key: cord-1031662-yirab3lw
authors: Chahla, R. E.; Medina Ruiz, L.; Ortega, E. S.; Morales, M. F.; Barreiro, F.; George, A.; Mansilla, C.; D'Amato, S. P.; Barrenechea, G.; Goroso, G. D.; Peral de Bruno, M. d. l. A.
title: A RANDOMIZED TRIAL - INTENSIVE TREATMENT BASED IN IVERMECTIN AND IOTA-CARRAGEENAN AS PRE-EXPOSURE PROPHYLAXIS FOR COVID- 19 IN HEALTHCARE AGENTS
date: 2021-03-30
journal: nan
DOI: 10.1101/2021.03.26.21254398
sha: 77338d4e40f6426a9326a2a73200a78ddc17f373
doc_id: 1031662
cord_uid: yirab3lw

IMPORTANCE: The emergency of COVID-19 requires the implementation of urgent strategies to prevent the spread of the disease, mainly in health personnel, who are the most exposed and has the highest risk of becoming infected with the SARS-COV-2. Drug repurposing is a pragmatic strategy, a faster and cheaper option, compared to the new drug development that has proven successful for many drugs and can be a key tool in emergency situations such as the current one that requires quick action. In addition, considering the limited access to vaccines for developing countries, preventive use of ivermectin can be a palliative that minimizes the risks of infection. OBJECTIVE: To evaluate the protective effect of the combination Ivermectin / Iota- Carrageenan (IVER/IOTACRC), intensive treatment with repeated administration in oral- and nasal-spray, respectively, as a prophylaxis treatment prior to exposure to SARS-CoV-2, in health personnel at Public Healthcare Centers. PARTICIPANTS, DESIGN AND SETTING: Randomized controlled 1-1 clinical trial in Personal Health, n = 234. The subjects were divided into experimental (EG: n=117; 39.6 {+/-} 9.4 years old, 65F) and control groups (CG: n=117; 38.4 {+/-} 7.4 years old, 61F). The EG received Ivermectin orally 2 tablets of 6 mg = 12 mg every 7 days, and Iota-Carrageenan 6 sprays per day for 4 weeks. All participants were evaluated by physical examination COVID-19 diagnosed with negative RT-PCR at the beginning, final, and follow-up of the protocol. Differences between the variables were determined using the Chi-square test. The proportion test almost contagious subject and the contagion risk (Odds Ratio) were calculated using software STATA. The level of statistical significance was reached when p-Value < 0.05. RESULT: The number of subjects who were diagnosed with COVID-19 in EG was lower, only 4 of 117 (3.4%) than subjects in CG: 25 of 117 (21.4%) (P-Value = 1.10-5). Nineteen patients had mild symptoms, 4 were in EG whereas, 15 were in CG (p-Value = 0.001). Seven subjects were moderate, and 3 with severe diagnostics, all them in CG. The probability (Odds Ratio) of becoming ill with COVID-19 was significantly lower in EG with values of 0.13, 95% 0.03 to 0.40; p-Value = 1.10-4, this value (<1) indicates a protective effect of the IVER/IOTACRC in the EG. Logistic regression test demonstrated that treatment was effective to prevent COVID-19 (Odds Ratio 0.11, 95% 0.03 to 0.33; p-Value = 1.10-4). We also found that when increase the age, decrease contagious risk (Odds Ratio 0, 93, 95% 0.88 to 0.98, p-Value= 0, 02). On the other hand, the probability of contracting COVID-19 was dependent on the patient's preexisting comorbidity (Odds Ratio 5.58, 95% 2.20 to 14.16, p-Value = 1.10-5). The other variables sex and designation were independent. CONCLUSION: The intensive preventive treatment (short-term) with IVER/IOTACRC was able to reduce the number of health workers infected with COVID-19. This treatment had also effect in preventing the severity of the disease, since all patients treated were mild. We propose a new therapeutic alternative for prevention and short-term intervention scheme (intensive) that is of benefit of the health worker in this pandemic accelerated time. This intervention did not produce lack of adherence to treatment or adverse effects.

The total group n = 300 to enroll included personnel who perform patient care presenting symptoms related to COVID-19 disease, concurrent autoimmune or chronic 194 disease, immune suppression, active infectious diseases, a history of previous CoV-2 infection confirmed by RT-PCR, medical history, and a clinical questioning. 196 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 30, 2021. ; https://doi.org/10.1101/2021.03.26.21254398 doi: medRxiv preprint patient was assigned an ID corresponding to a number from 1 to 234. The selection to 200 each group was performed through a random number generation process by an Excel 201 spreadsheet. Then, 117 of them were randomly selected to generate the CG and EG. 202 were evaluated every 7 days in 4 visits from the beginning of the study. Enrolled 217 subjects completed symptom questionnaires (including reporting any adverse effects of 218 treatment), physical examinations, and COVID-19 nasopharyngeal secretion tests (RT-219 PCR) at each time. Also in the visit, in person, was supplied the corresponding dose for 220 the week. Cases will be classified according to the WHO definitions of COVID-19 221 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Table 2 shows the clinical report of the health agents after being recruited in the 271 research. All health professionals and non-professionals were exposed to contracting 272 COVID-19 for work reasons typical of the service. 273 274 < abdominal pain (8), and low oxygen saturation (SpO 2 ) (6) were reported. Symptoms 282 related to ALRI symptoms and signs (1) were reported with lower frequencies. Table 2  283 shows the significant differences (p-Value < 0.05) between EG vs CG in relation to Figure 2A shown that the number of subjects who were diagnosed with COVID-295 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 30, 2021. ; https://doi.org/10.1101/2021.03.26.21254398 doi: medRxiv preprint Value = 1.10 -4 ). Patients diagnosed with COVID-19 were classified as mild, moderate 297 and severe, according to the gravity cases. Figure 2B shows the distribution of cases in 298 each group and their respective classification. 299

Nineteen patients had mild classification for COVID-19, n= 4 in EG, and n= 15 300 in CG (p-Value = 0.001). Seven subjects were moderate, and 3 with severe diagnostics, 301 all them were in CG. In addition, it was found that in the EG people who contracted 302 COVID-19 only 1/4 had any symptoms, while the CG 24/25 (p-Value = 1.10 -5 ). 303 304

The probability (Odds Ratio) of becoming ill with COVID-19 was significantly 306 lower in EG with values of 0.13, 95% 0.03 to 0.40; p-Value = 1.10 -4 , than in GC with 307 values of 7.67, 95% 2.57 to 22.85; p-Value = 1.10 -4 . The value <1 indicates a protective 308 effect of the IVER / IOTACRC for EG. Consequently, people with treatment decrease 309 their chance of contracting COVID-19 by 87%. 310

Logistic regression test was also performed in order to determinate the influence 311 of different variables on the clinical trials. In this model dichotomous dependent 312 variable was used as having or not suffering from COVID-19 in relation to the five 313 variables: IVER/IOTACRC intervention, comorbidity, age, sex and designation. Figure  314 3 shows the influence of different variables on the probability to getting or not COVID-315 19. The probability (Odds Ratio) in relation at all variables was that becoming ill with 316 COVID-19 was maintained significantly lower in people treated with IVER/IOTAC 317 relative to non-treated people, Odds Ratio 0.11, 95% 0.03 to 0.33; p-Value = 1.10 -4 . We 318 find that the mean value, including the Confidence Interval (CI), was <1. This value 319

indicates that the protective effect of the IVER/IOTACRC in relation to the relative 320 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) When the variable was studied using a stratified model in four age interquartile 345 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 30, 2021. ; https://doi.org/10.1101/2021.03.26.21254398 doi: medRxiv preprint getting COVID-19 was independent of this variable (see Table 3 ). 350

Health personal is one of the most exposed groups to COVID-19 contagion, because of 352 their steady contact with infected patients. In our work we found a protective effect of Secondary outcome found was that IVER/IOTACRC not only prevents the infections 382 rate, but also has a protective effect on reduction in symptoms number's presence, and 383 protection against the appearance of severe stages for COVID-19 disease ( Figure 2 ). As 384 can be seen in Figure 2B , the EG only had mild cases, while the CG had mild, moderate 385 and severe cases, the differences between both groups being significant. We observed in 386 Table 2 that the symptoms description in the EG is significantly lower that CG. On the 387 other hand, it's necessary point out that the comorbidities or risk factor such as hyper-388 tension, DBT, obesity or over 60 years old were similar in booth group (Table 1) . So, 389 the results above mentioned, cannot attributed to presence to comorbidities in the CG. 390

In our greatest consideration, this would be an important contribution. When the effec-391 tiveness of IVER / IOTACRC treatment was analyzed together with the other variables, 392

we found that, even in the presence of the comorbidity variable, the protective effect of 393 IVER / IOTACRC was maintained, with Odds Ratio <1 (Table 3 ). It is observed that the 394 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The proposed prophylactic treatment is also independent of the designation (healthcare 402 and no healthcare). 403

During the study, there was no lack of adherence to IVER/IOTACRC treatment. We 404 hypothesized that good adherence was due to the design of the protocol, since it provid-405 ed for the follow-up of the enrolled subjects periodically. These were designed every 406 seven days using two strategies: i) face-to-face visits, and ii) remote monitoring via tel-407 emedicine. Another fact that may have influenced good adherence is that a short-term 408 intensive protocol was used. 409

Regarding adverse effects, they were not reported in any case. The explanation for this 411 is that it could be due to the fact that IVER/IOTACRC only produces these effects when 412 the drug acts as an anti parasitic, unlike the viricidal action proposed in this study. An-413 other fact that reinforces the absence of adverse effects is that the doses used in this pro-414 tocol are low doses, in which previously, in the literature, it has been reported that they 415 do not produce adverse effects 37 . 416

Benefits 417

Through this study, it was possible to show a prophylactic effect of IVER/IOTACRC 418 against COVID-19 disease. This association of drugs was inexpensive and is also 419 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 30, 2021. ; https://doi.org/10.1101/2021.03.26.21254398 doi: medRxiv preprint

The main limitation of this study was the number of agents to enroll. This trial does not 423 include the report of adverse event in the long run, so will be interesting to include in 424 future trials biochemical examination for control of potential adverse effects. The intensive preventive treatment (short-term) with IVER/IOTACRC was able 439 to reduce the health workers number infected with COVID-19. This treatment had an 440 additional effect in preventing the severity of the disease, since most of the patients who 441 received the treatment were mild. 442

In the presence of the comorbidity variable, the protective effect of IVER / 443 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 30, 2021. ; https://doi.org/10.1101/2021.03.26.21254398 doi: medRxiv preprint

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