| Region | New cases | June | July | August | Population 2020 (1000) | % Decline in new cases between June and August 2020 |
| South | Itajaí | 2123 | 2854 | 998 | 223 | – 53% |
| Chapecó | 1760 | 1754 | 1405 | 224 | – 20% | |
| North | Macapá | 7966 | 2481 | 2370 | 503 | – 70% |
| Ananindeua | 1520 | 1521 | 1014 | 535 | – 30% | |
| North East | Natal | 9009 | 7554 | 1590 | 890 | – 82% |
| João Pessoa | 9437 | 7963 | 5384 | 817 | – 43% |
The decreases in case counts among the 3 Brazilian cities given in Table 1 were also associated with reduced mortality rates as summarized in Table 2.
| Region | State | % Change in average deaths/week compared with 2 weeks before |
| South | Santa Catarina | –36% |
| PARANÁ | –3% | |
| Rio Grande do Sul | –5% | |
| North | Amapá | –75% |
| AMAZONAS | –42% | |
| Pará | +13% | |
| North East | Rio Grande do Norte | –65% |
| CEARÁ | +62% | |
| Paraíba | –30% |
Currently, 7 trials that include a total of more than 3000 patients with mild outpatient illness have been completed, a set composed of 7 RCTs and 4 case series.49–60
The largest, a double-blinded RCT by Mahmud49 was conducted in Dhaka, Bangladesh, and targeted 400 patients with 363 patients completing the study. In this study, as in many other of the clinical studies to be reviewed, either a tetracycline (doxycycline) or macrolide antibiotic (azithromycin) was included as part of the treatment. The importance of including antibiotics such as doxycycline or azithromycin is unclear; however, both tetracycline and macrolide antibiotics have recognized anti-inflammatory, immunomodulatory, and even antiviral effects (58–61). Although the posted data from this study does not specify the amount of mildly ill outpatients versus hospitalized patients treated, important clinical outcomes were profoundly affected, with increased rates of early improvement (60.7% vs. 44.4% P < 0.03) and decreased rates of clinical deterioration (8.7% vs. 17.8%, P < 0.02). Given that mildly ill outpatients mainly comprised the study cohort, only 2 deaths were observed (both in the control group).
Ravikirti performed a double-blinded RCT of 115 patients, and although the primary outcome of PCR positivity on day 6 was no different, the secondary outcome of mortality was 0% versus 6.9%, P = .019.60 Babalola in Nigeria also performed a double-blinded RCT of 62 patients, and in contrast to Ravikirti, they found a significant difference in viral clearance between both the low-dose and high-dose treatment groups and controls in a dose dependent fashion, P = .006.59
Another RCT by Hashim et al53 in Baghdad, Iraq, included 140 patients equally divided; the control group received standard care, and the treated group included a combination of both outpatient and hospitalized patients. In the 96 patients with mild-to-moderate outpatient illness, they treated 48 patients with a combination of ivermectin/doxycycline and standard of care and compared outcomes with the 48 patients treated with standard of care alone. The standard of care in this trial included medicines such as dexamethasone 6 mg/d or methylprednisolone 40 mg twice per day if needed, vitamin C 1000 mg twice/day, zinc 75–125 mg/d, vitamin D3 5000 IU/day, azithromycin 250 mg/d for 5 days, and acetaminophen 500 mg as needed. Although no patients in either group progressed or died, the time to recovery was significantly shorter in the ivermectin-treated group (6.3 days vs. 13.7 days, P < 0.0001).
Chaccour et al conducted a small, double-blinded RCT in Spain where they randomized 24 patients to ivermectin versus placebo, and although they found no difference in PCR positivity at day 7, they did find statistically significant decreases in viral loads, patient days of anosmia (76 vs. 158, P < 0.05), and patient days with cough (68 vs. 98, P < 0.05).57
Another RCT of ivermectin treatment in 116 outpatients was performed by Chowdhury et al in Bangladesh where they compared a group of 60 patients treated with the combination of ivermectin/doxycycline to a group of 60 patients treated with hydroxychloroquine/doxycycline with a primary outcome of time to negative PCR.54 Although they found no difference in this outcome, in the treatment group, the time to symptomatic recovery approached statistical significance (5.9 days vs. 7.0 days, P = 0.07). In another smaller RCT of 62 patients by Podder et al, they also found a shorter time to symptomatic recovery that approached statistical significance (10.1 days vs. 11.5 days, P > 0.05, 95% CI, 0.86–3.67).55
A medical group in the Dominican Republic reported a case series of 2688 consecutive symptomatic outpatients seeking treatment in the emergency department, most whom were diagnosed using a clinical algorithm. The patients were treated with a high-dose ivermectin of 0.4 mg/kg for one dose along with 5 days of azithromycin. Remarkably, only 16 of the 2688 patients (0.59%) required subsequent hospitalization with only a single death recorded.61
In another case series of 100 patients in Bangladesh, all treated with a combination of 0.2 mg/kg ivermectin and doxycycline, they found that no patient required hospitalization nor died, and all patients' symptoms improved within 72 hours.62
A case series from Argentina reported on a combination protocol that used ivermectin, aspirin, dexamethasone, and enoxaparin. In the 135 mild illness patients, all survived.50 Similarly, a case series from Mexico of 28 consecutively treated patients with ivermectin, all were reported to have recovered with an average time to full recovery of only 3.6 days.58
Studies of ivermectin among more severely ill hospitalized patients include 6 RCTs, 5 OCTs, and a database analysis study.45,51–53,63–70
The largest RCT in hospitalized patients was performed concurrent with the prophylaxis study reviewed above by Elgazzar et al.45 Four hundred patients were randomized among 4 treatment groups of 100 patients each. Groups 1 and 2 included mild/moderate illness patients alone, with group 1 treated with one dose 0.4 mg/kg ivermectin plus standard of care (SOC) and group 2 received hydroxychloroquine 400 mg twice on day 1 then 200 mg twice daily for 5 days plus standard of care. There was a statistically significant lower rate of progression in the ivermectin-treated group (1% vs. 22%, P < 0.001), with no deaths and 4 deaths, respectively. Groups 3 and 4 included only severely ill patients, with group 3 again treated with a single dose of 0.4 mg/kg plus SOC, whereas group 4 received hydroxychloroquine plus SOC. In this severely ill subgroup, the differences in outcomes were even larger, with lower rates of progression 4% versus 30% and mortality 2% versus 20% (P < 0.001).
The one largely outpatient RCT conducted by Hashim reviewed above also included 22 hospitalized patients in each group. In the ivermectin/doxycycline-treated group, there were 11 severely ill patients and 11 critically ill patients, whereas in the standard of care group, only severely ill patients (n = 22) were included because of their ethical concerns of including critically ill patients in the control group (45). This decision led to a marked imbalance in the severity of illness between these hospitalized patient groups. However, despite the mismatched severity of illness between groups and the small number of patients included, beneficial differences in outcomes were seen, but not all reached statistical significance. For instance, there was a large reduction in the rate of progression of illness (9% vs. 31.8%, P = 0.15) and, most importantly, there was a large difference in mortality among the severely ill groups that reached a borderline statistical significance (0% vs. 27.3%, P =0.052). Another important finding was the relatively low mortality rate of 18% found among the subset of critically ill patients, all of whom were treated with ivermectin.
A recent RCT from Iran found a dramatic reduction in mortality with ivermectin use.65 Among multiple ivermectin treatment arms (different ivermectin dosing strategies were used in the intervention arms), the average mortality was reported as 3.3%, whereas the average mortality within the standard care and placebo arms was 18.8%, with an odds ratio (OR) of 0.18 (95% CI 0.06–0.55, P < 0.05).
Spoorthi64 and Sasanak performed a prospective trial of 100 hospitalized patients whereby they treated 50 with ivermectin and doxycycline, whereas the 50 controls were given a placebo consisting of vitamin B6. Although no deaths were reported in either group, the ivermectin treatment group had a statistically significant shorter hospital length of stay (LOS) 3.7 days versus 4.7 days, P = 0.03, and shorter time to complete resolution of symptoms, 6.7 days versus 7.9 days, P = 0.01.
The largest OCT (n = 280) in hospitalized patients was conducted by Rajter et al at Broward Health Hospitals in Florida and was recently published in the major medical journal Chest (43). They performed a retrospective OCT using a propensity-matched design on 280 consecutive treated patients and compared those treated with ivermectin to those without. One hundred seventy-three patients were treated with ivermectin (160 received a single dose and 13 received a second dose at day 7) while 107 were not.63 In both unmatched and propensity-matched cohort comparisons, similar, large, and statistically significant lower mortality was found among ivermectin-treated patients (15.0% vs. 25.2%, P =0.03). Furthermore, in the subgroup of patients with severe pulmonary involvement, mortality was profoundly reduced when treated with ivermectin (38.8% vs. 80.7%, P =0.001).
Another large OCT in Bangladesh compared 115 patients treated with ivermectin to a standard care cohort consisting of 133 patients.51 Despite a significantly higher proportion of patients in the ivermectin group being men (ie, with well-described, lower survival rates in COVID), the groups were otherwise well matched, yet the mortality decrease was statistically significant (0.9% vs. 6.8%, P < 0.05). The largest OCT is a study from Brazil, published as a letter to the editor and included almost 1500 patients.66 Although the primary data were not provided, they reported that in 704 hospitalized patients treated with a single dose of 0.15 mg/kg ivermectin, compared with 704 controls, overall mortality was reduced (1.4% vs. 8.5%, HR 0.2, 95% CI 0.12–0.37, P < 0.0001). Similarly, in the patients on mechanical ventilation, mortality was also reduced (1.3% vs. 7.3%). A small study from Baghdad, Iraq, compared 16 ivermectin-treated patients with 71 controls.52 This study also reported a significant reduction in length of hospital stay (7.6 days vs. 13.2 days, P < 0.001) in the ivermectin group. In a study reporting on the first 1000 patients treated in a hospital in India, they found that in the 34 patients treated with ivermectin alone, all recovered and were discharged, whereas in more than 900 patients treated with other agents, there was an overall mortality of 11.1%.70
Meta-analyses of the above controlled treatment trials were performed by the study authors focused on the 2 important clinical outcomes: time to clinical recovery and mortality (Figures 2 and 3). The consistent and reproducible signals leading to large overall statistically significant benefits from within both study designs are remarkable, especially given that in several of the studies treatment was initiated late in the disease course.FIGURE 2.:
Details of the prophylaxis, early, and late treatment trials of ivermectin in COVID-19 can be found in Table 3.
| Prophylaxis Trials Author, Country, source | Study design, size | Study subjects | Ivermectin dose | Dose frequency | Clinical outcomes reported |
| Prophylaxis trials | |||||
| Shouman W, Egypt www.clinicaltrials.gov NCT04422561 | RCT N = 340 | Household members of pts with +COVID-19 PCR test | 40–60 kg: 15 mg, 60–80 kg: 18 mg, and > 80 kg: 24 mg | Two doses, 72 hours apart | 7.4% versus 58.4% developed COVID-19 symptoms, P < 0.001 |
| Elgazzar A, Egypt ResearchSquare doi.org/10.21203/rs.3.rs-100956/v1 | RCT N = 200 | Health care and household contacts of pts with +COVID-19 PCR test | 0.4 mg/kg | Two doses, day 1 and day 7 | 2% versus 10% tested positive for COVID-19 P < 0.05 |
| Chala R, Argentina NCT04701710 Clinicaltrials.gov | RCT N = 234 | Health care workers | 12 mg | Every 7 d | 3.4% versus 21.4%, P = 0.0001. |
| Carvallo H, Argentina Journal of Biochemical Research and Investigation doi.org/10.31546/2633–8653.1007 | OCT N = 229 | Healthy patients negative for COVID-19 PCR test | 0.2 mg drops | 1 drop 5 times a d x 28 d | 0.0% versus 11.2% contracted COVID-19 P < 0.001 |
| Alam MT, Bangladesh European J Med Hlth Sciences 10.24018/ejmed.2020.2.6.599 | OCT N = 118 | Health care workers | 12 mg | Monthly | 6.9% versus 73.3%, P < 0.05 |
| Carvallo H, Argentina Journal of Biochemical Research and Investigation doi.org/10.31546/2633–8653.1007 | OCT N = 1195 | Health care workers | 12 mg | Once weekly for up to 10 wk | 0.0% of the 788 workers taking ivermectin versus 58% of the 407 controls contracted COVID-19. |
| Behera P, India medRxiv doi.org/10.1101/2020.10.29.20222661 | OCT N = 186 case control pairs | Health care workers | 0.3 mg/kg | Day 1 and day 4 | 2 doses reduced odds of contracting COVID-19 (OR 0.27 95% CI 0.16–0.53) |
| Bernigaud C, France Annales de Dermatologie et de Venereologi doi.org/10.1016/j.annder.2020.09.231 | OCT N = 69 case control pairs | Nursing home residents | 0.2 mg/kg | Once | 10.1% versus 22.6% residents contracted COVID-19 0.0% versus 4.9% mortality |
| Hellwig M, USA J Antimicrobial Agents doi.org/10.1016/j.ijantimicag.2020.106,248 | OCT N = 52 countries | Countries with and without IVM prophylaxis programs | Unknown | Variable | Significantly lower-case incidence of COVID-19 in African countries with IVM prophylaxis programs P < 0.001 |
| Clinical trials–Outpatients | % Ivermectin versus % Controls | ||||
| Prophylaxis Trials Author, Country, source | Study design, size | Study subjects | Ivermectin dose | Dose frequency | Clinical outcomes reported |
| Mahmud R, Bangladesh www.clinicaltrials.gov NCT0452383 | DB-RCT N = 363 | Outpatients and hospitalized | 12 mg + doxycycline | Once, within 3 days of PCR+ test | Early improvement 60.7% versus 44.4%, P < 0.03, deterioration 8.7% versus 17.8%, P < 0.02 |
| Chowdhury A, Bangladesh Research Square doi.org/10.21203/rs.3.rs-38896/v1 | RCT N = 116 | Outpatients | 0.2 mg//kg + doxycycline | Once | Recovery time 5.9 versus 9.3 days (P = 0.07) |
| Ravikirti, India medRxiv doi.org/10.1101/2021.01.05.21249310 | DB-RCT N = 115 | Mild–moderate illness | 12 mg | Daily for 2 d | No diff in day 6 PCR + 0% versus 6.9% mortality, P = 0.019 |
| Babalola OE, Nigeria medRxiv doi.org/10.1101/2021.01.05.21249131 | DB-RCT N = 62 | Mild–moderate illness | 6 mg and 12 mg | Every 48 hours × 2 wk | Time to viral clearance: 4.6 days high dose versus 6.0 days low dose versus 9.1 days control (P = 0.006) |
| Podder CS, Bangladesh IMC J Med Sci 2020;14(2) | RCT N = 62 | Outpatients | 0.2 mg/kg | Once | Recovery time 10.1 versus 11.5 days (NS), average time 5.3 versus 6.3 (NS) |
| Chaccour C. Spain Research Square doi.org/10.21203/rs.3.rs-116547/v1 | DB-RCT N = 24 | Outpatients | 0.4 mg/kg | Once | No diff in PCR+ day 7, lower viral load d 4 and 7, (P < 0.05), 76 versus 158 pts. d of anosmia (P < 0.05), 68 versus 98 pts. d of cough (P < 0.05) |
| Morgenstern J, Dominican Republic medRxiv doi.org/10.1101/2020.10.29.20222505 | Case series N = 3099 | Outpatients and hospitalized | Outpatients: 0.4 mg/kg hospital patients: 0.3 mg/kg | Outpatients:0.3 mg/kg × 1 dose Inpatients: 0.3 mg/kg, days 1,2,6, and 7 | Mortality = 0.03% in 2688 outpatients, 1% in 300 non-ICU hospital patients, and 30.6% in 111 ICU patients |
| Carvallo H, Argentina medRxiv doi.org/10.1101/2020.09.10.20191619 | Case series N = 167 | Outpatients and hospitalized | 24 mg = mild, 36 mg = moderate, and 48 mg = severe | Days 0 and 7 | All 135 with mild illness survived, 1/32 (3.1% of hospitalized) patients died |
| Alam A, Banglades J of Bangladesh College Phys and Surg, 2020; 38:10-15 doi.org/10.3329/jbcps.v38i0.47512 | Case series N = 100 | Outpatients | 0.2 mg/kg/kg + doxycycline | Once | All improved within 72 h |
| Espatia-Hernandez G, Mexico Biomedical Research www.biomedres.info/biomedi..-proof-of-concept-study-14435.html | Case series N = 28 | Outpatients | 6 mg | Days 1,2, 7, and 8 | All pts recovered average recovery time 3.6 d |
| Clinical trials–Hospitalized patients | % Ivermectin versus % Controls | ||||
| Prophylaxis Trials Author, Country, source | Study design, size | Study subjects | Ivermectin dose | Dose frequency | Clinical outcomes reported |
| Elgazzar A, Egypt ResearchSquare doi.org/10.21203/rs.3.rs-100956/v1 | OL-RCT N = 400 | Hospitalized patients | 0.4 mg/kg | Daily for 4 days | Moderately ill: worsened 1% versus 22%, P<0.001. Severely ill: worsened 4% versus 30% mortality 2% versus 20% both with P < 0.001 |
| Niaee S. M, Research Square doi.org/10.21203/rs.3.rs-109670/v1 | DB-RCT N = 180 | Hospitalized patients | 0.2, 0.3, and 0.4 mg/kg (3 dosing strategies) | Once versus Days 1,3,5 | Mortality 3.3% versus 18.3%. OR 0.18, (0.06–0.55, P < 0.05) |
| Hashim H, Iraq medRxiv doi.org/10.1101/2020.10.26.20219345 | SB-RCT N=140 | 2/3 outpatients and 1/3 hospital pts | 0.2 mg/kg + doxycycline | Daily for 2–3 d | Recovery time 6.3 versus 13.6 days (P<0.001), 0% versus 27.3% mortality in severely ill (P = 0.052) |
| Spoorthi S, India AIAM, 2020; 7(10):177-182 | PCT N = 100 | Hospitalized patients | 0.2 mg/kg+ doxycycline | Once | Shorter hospital LOS, 3.7 versus 4.7 days, P = 0.03, faster resolution of symptoms, 6.7 versus 7.9 days, P = 0.01 |
| Ahmed S. Dhaka, Bangladesh International journal of Infectious disease doi.org/10.1016/j.ijid.2020.11.191 | DB-RCT N = 72 | Hospitalized patients | 12 mg | Daily for 5 d | Faster viral clearance 9.7 versus 12.7 days, P = 0.02 |
| Chachar AZK, Pakistan Int J Sciences doi.org/10.18483/ijSci.2378 | DB-RCT N = 50 | Hospitalized patients-mild | 12 mg | Two doses day 1 and one dose day 2 | 64% versus 60% asymptomatic by day 7 |
| Portman-Baracco A, Brazil Arch Bronconeumol. 2020 doi.org/10.1016/j.arbres.2020.06.011 | OCT N = 1408 | Hospitalized patients | 0.15 mg/kg | Once | Overall mortality 1.4% versus 8.5%, HR 0.2, 95% CI 0.12–0.37, P < 0.0001 |
| Rajter JC, Florida Chest 2020 doi.org/10.1016/j.chest.2020.10.009 | OCT N=280 | Hospitalized patients | 0.2 mg/kg + azithromycin | Day 1 and day 7 if needed | Overall mortality 15.0% versus 25.2%, P = 0.03, severe illness mortality 38.8% versus 80.7%, P = 0.001 |
| Khan X, Bangladesh Arch Bronconeumol. 2020 doi.org/10.1016/j.arbres.2020.08.007 | OCT N = 248 | Hospitalized patients | 12 mg | Once on admission | Mortality 0.9% versus 6.8%, P < 0.05, LOS 9 versus 15 days, P < 0.001 |
| Gorial FI, Iraq medRxiv doi.org/10.1101/2020.07.07.20145979 | OCT N = 87 | Hospitalized patients | 0.2 mg/kg + HCQ and azithromycin | Once on admission | LOS 7.6 versus 13.2 days, P < 0.001, 0/15 versus 2/71 died |
| Budiraja S. India medRxiv doi.org/10.1101/2020.11.16.20232223 | OCT N = 1000 IVM=34 | Hospitalized patients | n/a | n/a | 100% IVM pts recovered 11.1% mortality in non-IVM-treated pts |
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