reached significance even at day four (one day after ending the treatment) with 86% negative patients compared to 59% in the placebo group (P=0.04) (see Table 2
Among all the 116 randomized patients, three patients reported having diarrhea following the treatment, two (3.5%) in the ivermectin group and one (1.7%) in the placebo group. In all cases the diarrhea resolved in two days. Two patients in the placebo arm reported rash during the treatment course which subsided within one to two days. No other adverse effects were reported. All of the eligible 89 patients for analysis reported to be adherent to the treatment as guided.
In this double-blind, randomized trial with mild COVID-19 patients, ivermectin significantly reduced time of viral shedding and affected viral viability when initiated at the first week after evidence of infection. Our primary endpoint was to show the benefit of ivermectin on day six (three days after ending treatment) which was achieved with 72% of samples being non-infectious (Ct>30) in comparison to 50% among the placebo group (OR 2.6). Even at day four (one day after treatment end) the ivermectin group showed an OR of 2.4, although this did not reach significance. In the multivariable logistic regression model, the superiority of ivermectin reached significance at day eight only, possibly due to a small sample size, .
The anti-viral activity was also reflected in the Kaplan-Meier curve where the effect of the drug was seen after the second day of treatment (Figure 3
To further explore the anti-viral activity, we tested the culture viability in both placebo and ivermectin groups. This analysis became available in our institution at the end of the study only, when the BSL-3 lab was established (January 2021). The results show the advantage of ivermectin where only 13% of samples stayed positive on days two to six, while 48% stayed positive in the placebo group (P=0.008). The anti-viral properties of ivermectin against SARS-CoV-2 was shown in an in-vitro model.(Caly et al., 2020) A major criticism regarding this in-vitro model was that the ivermectin concentration used was more than 35 times higher than the maximum plasma concentration after oral administration of the approved dose.(Bray et al., 2020) Hence, our study demonstrates the anti-COVID activity of ivermectin in dosage that can be used in clinical scenario. In-fact, the new anti-COVID drug molnupiravir (manufactured by Merck) was tested in a similar design to our protocol and demonstrated in the same way its anti-SARS-CoV-2 activity.(Fischer et al., 2022) Reduction in viral load was also demonstrated following remdesivir treatment and was consider as a marker for anti-viral properties.(Biancofiore et al., 2022)
The broad-spectrum antiviral activity of ivermectin is considered to be related to its ability to target the host importin (IMP) α/β1 nuclear transport proteins responsible for nuclear entry of cargoes of viral proteins, which in turns block the host anti-viral activity.(Wagstaff et al., 2012) It is also interferes with SARS-CoV-2 cell entry by docking in binding sites of S protein and ACE-2 receptor and by interrupting the priming of the S protein by the TMPRSS2 protein. (Choudhury et al., 2021; Eweas et al., 2021; LEHRER and RHEINSTEIN, 2020) Furthermore, it may inhibit RNA-virus replication by interaction with RNA-dependent RNA polymerase (RdRp), nsp14, N phosphoprotein, M protein, Mpro, PLpro, 3 chymotrypsin-like proteases and by inhibits the KPNA/KPNB1- mediated nuclear import of viral proteins.(Zaidi and Dehgani-Mobaraki, 2022)
The clinical implication of using ivermectin in preventing hospitalization and reducing mortality as well as using it for prophylaxis is an ongoing debate.(Santin et al., 2021) Several meta-analyses were performed which did not resolve the debate and in fact perpetuate the saga.(Hill et al., 2022; Schwartz, 2022a; Siedner, 2021) These aspects were beyond the goal of our study, however, shortening the infectiousness period may have an enormous impact on public health and our study can support this aspect. Taking the two composites; Ct values above 30 and negative cultures, in our study demonstrates an almost 90% non-infectious status at day four (one day after ending treatment) and 94% at day 6 among ivermectin users (Table 2
). The recommended isolation period was recently reduced to 5-7 days by the CDC and by many other health authorities, and even the requirement for facial masks are gradually being removed. However, studies have shown that in these 5-7 days, patients are still infectious at a rate of 59%, similar to the results we obtained with our placebo group.(Lefferts et al., 2022) Thus, decreasing the viral shedding duration by the drug could both decrease transmission and contribute to public health.
Our study has several limitations. First, the sample size was relatively small, and was designed to look for differences in viral load, but not for clinical deterioration and prevention of hospitalization. Indeed, this was planned as a second stage after proving its anti-COVID activity. The second limitation was that drug therapy was not physically observed by investigators. Another limitation was the male predominance in ourstudy. Finally, our study was conducted among mild-non-hospitalized patients and therefore the results cannot be applied to more severe or immune-suppressed populations.
The strength of our study was its double-blind structure with more concrete outcomes such as Ct values and culture viability where the laboratory personnel was blinded to the patients’ assignment.
In conclusion, our study supports the notion that ivermectin has anti-SARS-CoV-2 activity. If used at the early stage of disease onset, it may shorten the isolation time and reduce transmission.
Further studies are needed to test its ability to prevent clinical deterioration for high-risk groups and to examine its potential as a prophylactic drug. Vaccines are now available, but it will take years before they are distributed worldwide. As this drug may also reduce mortality, urgent intervention with further well-designed studies are needed, Since in most countries ivermectin has not been approved for COVID treatment, performing ivermectin vs. placebo studies appears to be unethical when the newer drugs, paxlovid,and molnupiravir, have been officially approved by health-authorities. However, offering ivermectin to those who refuse the new drugs seems to be a reasonable option. Since eligibility criteria in getting these early treatments are targeted to high-risk patients by only), observing the outcome of these arms of oral treatment: paxlovid vs. molnupiravir or ivermectin might shed light on the value of ivermectin in comparison to the newer drugs. (Schwartz, 2022b) In addition, as we know from treatment of other diseases, a single drug will not be sufficient, but rather combined therapy, thus proving ivermectin as a drug with anti SARS-Cov-2 activity may be useful as partner drug to combat this virus.
We would like to thank Super-Pharm Professional for donating the drug and the placebo pills, Ms. Liraz Olmer for statistical analysis support, Ms. Rivka Goldis for administration aids, Dr. Emiliano Cohen for graph producing, and Mr. Nadav Cain for his logistic support. Finally we would like to thank the Dirctorate of Defense Research and Development (DDR&D) at Israel’s Ministry of Defense and Home Front Command staff who helped us accessing the dedicated corona hotels, without their support the study could not been performed.
Conceptualization: ES; Data curation: ES, AB, MM; Formal analysis: ES, AB, MM, OE; Investigation: AB, MM, GH, DL, LR, AS, IN, LK, OE, ES; Methodology: ES, AB, MM, OE; Supervision: ES, AB; Writing – original draft: ES, AB, DL; Writing – review & editing: all authors contributed, reviewed and approved the last draft. There are no conflicts of interest for any of the authors.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: