Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos

Summary

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 randomized, double blind placebo controlled, dose response and parallel group study of IV efficacy in RT—polymerase chain reaction proven COVID 19 positive patients. Sixty-two patients were randomized to three treatment groups. (A) IV 6 mg regime, (B) IV 12 mg regime (given Q84 h for 2 weeks) (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. Two way repeated measures ANOVA of ranked COVID 19 +/– scores at 0, 84, 168 and252h 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 × 10³/ml. The platelet count increase was inversely correlated to DTN (r = –0.52, P = 0.005). No SAE was reported.

Conclusions

12mg IV regime given twice a week may have superior efficacy over 6mg IV given twice a week, and certainly over the non IV arm of the study. IV should be considered for use in clinical management of SARS-COV2, and may find applications in prophylaxis in high risk areas.

Introduction

The Corona Virus Disease 2019 (COVID 19) pandemic caused by the Severe Acute Respiratory Syndrome Corona virus-2 (SARS-CoV-2)¹ led to a World Health Organization declared global pandemic on 11 March 2020.² As of as of 8 February 2021, more than 106.7 million people on all continents had been infected and more than 2.3 million people had died globally.³ Prolonged morbidity after recovery from acute COVID 19⁴ and astronomical hospital costs,⁵ has left hospitals swamped and health workers exhausted. In addition, the global economy is in a depression⁶ 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 anti-parasitic, 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

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 (120 mg) 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 h, and is highly lipophilic with a high volume of distribution, indicating preferential lung and tissue accumulation.¹⁷

Pharmacodynamically, Ivermectin dose-dependently inhibits lipopolysaccharide (LPS) induced release of inflammatory cytokines (interleukins) in mice and improved LPS-induced survival.¹⁸ Collectively, there are multiple pharmacodynamic and pharmacokinetic indicators 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-polymerase chain reaction (PCR) proven SARS-CoV-2 positivity.

Methodology

The study was a Proof of Concept (PoC), double blind, randomized controlled trial, of a parallel group and dose-response design. There were three treatment groups to which COVID 19 positive patients were randomized. One group received Ivermectin 6 mg (given every 84 h) twice a week, another group received Ivermectin 12 mg (given every 84 h) for 2 weeks and the third group received lopinavir/ritonavir daily for 2 weeks plus placebo. Lopinavir/Ritonavir was the Standard of Care (SOC) at the Lagos University Teaching Hospital (LUTH) before the onset of the trial. It was considered unethical not to avail the control arm of some form of treatment. However, a look alike placebo was dispensed in addition, to the patients in the control arm, in order to maintain concealment.

Sample size: A convenient sample size of 60 with 20 in each arm, was planned. However, 62 were ultimately randomized. There had not been any prior study of Ivermectin on Covid-19 or other viruses in humans as we planned the study. Power calculation to obtain an N (Study population) is achievable when the variance of the effect difference is known and measurement is singular.

Moreover, repeated measures ANOVA was used to assess time, and effect and time × treatment interaction. We felt this was both a hard end point and a mechanistic study, which allowed for a dose—response (if any) to be assessed. This, we felt, should provide enough statistical power to avoid a beta or type 2 error.

Blinding: The Blinding was assured by ensuring that the study medications were in labeled envelopes prepared by pharmacy, held by the nursing staff and administered by them without the knowledge of the clinical research team. Virological assays were done in a separate building on samples labelled only with the patients’ trial number.

Ivermectin came in 3 mg tablets and all looked alike for the 12 and 6 mg arms.

The lopinavir/ritonavir tablets were not identical to the ivermectin tablets but neither the patients nor the investigators were aware of what was administered until the code was broken at the end of the study. The dispensing pharmacist, was the only one with knowledge of the group allocation.

Randomization: Computers were used to generate random numbers which were used for the allocation. Patients were allocated an envelope depending on the sequence, assigning them to one of three groups.

‘Mild’ disease was defined as signs and symptoms, with no clinical or imaging evidence of pneumonia. A Patient with ‘moderate’ disease has fever or respiratory tract symptoms, and imaging shows pneumonia. ‘Severe’ disease describes a patient with respiratory distress, a respiratory rate of over 30 per minute and/or SPO2 less than 93%. A patient is ‘critical’ if he needs mechanical ventilation or is in shock/organ failure or intensive care is required.

The study protocol received ethical review and approval of the Institutional Review Board of the LUTH, Lagos and Nigeria. The protocol was also reviewed and approved by the National Agency for Food and Drug Administration and Control in Lagos.

The patient inclusion criteria were COVID 19 PCR proven positive patients, who gave informed, written consent to participate in the study and were either asymptomatic or had mild/moderate symptoms.

Study exclusion criteria were COVID 19 negative patients, patients who had COVID pneumonia or requiring ventilator therapy, renal failure, thromboembolic complications, or unconscious by reduced Glasgow Coma Scale.

There were 62 patients randomized to the 3 treatments. COVID 19 PCR testing was undertaken at baseline (pretreatment time 0 h) and after dosing at 0 h, 84 h, 168 h, 252 h and 336 h.

The baseline demographic, clinical, laboratory and virological data of the three patient groups is summarized on Table 1.

Table 1.

Distribution of baseline variables by trial arm (SD/95%CI)

Variable	Trial arm			Overall	P-value
	6 mg Ivermectin	12mg Ivermectin B	Control C
Number per arm	21	21	20	62
Age (years)	48.3	39.7	44.8	44.1(14.7)	0.180
Male	15	14	14	43	0.924
Female	6	7	6	19
Symptoms
Fever	30%	42.8%	20%	31.2%	0.28
Headache	50%	57%	25%	44.3%	0.096
Cough	30%	19%	45%	31.5%	0.198
Dyspnea	20%	23%	10%	18.0%	0.497
Signs
Anosmia/Ageusia	25%	15%	0	12.7%	0.081
Resp. rate/min	26(6.2)	23.6(6.9)	23.7(6.3)	24.2(6.4)	0.7
Temp Co	36.4	36.3	36.6	36.4	0.29
Comorbidities
Hypertension	2	2	5	9
Diabetes M	1	1	0	2
Labs
Platelet count/ml (000)	215(68)	241(128)	211(69)	223(93)	0.57
Lymphocyte count/ml (000)	2.0	1.8	2.1	1.9	0.70
SpO2	97.5(1.4)	96.8(2.2)	95.8(6.4)	96.7(4.2)	0.64
Prothrombin time	18.2(4.5)	16.3(2.5)	18.1(4.8)	17.5(4.0)	0.36
SGOT units/l	55.7(36.1)	45.0(18.8)	41.3	47.5(25.2)	0.37
SGPT units/l	55.6(52.5)	32.5(24.3)	24.6(14.7)	36.2(34.1)	0.08
Alkaline phosphatase units/ml	65.4 (24.5)	65.9(26.2)	58.8(17.6)	63.3(22.5)	0.68
Blood urea nitrogen BUN mg/dl	29.23(7.9)	24.05(7.9)	28.38(4.5)	27.23(7.0)	0.29
Creatinine mg/dl	0.87 (0.21)	0.84(0.18)	0.88(0.27)	0.86(0.21)	0.930
Ct (ORF gene)	27.8(7.3)	33.12(5.0)	33.1(5.1)	31.2(6.3)	0.049
Ct EN gene	23.9(7.3)	26.6(17.1)	21.4(13.1)	24(11.5)	0.83
Ct N gene	21.5(9.1)	28.2(12.6)	32.1(3.9)	27.9(9.2)	0.02
Medication
Dexamethasone	1	1	2	Not additive	Similar
Zinc	16	17	18	Not Additive	Similar
Supplemental oxygen use	0	3	2	Not additive	Similar
Enoxaparine	2	1	1	4	Similar
Total   Bilirubin mg/dl	1.0	0.7	1.3	1.0	0.12

RT—PCR: COVID 19 test was by RT PCR testing for 3 genes. Using a gene expert machine and testing simultaneously for three genes (Orf, EN and 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.

Primary outcome measure was the number of Days-to-Negative (DTN) of the PCR test and the Treatment effect by Two-way Repeated Measures Analysis of Variance (RAMOVA).

Secondary outcome measures were change in clinical status, change in SPO2, change in Liver Function Tests, change in Kidney Function Tests (KFT) and change in rheological variables like platelet count and Prothrombin time.

Results

This study was undertaken between May 2020 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 randomized into three arms of the study. There was 1 withdrawal, thus 62 patients completed the study. The average age was 44.1 years (SD14.7), ranging from 20 to 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, three in the 12 mg 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. Of about 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, 21 patients were each randomized into the 6 mg (A) and 12 mg (B) Ivermectin arms while 20 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 KFTs. There were however slight differences in the baseline 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.

Changes in variables over time was assessed

The time to SARS-CoV-2 negativity is described in Figures 1A and B and Table 2. Ivermectin significantly and dose-dependently reduced time to negativity compared to the control group. The mean DTN in the control arm was 9.15 (CI 5.68–12.62) while for combined Ivermectin arms it was 5.33 (CI 4.33–6.32). Average DTN in the combined Ivermectin arms (any Ivermectin) was thus shorter by 3.83 days (95% CI 6.54–1.11) compared to controls P = 0.0066. (Student t-test).

Figure 1.

(A) Boxplot showing distribution of Days to Negative between the three arms of the study: A = 6 mg Ivermectin, B = 12 mg Ivermectin, C= Control. (B) Kaplan Meir Curve showing time sequence of days to negativity in the three arms of the study. (C) Kaplan Meir Curve showing time sequence of days-to-negativity, ‘Any Ivermectin’ vs. Control.

Table 2.

Days to negative in the three trial arms

Trial arm	Mean days-to- negative (95% Confidence Interval)	Standard deviation	N
A   6 mg Ivermectin	6.0   (4.61–7.38)	2.96	20
B   12 mg Ivermectin	4.65   (CI 3.15–6.15)	3.2	20
A&B   (Any Ivermectin)	5.33   (CI 4.33–6.32)	3.12	40
C   Control	9.15   (CI 5.68–12.62)	7.42	20
Total study population	6.6   (CI 5.25–7.95)	5.24	60

Notes: Tests were not completed in two cases. The one-way ANOVA P > F = 0.017. T-test comparing ‘Any Ivermectin’ and control P = 0.0066.

Mean DTN for the 12 mg arm was however shortened by 4.5 days, and by 3.15 days for the 6 mg arm compared to controls. These differences were significant by ANOVA P > F = 0.0179.

The distribution of the DTN are depicted in Figure 1A. Figure 1B depicts a Kaplan Meier (KM) curve comparing time to negative (failure) for the three arms. Log rank test for equality of survival functions gave P > chi = 0.0363.

Figure 1C depicts KM curve comparing ‘Any Ivermectin’ with controls. P > chi = 0.019.

Cox proportional hazard model enabled computation of Hazard Ratio (HR) using the control arm as base. HR for the 6 mg arm was 1.68, (P = 0.120, CI 0.87—3.25) while for the 12 mg arm, HR was 2.38 (P = 0.011, CI 1.22—4.65). This 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 6 mg arm, it did not achieve statistical significance.

The HR for ‘Any Ivermectin’ was 1.96, P = 0.024, CI 1.09–3.51.

A RAMOVA concerning SARS-CoV-2 PCR assays was carried out to compare means and variances of each of the three treatments at the different time points to obtain treatment effect, Time effect and Time Treatment interaction. A plot of the Means and Standard Error of the Means of 20 patients in each of group A, B and C is shown in Figure 2. There was a significant treatment (P = 0.035) and time effect (P < 0.0001) of Ivermectin on COVID 19 ranked scores compared to controls.

Figure 2.

2-way repeat measures of analysis of variance (RAMOVA) SARS CoV-2 PCR ASSAY X axis: 1=84hrs, 2=168hrs, 3= 252hrs, 4=336hrs.

The likelihood of negativity by day 5 was explored. The Ivermectin arm was 3.45 times more likely to go negative by or before day 5, P = 0.0271, 95% CI 1.12–10.63. This effect is slightly mitigated by sex (adjusted OR 3.44 P > z 0.031 CI= 1.12–10.6) but more significantly by age (OR 2.77 P > z 0.113 CI = 0.79–9.8).

Changes in clinical and laboratory parameters at baseline and at 7 days (or as otherwise stated) were observed for the three arms and recorded in Table 3. Day 7 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 3A, in which baseline figures are compared with highest attained SpO2 (P = 0.073).

Figure 3.

(A) Difference in change in SpO2 from baseline to highest attained in study. (B) Change in platelet count (Day7-Baseline) Ivermectin group vs. control (SOC). (C) Scatterplot exploring relationship between change in platelet count and Days- to-negative PCR. r = –0.53, R² = 0.28 P > F = 0.0055.

Table 3.

Changes in variables over time, Ivermectin vs. Control arm

Variable	Change (Day 7-Baseline) (unless otherwise stated)			95% CI	P-value (Period)	Interpretation
	Ivermectin	Control	Mean difference control-Ivermectin
Liver enzymes
SGOT units/l	–4.9	–6.0	1.06	–17.0–19.1	0.89	Both Ivermectin and control arms show reduced SGOT
SGPT units/l	–6.75	–4.95	–1.76	–32.06–28.46	0.89	Ditto
Alkaline phosphatase units/ml	8.96	4.71	4.24	–39.4–48.24	0.84	Moderate increases in Alkaline Phosphatase both arms
Kidney functions
BUN mg/dl	3.82	–9.56	13.38	–17.33–44.11	0.32	Slight increase in the Ivermectin arm
Creatinine mg/dl	0.058	0.006	0.052	–0.21–0.32	0.881	Slight increase both arms
Hematology
Platelet count (000/ml)	20.05	–64.00	84.06	5.56–162.55	0.0369*	Significantly higher increase Ivermectin arm
Lymphocyte   (000/ml)	0.269	0.163	0.106	–0.71–0.92	0.792	Slightly higher increase Ivermectin arm
PLR ratio	–31.65	23.70	–55.35	–148.19–37.49	0.2299	No significant change
SpO2 %	0.125	–1.444	1.56	–0.85–3.99	0.0975*   (Day 2-1)	Slightly higher increase in PaO2 Ivermectin arm
Prothrombin time   (Secs)	0.97	1.94	–0.96	–4.91–2.99	0.61	Prothrombin time increases more in control arm
Clinical parameters
Respiratory rate/min	–1.27	–4.0	2.72	–3.93–9.39	0.390	No difference
Heart rate/min	–2.52	–0.18	–2.33	–9.35–4.68	0.505*   (Day 3-2)	No difference
Heart rate/min	–12.83	–6.0	–6.83	–31.29–17.62	0.556   Day 7-Baseline	No difference
Symptoms
Cough (Likert scale)	–0.06	–0.2	0.15	–0.15–0.44	0.310	No difference
Temperature Co	0.08	0.37	–0.29	–0.79–0.21	0.244   (Day3-2)	No difference
Dyspnea (Likert)	0	–0.2	0.2	–0.18–0.58	0.29	No difference

Notes: *Indicates difference is other that n between day 7 and day 1. Actual days in brackets.

Because the drug Ivermectin is essentially metabolized in the liver via CYP34A, changes in liver enzymes such as SGOT (serum glutamic-oxaloacetic transaminase), SGPT (Serum glutamic pyruvic transaminase) and Alkaline Phosphatase were analysed. Both arms of treatment showed reduction in SGOT and SGPT and moderate increases in Alkaline phosphatase. None of these were statistically significant.

There were also no significant differences in changes in KFTs 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 DTN and increase in platelet count. The higher the change in platelet count, the fewer the DTN. Pearson’s r = –0.53, R² = 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 DTN 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.

Discussion

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 time effect (P < 0.0001) of Ivermectin on COVID 19 ranked scores compared to controls by RAMOVA. A HR of 2.38 in the 12 mg arm suggests that negativity events such as described above are likely to occur more than twice as fast with Ivermectin. In addition, Ivermectin appears to be 3.45 times more likely (P = 0.0271, 95% CI 1.12–10.63.) to induce negativity by day 5 compared to controls. Collectively, these results demonstrate a likely beneficial treatment effect of Ivermectin, to reduce the duration of illness, elicit faster recovery and diminution of qualitative indices of SARS-CoV-2 viral load compared to the usual treatment.

These results are consistent with those of Ahmed et al.²¹ who demonstrated a significant reduction in time to COVID 19 virological clearance with Ivermectin of 3 days on average, albeit at a higher dose of 12 mg daily for 5 days in Bangladesh. Similar findings were reported by Elgazzar and colleagues in Egypt.²²

Our results demonstrate a dose-response in the effects of Ivermectin 6 mg and 12 mg twice weekly in time to SARS-CoV-2 negativity. The DTN (mean ± SD) in the treatment arms were; 6 mg; 6 ± 2.95, 12 mg; 4.65 ± 3.19 and the controls 9.15 ± 7.26, P = 0.02 ANOVA. When both Ivermectin groups were combined (with a new mean 5.34 ± 0.07 days n = 41) the mean difference/SEM from placebo control, of—3.81 ± 1.34 days was statistically significant P = 0.0066, 95% CI–1.13 to—6.49 days.

These collectively suggest that the 12 mg dose achieved a faster SARS-CoV-2 virological clearance compared to the 6 mg dose, and that using these standard doses of Ivermectin employed in onchocerciasis treatment caused a 3.8 days faster virological clearance, and clinical amelioration compared to controls on lopinavir/ritonavir.

The findings also provide Poc of Ivermectin efficacy against SARS-CoV-2 at the doses that were initially considered inadequate based on pharmacokinetic simulations.^15,17

The progressive reduction in COVID 19 positivity in the Ivermectin-treated group over time, as well as the treatment effect were sustained with no time-treatment 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 (Figure 3A) P = 0,073 and 95% CI of –0.39–2.59. 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 whites²³ thus, the real change in SPO2 with Ivermectin may have been masked.

Platelet count is another prognostic index in COVID 19 with thrombocytopenia reflecting platelet consumption in SARS-CoV-2 as part of sepsis-induced coagulopathy, even before frank Disseminated Intravascular Coagulation manifests as hemorrhage or thrombosis.²⁴ Ivermectin treatments (combined 6 mg and 12 mg dose) caused an increase in platelet count relative to the control group patients with a 95% CI for the difference of 5.55–162.55 x 10⁹/l P = 0.037 ANOVA, F = 4,88, df –24. (Table 3). Further, there was an inverse correlation (r = –0. 52, R² = 0. 28, P = 0.005) between the Ivermectin induced increase in platelets and the time to SARS-CoV-2 negativity in the patients (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 s), but no effect of treatment in any group was apparent. The concurrent trend to Ivermectin improvement of COVID 19-associated arterial hypoxemia, concomitant with a reduction in prothrombotic hematological coagulopathy (reversal of platelet consumption) may be a consequence of ivermectin anti-inflammatory reduction in COVID-19 hypercytokinemia (‘cytokine storm’), and is entirely consistent with reduction in mortality and especially in patients with SARS-CoV-2 pulmonary complications.^25–28 Meta-analysis revealed that IL-6 and associated cytokines are correlated with SARS-CoV-2 severity in patients²⁹ which are under Janus Kinase (JAK-STAT) signaling pathway.³⁰ Given the known effect of Ivermectin to inhibit IL-6, TNF-alpha in vivo and in vitro and its suppression of NF-kappa B translocation in mice,¹⁸ a formal controlled study of the effect of Ivermectin on hyper-cytokinemia is now indicated in COVID 19.

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 from 3.45 to 2.77.

Ivermectin was remarkably well tolerated and there was no adverse drug event reported spontaneously or in response to inquiry.

In conclusion, Ivermectin exhibited a dose-dependent significant inhibitory effect on SARS-CoV-2. This study provides support for the translation of the in vitro findings of Caly et al.¹² at doses that were initially thought to be suboptimal in humans. The 12 mg twice weekly regime appears to confer a superior efficacy. Ivermectin modified prognostic factors such as arterial oxygenation and platelet and hematological indices of SARS-CoV-2 infections.

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.

Further study of Ivermectin 12 mg in the pre-exposure prophylaxis and prevention of community transmission of SARS-CoV-2, such as spoke-and-wheel or targeted hotspots treatment, is now warranted, especially as an interim measure in countries that cannot immediately roll out vaccination programs. We cannot conclude in this study that Ivermectin has a place in prophylaxis, but this warrants investigation.

Acknowledgements

The authors wish to acknowledge the contributions of the following: Mr. T. Babalola (Jotform design), Prof. Amam C. Mbakwem (Data Safety Monitoring). LUTH COVID-19 Management Team, Dr. Christopher Esezobor, Dr. Paul Agabi, Dr. Bolaji Olopade, Dr. Uyiekpen Ima-Edomwonyi, Dr. Patricia Akintan, Dr. Yeside Akinbolagbe, Dr. Adefolarin Opawoye, Dr. Danladi Nmadu, Dr. Aramide Olasope, Dr. O. G. Akinbode, Dr. Elizabeth Otokiti, Dr. A. Ogundare, Dr. Precious Enajeroh, Dr. Ejiofor Iloka, Dr. Lanre Modele, Dr. Gbenga Jegede, Dr. Akinpeloye, Dr. Femi Bankole, Dr. Kalejaiye, Pharm Opanuga, ADNS Adeyemo and the COVID-19 Nursing Staff.

Funding

The Central Bank of Nigeria Health Sector Research and Development Intervention Scheme (CBN HSRDIS).

Conflict of interest. None declared.