key: cord-1028242-407va85q
authors: Babalola, O. E.; Bode, C. O.; Ajayi, A. A.; Alakaloko, F. M.; Akase, I. E.; Otrofanowei, E.; Salu, O. B.; Adeyemo, W. L.; Ademuyiwa, A. O.; Omilabu, S. A.
title: Ivermectin shows clinical benefits in mild to moderate Covid19 disease: A randomised controlled double blind dose response study in Lagos.
date: 2021-01-06
journal: nan
DOI: 10.1101/2021.01.05.21249131
sha: 8f284acc26888f4bb1bbe5e0223df1f19bb966af
doc_id: 1028242
cord_uid: 407va85q

Introduction: In vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS - CoV- 2 viral replication, but questions remained as to In-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19. Methods: We conducted a translational proof of concept (PoC) randomized, double blind placebo controlled, dose response, parallel group study of IV efficacy in RT - PCR proven COVID 19 positive patients. 62 patients were randomized to 3 treatment groups. (A) IV 6mg regime, (B)IV 12 mg regime (given Q84hrs for 2weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care. Results: The Days to COVID negativity [DTN] was significantly and dose dependently reduced by IV (p = 0.0066). The DTN for Control were, = 9.1+/-5.2, for A 6.0 +/- 2.9, and for B 4.6 +/-3.2 . 2 Way repeated measures ANOVA of ranked COVID 19 + / - scores at 0, 84, 168, 232 hours showed a significant IV treatment effect (p=0.035) and time effect (p <0.0001). IV also tended to increase SPO2 % compared to controls, p = 0.073, 95% CI - 0.39 to 2.59 and increased platelet count compared to C (p = 0.037) 95%CI 5.55 - 162.55 multiplied by 10^3/ml. The platelet count increase was inversely correlated to DTN (r = -0.52, p = 0.005). No SAE was reported. Conclusions: 12 mg IV regime may have superior efficacy. IV should be considered for use in clinical management of SARS-Cov-2, and may find applications in community prophylaxis in high-risk areas. Keywords: Ivermectin, COVID-19, RCT, Efficacy, Safety, Days-to-Negative.

The Corona Virus Disease 2019 (COVID 19) pandemic caused by the Severe Acute Respiratory Syndrome Corona virus -2 (SARS-CoV-2) 1 

Health Organization declared global pandemic on March 11, 2020 2 . As of December 22, 2020, more than 77.7 million people on all continents had being infected and more than 1.7 million people had died globally 3 . Prolonged morbidity after recovery from acute COVID 19 4 and astronomical hospital costs 5 , has left hospitals swamped and health workers exhausted. In addition, the global economy is in a depression 6 with massive job losses, furloughing and social movement restrictions.

There have been concerted attempts to seek preventive and interventional modalities to arrest the spread of the contagion by public health measures such as masking, social distancing, self isolation and hygiene, or more recently by vaccines 7, 8 There are also pharmaceutical/ therapeutic agents with antiviral properties, being repurposed to urgently treat or serve as chemoprevention for COVID 19.

One such drug is Ivermectin, which has exhibited broad spectrum antiparasitic, anti-bacterial and antiviral properties against many RNA viruses 9,10 . Ivermectin is extensively used, with good safety profile in Nigeria and other African nations in treating ocular onchocerciasis 11 . Of more current import, Ivermectin was shown to exhibit a 5000-fold reduction in SARS-C0V-2 viral RNA in vitro in Vero-h/SLAM cells in a study from Australia. 12 There are several mechanisms by which Ivermectin may inhibit SARS-CoV-2 in COVID 19 patients, including by inhibition of RNA -dependent RNA polymerase (RdRP) required for viral replication, 13 abolition of importin-α/β1 heterodimer nuclear transport of SARS-CoV-2 from the cytosol to the nucleus, and inhibition of viral mRNA and viral protein translation 14 .

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The copyright holder for this preprint this version posted January 6, 2021. ; https://doi.org/10.1101/2021.01.05.21249131 doi: medRxiv preprint However, there has been skepticism as to whether the virucidal IC50 of Ivermectin against SARS-CoV-2 of 2.4uM (obtained in vitro) could be feasible or attainable in humans or patients with COVID 19. This is because a 10-fold dose of Ivermectin (120mg) simulations-based kinetics in cattle still did not yield peak drug levels (Cmax) approaching the IC50 for in vitro SARS-CoV-2 inhibition 15 . In yet another simulation, based on human pharmacokinetics of different potential antiviral SARS-CoV-2 repurposed drugs, Ivermectin was one of the drugs predicted to have 10-fold concentrations higher than their reported 50% effective concentration [EC50]. 16 There is thus conflicting report on simulations from cattle and human pharmacokinetics in the effective anti-SARS-CoV-2 concentration attainable by Ivermectin dosing. Ivermectin has a long half life (t 1/2 ) of 81-91 hours, and is highly lipophilic with a high volume of distribution (Vd), indicating preferential lung and tissue accumulation. 17 Pharmacodynamically, Ivermectin dose-dependently inhibits lipopolysacharide (LPS) induced release of inflammatory cytokines (interleukins) in mice and improved LPS-induced survival. 18 Collectively, there are were multiple pharmacodynamic and pharmacokinetic basis that suggest a potential utility and efficacy of Ivermectin in COVID 19.

We therefore tested the hypothesis that Ivermectin will exert a clinically and therapeutically beneficial effect in mild to moderate COVID 19 patients in a randomized double blind controlled clinical trial in Nigerian COVID 19 patients with RT-PCR proven SARS-CoV-2 positivity.

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The copyright holder for this preprint this version posted January 6, 2021. Using a geneexpert machine and testing simultaneously for three genes . CC-BY 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 January 6, 2021. ; https://doi.org/10.1101/2021.01.05.21249131 doi: medRxiv preprint (Orf, EN, N) A positive COVID 19 test requires all the 3 genes to be present, and a negative test requires all the genes to be functionally absent.

The Cycle threshold (Ct) of the gene tester of more than 40 was regarded as negative, and values below 40 are positive where the Ct value bears an inverse logarithmic relationship to the SARS -CoV-2 viral load. 19, 20 Routine biochemistry, hematology, arterial oxygen saturation (Pa02) temperature and clinical data were gathered, and prognostic ones were recorded at the aforementioned times.

This study was undertaken between May and November 2020. A general description of the study population and the spread over three arms is found in Table 1 . Sixty-three patients with positive PCR result were randomised into three arms of the study. There was one withdrawal, thus sixty-two patients completed the study. The average age was 44.1years (SD14.7), ranging from 20-82. There were 43 males and 19 females. The patients had mild to moderate clinical symptoms and none of them required ventilator, although five required intranasal oxygen, 3 in the 12mg arm (B) and two in the control arm (C). One third of the patients reported with a fever and cough, while 44% and 18% respectively reported with headache and difficulties with breathing. 12% reported with anosmia/ageusia. The commonest comorbidities were Diabetes Mellitus (DM) (2) and Hypertension (9), while some had combined hypertension and DM. Some patients required concomitant medications such as dexamethasone, enoxaparin, and supplemental oxygen.

The effectiveness of randomization was assessed, and the results are displayed in Table 1 . In all, twenty-one patients were each randomised into the 6mg (A) and 12mg (B) Ivermectin arms while twenty went into the control arm (C).

There was no significant difference in the distribution of the age, sex and symptoms, comorbidities, blood counts, prothrombin time, liver function and . CC-BY 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 January 6, 2021. ; https://doi.org/10.1101/2021.01.05.21249131 doi: medRxiv preprint kidney function tests. There were however slight differences in the baseline Cycle threshold (Ct) values, being lower in the A arm than the other two arms with regards to the ORF and N genes, but similar for the EN gene. The distribution of other supplemental medications taken by participants, aside from Ivermectin, was broadly similar. These included Zinc, ascorbic acid, vitamin D and Azithromycin.

The time to SARS-CoV-2 negativity is described in Figures 1A and B and Mean days-to-negative for the 12mg arm was however shortened by 4.5 days, and by 3.15 days for the 6mg arm compared to controls. These differences were significant by ANOVA P>F =0.0179.

The distribution of the days-to-negative are depicted in Figure 1A . Figure suggests that the 12 mg treatment arm will cause the patient to progress 2.38 times faster than the control group. Although there is a HR of 1.68 for the 6mg arm, it did not achieve statistical significance.

The HR for "Any Ivermectin" was 1.96, P= 0.024, CI 1.09 -3.51.

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The copyright holder for this preprint this version posted January 6, 2021. Changes in clinical and laboratory parameters at baseline and at seven days (or as otherwise stated) were observed for the three arms and recorded in Table 3 .

Day seven was used as a midway point in the trial. Of note was that there was a moderate increase in SpO2 in the Ivermectin arm, although this did not attain significance (P=0.098). The difference from baseline to highest attained SpO2 during the study for each participant is also depicted in Figure . CC-BY 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 January 6, 2021. ; https://doi.org/10.1101/2021.01.05.21249131 doi: medRxiv preprint There were also no significant differences in changes in kidney function tests such as Blood Urea Nitrogen and Creatinine between the three groups.

There was a notable significant increase in platelet counts in the ivermectin arm relative to the control arm (P=0.037). See Figure 3B . There was also a moderate but not significant relative increase in lymphocyte count. The overall Platelet Lymphocyte Ratio (PLR) was not significantly changed ( Table 2 ). In Figure 3C , we note a statistically significant (P=0.0055) negative correlation between daysto-negative and increase in platelet count. The higher the change in platelet count, the fewer the days-to-negative. Pearson's r= -0.53, R 2 =0.28

There were slight increases in prothrombin time across all arms, more so in the control arm. Rate of increase was not significantly different across arms.

There were no significant changes over time, across the three groups in clinical parameters such as Respiratory rate, Heart rate, Temperature, and symptoms such as cough and dyspnea as assessed by Likert scales.

There was no significant overall effect of age on days-to-negative by linear regression analysis (r =0.046 p = 0.728). However, those in the 30-40-year age band had a lower time to negative relative to others.

No adverse effects of Ivermectin was reported in response to questioning or spontaneous report.

Symptomatic improvement was seen in all patients, with resolution of fever dypnea and other signs. There was no mortality and the patients remained well on follow up.

Our findings show a statistically significant and dose dependent effect of Ivermectin to reduce the time to SARS-CoV-2 negativity in RT-PCR COVID 19 positive patients (p =0.0066) and significant treatment (p=0.035) and

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The copyright holder for this preprint this version posted January 6, 2021. ; . CC-BY 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 January 6, 2021. ; 1 1 The progressive reduction in COVID 19 positivity in the Ivermectin-treated group over time, as well as the treatment effect were sustained with no timetreatment interactions ( Figure 2 . Table 2 ). This was associated both with symptomatic improvements as well as Ivermectin-induced reversal of abnormal COVID 19 prognostic parameters. Ivermectin treatment was associated with a strong trend to an increase in arterial oxygen saturation (SPO2%) compared to controls (See Figure 3A ) p= 0,073 and 95% CI of -0.39 to 2.59. Pulse oximetry at the finger digits, has recently been shown to exhibit racial divergences with a higher likelihood of overrating SPO2% and leading to "occult hypoxemia"

occurring more in black people in comparison to whites 23 Table 3 ). Further, there was an inverse correlation (r = -0. 52 , R 2 = 0. 28, p = 0.005) between the Ivermectin induced increase in platelets and the time to SARS-CoV-2 negativity in the patients ( See Figure 3C ). These platelet results indicate an Ivermectin effect to reverse a negative prognostic factor, and the increase in platelets is associated with a faster resolution and inhibition of SARS-CoV-2 virological proliferation.

The baseline prothrombin time appeared slightly prolonged in all the patients ( >0.15 seconds), but no effect of treatment in any group was apparent. The concurrent trend to Ivermectin improvement of COVID 19-associated arterial . CC-BY 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 January 6, 2021. There were no significant changes in hepatic and renal functions given that Ivermectin is hepatically metabolized. The gender of participants did not exert any effects on the pharmacodynamic effects of Ivermectin in time to COVID 19 negativity. However, the likelihood of negativity by day 5 was mitigated by age The mechanisms of the benefits were not established in this study, but an effect on JAK-STAT and NF-kappa B related cytokines should be studied in patients.

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The copyright holder for this preprint this version posted January 6, 2021. . CC-BY 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 January 6, 2021. ; https://doi.org/10.1101/2021.01.05.21249131 doi: medRxiv preprint 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 January 6, 2021. 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 January 6, 2021. 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 January 6, 2021. ; 1 7 . CC-BY 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 January 6, 2021. ; https://doi.org/10.1101/2021.01.05.21249131 doi: medRxiv preprint 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 January 6, 2021. 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 January 6, 2021. 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 January 6, 2021. . CC-BY 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 January 6, 2021. ; Key: Time sequence 1=+84hrs 2=+168hrs 3=+232hrs 4=+336hrs . CC-BY 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 January 6, 2021. ; Figure 3A : Difference in change in SpO2 from baseline to highest attained in study.

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The copyright holder for this preprint this version posted January 6, 2021. ; 1= Ivermectin. 2=Standard of Care . CC-BY 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 January 6, 2021. ; Figure 3C : Scatterplot exploring relationship between change in platelet count and Days-to-negative. PCR. r= -0.53, R 2 =0.28 P>F=0.0055.

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