The effect of ivermectin on the viral load and culture viability in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial
The effect of ivermectin on the viral load and culture viability in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial
Highlights
•
Drug-repurposing is a desirable approach to combat a new pathogen.
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The value of ivermectin as an anti-SARS-CoV-2 agent is debatable.
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Our study shows ivermectin treatment decreased viral-load and culture viability.
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These may reflect an anti-SARS-CoV-2 activity of ivermectin.
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Further studies are needed to explore its role in combating COVID.
Abstract
Objectives
Ivermectin, an anti-parasitic agent, also has anti-viral properties. Our aim was to assess whether ivermectin has anti-SARS-CoV-2 activity.
Methods
The double-blinded trial compared patients receiving ivermectin for three days vs. placebo in non-hospitalized adult COVID-19 patients. RT-PCR from a nasopharyngeal-swab was obtained at recruitment and then every two days for at least 6 days. Primary endpoint was reduction of viral-load on the sixth-day as reflected by Ct level>30 (non-infectious level). The primary outcome was supported by determination of viral-culture viability.
Results
Out of 867 patients screened, ultimately 89 were per-protocol evaluable (47 ivermectin and 42 placebo). On day 6, OR was 2.62 (95% CI: 1.09-6.31) in ivermectin arm reaching the endpoint. In a multivariable logistic regression model, the odds of a negative-test at day six was 2.28 time higher in the ivermectin group but reach significance only on day 8 (OR 3.70; 95% CI: 1.19-11.49, p=0.02). Culture-viability at days two to six were positive in 13.0% (3/23) of ivermectin samples vs. 48.2% (14/29) in the placebo group (p=0.008).
Conclusions
There were lower viral-loads and less viable-cultures in the ivermectin group, which shows its anti-SARS-CoV-2 activity. It could lead to reduce transmission in these patients and encourage further studies with this drug.
The study is registered at ClinicalTrials.gov: NCT 04429711.
Background
Ivermectin is an FDA-approved broad spectrum anti-parasitic agent, which was initially approved for humans in 1987 to treat onchocerciasis, awarding the discoverers the Nobel Prize of Medicine in 2015. Its main use is treatment of infections caused by roundworm parasites. Over the years, the spectrum was extended to include a variety of parasitic skin infections, such as scabies. (Laing et al., 2017)
In the last decade, several in-vitro studies have shown its anti-viral activity against a broad range of viruses, mainly RNA viruses including HIV, influenza and several flaviviruses such as Dengue virus (DENV), Zika, and West Nile Virus. (Caly et al., 2012; Götz et al., 2016; Lundberg et al., 2013; Tay et al., 2013; Wagstaff et al., 2012) Ivermectin was tested in vitro against SARS-CoV-2 and showed ∼5000-fold reduction (99.8%) in viral RNA after 48 hours. (Caly et al., 2020) However, it was criticized that the dosing used in the study cannot be achieved with the current approved dose and its anti-SARS-CoV-2 activity in humans has never been proven. (Bray et al., 2020)
Ivermectin has in addition, anti-inflammatory properties. (Zhang et al., 2008) Since the excessive inflammatory response to SARS-CoV-2 is thought to be a major cause of disease severity and death in patients with COVID-19, ivermectin may have further value in addition to its anti-viral properties. (Mehta et al., 2020)
With its good safety profile, ivermectin is a potential treatment against COVID-19 in its different stages. Some clinical studies and meta-analyses have shown beneficial results regarding clinical outcomes and the length of viral shedding, however most of them are lacking a high standard of rigorous methodology. (Bryant et al., 2021; Hill et al., 2022; Padhy et al., 2020; Zein et al., n.d.)
Here we conducted a double-blinded randomized control trial to assess whether ivermectin shows anti-SARS-Cov-2 activity as reflected by shortening the viral shedding, in non-hospitalized patients at the early stage of COVID-19 infection. In addition, we were able to test and to show the impact of ivermectin on culture viability.
Methods
Ethics
Institutional Review Board (IRB) approval was given by the Sheba Medical Center’s IRB (7156/20). Written informed consent was received from each participating individual before recruitment.
Study design
A randomized controlled, double blinded trial to evaluate the effectiveness of ivermectin in reduction of viral shedding among mild to moderate COVID-19 patients. The study was conducted in hotels located in Tel-Aviv, Jerusalem and Ashkelon Israel, that have been designated as isolation facilities for mild to moderate COVID-19 patients, not requiring oxygen.
Study population
Patients were eligible for enrollment in the study if they were 18 years of age or older; not pregnant; with molecular confirmation of COVID-19 by RT-PCR; and with the intention to include only those who received results within the first three days from symptoms onset. However, due to the delay (three to four days) in testing the participants and the delayed results coming back from the laboratories, we extended the time up to seven days from symptoms onset. Since our main outcome was the change in viral shedding (as reflected by Ct value), asymptomatic cases were also included within five days from molecular diagnosis.
Patients were excluded if they weighed below 40kg, were with known allergy to the drug, unable to take oral medication or participating in another RCT for treatment of COVID-19. In addition, patients who had post-randomization RT-PCR results with Ct (cycle threshold) value >35 in first two consecutive tests were excluded for further analysis. Patients with comorbidities of cardiovascular disease, diabetes, chronic respiratory disease (excluding mild intermittent asthma), hypertension, and/or cancer were included and defined as high-risk patients.
Randomization
Randomization in a 1:1 ratio, in a simple randomization method, was done by computer-generated program using randomization.com (http://www.jerrydallal.com/random/randomize.htm) by Clinical Research Coordinator (CRC), blinded to the rest of the study team. This CRC was not recruiting patients and the numbered pills bottles were available only for the physicians who were recruiting. The envelope with the randomization codes was opened only at the end of the study.
Patients assigned to the intervention arm received ivermectin in a dosage regimen according to body weight; patients weighing between 40-69 kg received four tablets (=12mg) daily and patients weighing ≥70kg received five tablets (=15mg) daily, all for three days. Patients assigned to the placebo arm received the same number and same appearance of pills per weight daily, for three days. They were guided to take the pills one hour before a meal. The investigators and patients were blinded to the assignment.
Intervention
On the day of randomization and treatment initiation, patients were tested for SARS-CoV-2 by reverse transcriptase polymerase chain reaction (RT-PCR) from nasopharyngeal (NP) swabs (day zero). Tests were then administered every two days from day six up to day 14 unless patients were discharged earlier from the isolation facilities. The protocol was amended at the beginning of September when the Ministry of Health changed the policy of isolation and allowed infected patients to leave the facility ten days from symptom onset without further testing. At this point testing at day two and four were added to the protocol.
Since results of the test could have been influenced by the examiner who performed the swab and with differences between labs, (Basso et al., 2020; Carroll and McNamara, 2021) a small number of trained practitioners were allocated to obtain the swab during the entire trial and were instructed to use a uniform technique. In addition, all RT-PCR tests, including verification that patients were positive on day zero, were conducted by the same lab, at the Israel Central Virology Laboratory of the Ministry Of Health (located at Sheba Medical Center).
Patients were followed up daily by telephone until their discharge. Patients were asked whether they took the pills as guided, if they noticed any adverse effect following treatment and whether there were any follow up of symptoms.
Unexpectedly, some patients who were isolated in the hotels as verified positive patients were found to be borderline or negative upon our RT-PCR test (Figure 1). Therefore, patient who had RT-PCR results with Ct (cycle threshold) value >35 in first two consecutive RT-PCR tests were excluded (two consecutive tests were done in order to be sure that a borderline test was not at very early stage of the disease, but rather they already were cured or were sent to hotel by mistaken results), and equivalent number of patients were further recruited. This was amended by IRB in November 2020.
Figure 1
Outcomes
The primary clinical endpoint was viral clearance following a diagnostic swab taken on the sixth day (third day after termination of treatment), in the intervention group compared to placebo. Although negative PCR is defined in Israel with Ct>40, and borderline as Ct level>35, it was found that reaching this level may take a few weeks. On the other hand, at early stage of the pandemic significant evidence showed that a non-infectious state is usually achieved at Ct level>30, (Brown et al., 2020; Bullard et al., 2020; Gilad et al., 2021; Poopalasingam et al., 2022; Wölfel et al., 2020)and therefore isolation time in Israel was changed at September 2020 and was reduced to 10 days without looking for complete negative results. Therefore, we defined a negative test at a non-infectious level as measured by RT-PCR of Ct values >30 (less than 3.4 × 104 viral copies per reaction, equal to less than 106 copies/ml).
Culture viability analysis: Toward the end of our study (January 2021) the central virology lab established a Biosafety Level 3 (BSL-3) unit, allowing us the ability to culture the virus. Since positive medium of participating patients were kept in -80°C, we were able to culture them. Thus, an end point of culture viability at days two to six post-intervention was added.
PCR testing
The presence of the SARS-CoV-2 RNA was detected using the Seegene Allplex CoV19 detection kit, according to the manufacturer’s instructions (See supplement). The test detects three viral genes: envelope (E), nucleocapsid (N) and RNA-dependent RNA polymerase (RdRp). For each sample, Ct level was defined as the Ct level of the highest viral load (low Ct).
In-Vitro cultures
Positive samples (Ct values ≤30) were stored at -80°C and were thawed for culturing on Vero E6 cells at 37°C for seven days, as detailed in the Supplementary methods.
Statistical methods
Sample size: Based on published data from the Ministry of Health at the time of study initiation, we expected less than 10% of patients at day six show a negative RT-PCR test. With the interventional drug we expected a reduction of at least 25% in the proportion of positive cases. Hence, considering a potential decrease from 90% to 67.5% (25% decrease), with a power (1-β) of 80% at a significance level of 5% (α= 0.05), a minimal sample size of 96 participants in total, was required to detect a statistically significant difference. Therefore, 48 patients were needed in each study arm.
Statistical analysis: Statistical analysis was done by the Biostatistics and Biomathematics Unit, Gertner Institute, Sheba Medical Center, Tel-Hashomer, Israel. The modified intention to treat (mITT) population included all randomly assign patients who had positive results upon recruitment, however our main analysis was done by per-protocol analysis excluding those who lost to follow up without any further test results. Continuous variables are presented as mean ± standard deviation or as median and interquartile range. Categorical variables are presented as N (%). Differences between ivermectin and placebo groups were assessed using a Chi-square test and t-test, for categorical and continuous data respectively. Where cross tabulation frequencies were less than five, the Fisher exact test was used. A multivariate logistic regression model was used to determine the impact of ivermectin while controlling for age, sex, weight, and being symptomatic or not on reduction of viral load on day six as reflected by Ct level>30. Results include adjusted odds ratios (OR), and 95% confidence intervals (CI). Kaplan-Meier curves were drawn, and survival analysis conducted with log-rank test using time to negative RT-PCR (Ct level>30) result. For all analyses, significance was set at p < 0.05. All data analyses were performed with the SAS 9.4 software (Cary, NC, USA).
Results
From May 15th, 2020 through January 25th 2021, a total of 867 patients were screened, out of them 116 (13.4%) were eligible and were randomized; ultimately 89 (76.7%) were per-protocol evaluable, 47 in ivermectin and 42 in placebo arm (Figure 1).The last follow up was ended in January 31th 2021 after reaching our calculated sample size (based on originally on 96 patients and additional 21 patients who were found to be negative immediate after randomization).
The baseline study of mITT and per-protocol population characteristics are detailed in Table 1. The median age of the patients was 35 years (range, 20 to 71), 24.2% (23/95) equal or older than 50 years and 8.4% (8/95) equal or older than 60 years. Most of the patients were males (78.7%, 74/95). Twelve (13.7%,13/95) patients had comorbidities associated with risk for severe disease (Wu and McGoogan, 2020); 16% (8/50) and 11.1% (5/45) among the ivermectin and placebo groups respectively, p=0.56.
Table 1Baseline study population.
Modified Intention to treat
Per protocol (eligible patients)
All (n=95)
Ivermectin group (N=50)
Placebo group (N=45)
All (N=89)
Ivermectin group (N=47)
Placebo group (N=42)
Male gender n, (%)
74
(78.7)
38
(77.6)
36
(80.0)
69
(78.4)
36
(78.3)
33
(78.6)
Age median (IQ range) *
35.0
(28.0-50.0)
35.0
(29.0-46.0)
37.0
(27.0-51.0)
35.0
(28.0-47.0)
36.0
(32.0-50.0)
33.5
(26.0-47.0)
Weight median, (IQ range)
79.0
(70.0-88.0)
80.0
(70.0-90.0)
76.0
(68.0-85.0)
79.0
(70.0-86.0)
80.0
(70.0-90.0)
75.0
(67.0-85.0)
Symptomatic n, (%)
77
(81.1)
39
(78.0)
38
(84.4)
72
(80.9)
37
(78.7)
35
(83.3)
Days from symptoms onset median (IQ range)⁎⁎
4.0
(3.0-5.0)
4.0
(3.0-5.0)
4.0
(3.0-5.0)
4.0
(3.0-5.0)
4.0
(3.0-5.0)
4.0
(3.0-5.0)
Ct value on day 0 median (IQ range)⁎⁎⁎
23.0
(20.0-28.0)
24.0
(20.5-29.0)
22.0
(19.0-27.0)
23.0
(20.0-28.0)
24.0
(21.0-28.0)
22.0
(19.0-27.0)
No variable was statistically significant different between the two groups by Fisher exact test for categorical variables or by Kruskal–Wallis test for continuous variables. *Three are missing. ⁎⁎Calculated for only for symptomatic patients. ⁎⁎⁎Two are missing.
The majority were symptomatic (77/95, 81.0%). The most common symptoms of fatigue, fever, cough, headache, and myalgia were prevalent in approximately half of the study population (Symptoms detailed in Table S1-supplement). None of these variables were statistically different between the two study arms.
Eighty-nine were eligible for analysis per protocol (Figure 1 and Table 1).
Study Outcome
The mean Ct values of the per-protocol population is detailed in Table 2 and the change of Ct values is demonstrated in Figure 2.. The Ct values of the ivermectin group increased faster (means the viral load decreased faster) in comparison to the placebo group at the early stage of the intervention, during the first four days. As spontaneous recovery took place also in the placebo group their Ct values increased as well, having similar Ct values since day six.
Table 2Mean Ct values of per-protocol participants.
Ivermectin
Placebo
N
Mean
SD
N
Mean
SD
p
Day 0
47
24.2
5.0
42
22.4
5.0
0.11
Day 2
26
28.8
6.4
19
23.9
6.5
0.02
Day 4
24
32.2
6.0
19
28.2
7.1
0.06
Day 6
36
33.9
5.5
30
31.6
6.9
0.14
Day 8
21
33.0
5.4
21
34.6
5.6
0.36
Day 10
18
34.2
4.1
16
35.0
5.1
0.63
Day 12
15
36.2
4.4
15
36.4
10.3
0.89
Day 14
8
37.6
2.5
12
33.1
4.6
0.02
SD- Standard deviation
Figure 2
As mentioned above, our calculations were based on negative results reflected in Ct >30. According to per-protocol analysis the rate of negative RT-PCR for SARS-CoV-2 at day four (one day after termination of treatment) through day ten was higher in patients receiving ivermectin but was statistically significant on days six to eight (Table 3).
Table 3Ratios for negative RT-PCR (Ct>30) tests at days 4 to 10 in per-protocol participants.
A. Based on RT-PCR (Ct>30) test
N
Ivermectin
Placebo
P value*
OR
95% CI
Day 4
50
15/28 (54%)
7/22 (32%)
0.12
2.47
0.77
7.92
Day 6
89
34/47 (72%)
21/42 (50%)
0.03
2.62
1.09
6.31
Day 8
89
39/47 (83%)
25/42 (59%)
0.01
3.32
1.25
8.82
Day 10
89
40/47 (85%)
29/42 (69%)
0.07
2.56
0.91
7.72
B. Based on RT-PCR (Ct>30) test together with non-viable cultures
Day 4
50
24/28 (86%)
13/22 (59%)
0.03
4.1538
1.0688
16.1439
Day 6
89
44/47 (94%)
31/42 (74%)
0.01
5.2043
1.3400
20.2129
Day 8
89
45/47 (96%)
32/42 (76%)
0.01
7.0313
1.4419
34.2875
Day 10
89
45/47 (96%)
36/42 (86%)
0.14**
3.7500
0.7135
19.7078
*P value by Chi squre test.
In the multivariable logistic regression model, the adjusted odds ratio of SARS-CoV-2 RT-PCR negative test (Ct>30) for treatment with ivermectin compared to placebo at day six was 2.28 (95% CI: 0.87–5.95, P=0.09) but reach significance only at day eight 3.70 (95% CI: 1.19–11.49, P=0.02) fold higher than for the placebo group, respectively. (Table 4)
Table 4Multivariable analysis for negative RT-PCR (Ct>30) test for SARS-CoV-2 results on day 6 and 8 in per-protocol participants.
Kaplan-Meier analysis (Figure 3) adjusted to symptom onset showed the significant difference between the ivermectin and placebo arms during treatment.
Figure 3
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).
Clinical outcome
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 2b).
Adverse events
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.
Discussion
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.
Acknowledgement
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.
Funding
None
Author contribution
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:
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