Ivermectin Arm Research Articles

USE OF REPOURPOSED DRUGS LOSARTAN AND IVERMECTIN IN PATIENTS WITH CANCER FOR PREVENTION OF COVID-19 SERIOUS EVENTS DURING PANDEMIC. A randomized, double-blind, placebo-controlled phase II study.

Introduction: Cancer patients are at higher risk of COVID-19 severe complications and also demonstrated a lower antibodies conversion after vaccination. Therefore, therapeutic approaches after COVID-19 infection are needed in this population. Repurposing drugs has emerged as an appealing strategy during pandemic, and drugs such as angiotensin 2 antagonists and ivermectin may have a role against COVID-19. Objective: This trial evaluated losartan plus ivermectin aimed at decreasing the incidence of severe outcomes due to coronavirus infection among cancer patients. Methods: This was a randomized, double-blind, and placebo-controlled phase II study. Cancer patients with recent diagnosis of mild to moderate COVID-19 were randomized to receive 50 mg of losartan for 15 days plus a single dose of 12 mg of ivermectin or placebo. The primary endpoint was the incidence of severe complications, defined as a need for admission to the intensive care unit (ICU), need for mechanical ventilation (MV), or death. Secondary endpoints were safety and adherence. Results: Thirty-five patients were randomized to intervention arm and 34 to placebo arm. Seven (20%) patients in the losartan + ivermectin arm experienced severe outcomes versus 8 (23.5%) patients in the placebo arm (p = 1.00). No difference was observed in the need for intensive care unit (17.1% versus 17.6%; p = 1.00) or in the need for mechanical ventilation (17.1% versus 11.8%; p = 0.73). Four patients died in the losartan + ivermectin arm, while 3 in the placebo arm (11.4% versus 8.8%; p = 1.00). Severe adverse events and adherence were similar between groups. Conclusions and Relevance: The combination of losartan and ivermectin did not improve severe COVID-19 outcomes among cancer patients. This is the first study registered on ClinicalTrials.gov that evaluates active treatment for COVID-19 exclusively for cancer patients. and more studies should be performed for a more aggressive approach in this high-risk population.

LB1528C. Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial

Abstract Background The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the United States with mild-to-moderate symptomatic coronavirus disease 2019 (COVID-19) is unknown. We evaluated the efficacy of ivermectin 400 µg/kg daily for 3 days compared with placebo for the treatment of early mild-to-moderate COVID-19. Methods ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial to evaluate repurposed therapies in outpatients with mild-to-moderate COVID-19. Non-hospitalized adults age ≥ 30 years with confirmed COVID-19, experiencing ≥ 2 symptoms of acute infection for ≤ 7 days were randomized to receive ivermectin 400 µg/kg daily for 3 days or placebo. The main outcome measure was time to sustained recovery, defined as achieving at least 3 consecutive days without symptoms. Secondary outcomes included a composite of hospitalization or death by day 28. Results Of the 3457 participants who consented to be evaluated for inclusion in the ivermectin arm, 1591 were eligible for this study arm, randomized to receive ivermectin 400 µg/kg (n=817) or placebo (n=774), and received study drug. Of those enrolled, 47% reported receiving at least 2 doses of SARS-CoV-2 vaccination. The posterior probability for any improvement in time to recovery was 0.91 (hazard ratio 1.07, 95% credible interval 0.96–1.17). The posterior probability of this benefit exceeding 24 hours was less than 0.01, as measured by the difference in mean time unwell. Hospitalizations or deaths were uncommon (ivermectin [n=10]; placebo [n=9]). Ivermectin at 400 µg/kg was safe and without serious adverse events as compared with placebo (ivermectin [n=10]; placebo [n=9]). Conclusion Ivermectin dosed at 400 µg/kg daily for 3 days resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods. Disclosures Susanna Naggie, MD/MHS, AbbVie: Grant/Research Support|BMS/PRA: Event adjudication|Gilead Sciences: Grant/Research Support|Pardes Biosciences: Advisor/Consultant|Personal Health Insights, Inc: Data Safety Monitoring Board Member|Silverback Therapeutics: Advisor/Consultant|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Stocks/Bonds.

The effect of ivermectin on the viral load and culture viability in early treatment of nonhospitalized patients with mild COVID-19 – a double-blind, randomized placebo-controlled trial

ObjectivesIvermectin, an antiparasitic agent, also has antiviral properties. In this study, we aimed to assess whether ivermectin has anti-SARS-CoV-2 activity. MethodsIn this double-blinded trial, we compared patients receiving ivermectin for 3 days versus placebo in nonhospitalized adult patients with COVID-19. A reverse transcriptase-polymerase chain reaction from a nasopharyngeal swab was obtained at recruitment and every 2 days for at least 6 days. The primary endpoint was a reduction of viral load on the sixth day as reflected by cycle threshold level >30 (noninfectious level). The primary outcome was supported by the determination of viral-culture viability. ResultsOf 867 patients screened, 89 were ultimately evaluated per-protocol (47 ivermectin and 42 placeboes). On day 6, the odds ratio (OR) was 2.62 (95% confidence interval [CI]: 1.09-6.31) in the ivermectin arm, reaching the endpoint. In a multivariable logistic regression model, the odds of a negative test on day 6 were 2.28 times higher in the ivermectin group but reached significance only on day 8 (OR 3.70; 95% CI: 1.19-11.49, P = 0.02). Culture viability on days 2 to 6 was positive in 13.0% (3/23) of ivermectin samples versus 48.2% (14/29) in the placebo group (P = 0.008). ConclusionThere were lower viral loads and less viable cultures in the ivermectin group, which shows its anti-SARS-CoV-2 activity. It could reduce transmission in these patients and encourage further studies with this drug.

Scabies in Koranic schools in Dakar, Senegal: Comparison of two therapeutic modalities

Background: In 2017, WHO recognized scabies as a neglected tropical disease. The optimal treatment is not well defined in some communities.Objective: This study aimed to compare ivermectin and benzyl benzoate in the treatment of scabies in Koranic schools (or "daara") in Dakar (region).Methods: This was a prospective randomized trial conducted from January to October 2018 in Senegal. Any resident living in the selected "daara" and diagnosed with scabies was included. The administered treatments were benzyl benzoate (BB) or ivermectin. At the outset, if one case of scabies was diagnosed, all residents received treatment. Ivermectin was given at the dose of 200 mg/kg. The same treatment was repeated on day 7 for each group, the endpoint was at D14, and the data were analyzed with STATA 14.Results: Fifteen "daara" were included. Of the 959 residents, 70 were diagnosed with scabies: prevalence of 7.29%. All patients except one were male; the mean age was 9.98 years (4-17). At D14, in the BB arm, cure rate was 42.85% (n = 15) while in the ivermectin arm, this rate was 5.71% (n = 2) with a significant difference (p = 0.01). On D28, the cure rate was still higher in the BB group 57.14 (n=20) versus ivermectin 21.42 (n = 6) with a significant difference (p = 0.004). On D42, all patients except eight were cured. At D14, we found a link between the cure rate, the number of people in the room (p = 0.01), and the number of showers per week (p = 0.01) but no link with the number of people per "daara" (p = 0.163). At D28, we found a link between the cure rate, the number of people sleeping in the room (p = 0.03), and the number of showers per week (p = 0.01) but not with the number of people per "daara" (p = 0.07).Conclusion: In Koranic schools, the cure rate is higher with benzyl benzoate compared to ivermectin.

Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomised Clinical Trial

Introduction: The rate of secondary attacks of SARS-COV-2 is high among household close contacts. Social distancing, isolation and infection control measures are important for preventing exposure to infection, but insufficient. Aim: The study aimed to evaluate possible role of oral ivermectin as a chemoprophylaxis in asymptomatic family close contacts with COVID-19 patients. Materials and Methods: A prospective interventional randomised open label-controlled study was conducted (registered at clinicaltrials.gov; NCT04422561) during June and July 2020. Two arms were designed according to use of ivermectin. In ivermectin arm, contacts received ivermectin according to Body Weight (BW) on day of the diagnosis of their index case. The non-intervention group received no treatment. Both groups were followed-up for two weeks for development of symptoms suggestive of COVID-19. Results: Ivermectin group included 203 contacts (to 52 index cases) aged 39.75±14.94 years; 52.2% were males. Non-intervention group included 101 contacts (to a total of 24 index cases) aged 37.69±16.96 years, 49.5% were males. Fifteen contacts (7.4%) developed COVID-19 in the ivermectin arm compared to 59 (58.4%) in the non-intervention arm (p<0.001). The protection rate for ivermectin was more prominent in contacts aged less than 60-year-old (6.2% infected compared to 58.7% if no treatment). Ivermectin in the protection against SARS-CoV-2 infection had an OR of 12.533 and 11.445 (compared to nontreatment) in both univariate and multivariate models, respectively. Side effects of ivermectin were reported in 5.4%; they were mild. Conclusion: Ivermectin is suggested to be a promising, effective and safe chemoprophylactic drug in management of COVID-19.

A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection.

BackgroundControl of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy. Effects on the parasite were also assessed.Methodology/Principal FindingsMen and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%–100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).Conclusions/SignificanceThe 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.Trial RegistrationClinicalTrails.gov NCT00300768

Initial Assessment of the Ability of Ivermectin to Kill Ixodes scapularis and Dermacentor variabilis Ticks Feeding on Humans

The purpose of this study was to determine Ixodes scapularis and Dermacentor variabilis tick mortality when fed on humans who have consumed 400 μg/kg oral ivermectin. Six study subjects, 3 in each group, were randomly assigned to receive either 400 μg/kg ivermectin or placebo in a blinded manner. After consuming either ivermectin or placebo, each study subject had 2 colostomy bags attached to his or her abdomen. One of the colostomy bags contained 7 I scapularis nymphs and 7 adults. The other colostomy bag contained 7 D variabilis nymphs and 7 adults. Tick mortality was recorded over the next 24 hours. Fifty-five percent (6 of 11) of the attached I scapularis nymphs exposed to ivermectin had morbidity (3 of 11) or died (3 of 11), compared with 0% morbidity and mortality in the 2 I scapularis nymphs that attached in the placebo group. No I scapularis adults or D variabilis nymphs attached to feed. Among D variabilis adults that attached to feed, there was a 0% mortality rate for both the placebo group (0 of 6) and the ivermectin group (0 of 8). We demonstrate a novel method to confine ticks to human subjects to study tick-borne diseases. While there was a trend toward I scapularis morbidity and mortality in the ivermectin arm, the low number of ticks that attached in the placebo group limited our analysis. Most ticks began feeding in the last 12 hours of the experiment, significantly limiting their exposure to ivermectin. Ivermectin does not cause early death in D variabilis adults.

Randomized Clinical Trial on Ivermectin versus Thiabendazole for the Treatment of Strongyloidiasis

BackgroundStrongyloidiasis may cause a life-threatening disease in immunosuppressed patients. This can only be prevented by effective cure of chronic infections. Direct parasitologic exams are not sensitive enough to prove cure if negative. We used an indirect immune fluorescent antibody test (IFAT) along with direct methods for patient inclusion and efficacy assessment.Methodology/Principal FindingsProspective, randomized, open label, phase III trial conducted at the Centre for Tropical Diseases (Verona, Italy) to compare efficacy and safety of ivermectin (single dose, 200 µg/kg) and thiabendazole (two daily doses of 25 mg/Kg for two days) to cure strongyloidiasis. The first patient was recruited on 6th December, 2004. Follow-up visit of the last patient was on 11th January, 2007. Consenting patients responding to inclusion criteria were randomly assigned to one of the treatment arms. Primary outcome was: negative direct and indirect (IFAT) tests at follow-up (4 to 6 months after treatment) or subjects with negative direct test and drop of two or more IFAT titers. Considering 198 patients who concluded follow-up, efficacy was 56.6% for ivermectin and 52.2% for thiabendazole (p = 0.53). If the analysis is restricted to 92 patients with IFAT titer 80 or more before treatment (virtually 100% specific), efficacy would be 68.1% for ivermectin and 68.9% for thiabendazole (p = 0.93). Considering direct parasitological diagnosis only, efficacy would be 85.7% for ivermectin and 94.6% for thiabendazole (p = 0.21). In ivermectin arm, mild to moderate side effects were observed in 24/115 patients (20.9%), versus 79/108 (73.1%) in thiabendazole arm (p = 0.00).ConclusionNo significant difference in efficacy was observed, while side effects were far more frequent in thiabendazole arm. Ivermectin is the drug of choice, but efficacy of single dose is suboptimal. Different dose schedules should be assessed by future, larger studies.Trial Registration Portal of Clinical Research with Medicines in Italy 2004–004693–87

Ivermectin efficacy still imprecise for scabies treatment

We thank Steer et al. for their comments.1 We do not agree with the statement that ivermectin was “sub-optimally given” in our study.2 Indeed, a second dose of ivermectin was systematically given when a clinical failure was established at day 14, with the exception of the eight patients with a patent aggravation at day 7 who received a second dose earlier (at day 7). Therefore, all the failures observed with ivermectin at day 28 had received two ivermectin doses. The 29 “bad compliants” with benzyl benzoate had either performed an excessive number of applications of benzyl benzoate (e.g. every day) or had not respected the scheduled periods of application. When considered separately, all except one were cured at day 28. Cases of irritant dermatitis seen in patients treated with benzyl benzoate were always mild. When several family members were included simultaneously, all were given the same treatment to avoid confusion (i.e. either ivermectin or benzyl benzoate once or twice). On another hand, family members who were not included (the most likely situation) were all prescribed benzyl benzoate, once. Thus, case contacts in the three arms benefited from identical procedures, with a similar compliance profile (P = 0.7), making asymmetric re-infection between arms unlikely. We agree that blinding might have improved, to a certain extent, our observations’ validity. However, we found it difficult to implement in this context, as it was also the case in three of the four studies cited by Steer et al. Above all, our criteria of cure seemed objective, especially superinfection that clearly occurred more commonly in the ivermectin arm, and this favours strongly a greater efficacy of benzyl benzoate at days 14 and 28 – although it is possible that delayed cures with ivermectin might have been missed. It is striking that, 16 years after the first promising report on ivermectin efficacy in scabies,3 all the studies reporting high cure rates with that drug had some serious methodological biases,2,4 making its efficacy range in common scabies – noticeably its speed of action – still imprecise. We hope we contributed to fill in that gap. All that, in addition to higher cost and questionable availability of ivermectin, certainly makes benzyl benzoate the first-line treatment of common scabies in Senegal. ■

Ivermectin worthy of further investigation

We read with interest the article by Ly et al. in the June issue of the Bulletin of the World Health Organization.1 The authors described a randomized controlled trial of treatment of scabies in a community setting in Senegal. They concluded that oral ivermectin is inferior to topical application of benzyl benzoate; indeed the trial was stopped following intermediate analysis because of the apparent superiority of benzyl benzoate and increased rate of bacterial superinfection in the ivermectin group. The findings of this study add to those from several other studies that have investigated the utility of ivermectin for treatment of scabies. A meta-analysis published in 2000 concluded that there were insufficient data from studies comparing ivermectin to benzyl benzoate to determine if either was more effective. Since that meta-analysis, two out of three studies comparing ivermectin to benzyl benzoate have demonstrated significantly higher cure rates for ivermectin (the third study found equivalence of the treatments).2–4 This was an equivalence study based on the assumption that the difference in effectiveness between the treatment arms was less than 15%. Ivermectin is known to have limited ovicidal action which means that a single dose may not prevent recrudescence from eggs residing on the skin at the time of treatment (which hatch approximately every four days), compared to benzyl benzoate and permethrin, which have ovicidal activity.5,6 We recommend two doses of ivermectin for the treatment of scabies separated by 7 to 14 days, an approach supported by other studies.6,7 However, from the available data, it appears that ivermectin was used suboptimally in the trial in Senegal. While the authors report in the Methods that treatment was repeated at day 7 if any patient had worsened and repeated again at day 14 if there was treatment failure, the flowchart does not clearly support this. Unfortunately, no detailed outcome data were presented regarding the outcome of the eight patients in the ivermectin arm that were observed to have clinically deteriorated at day 7 (particularly if they were among the 16 patients at day 14 that were cured). Patients in the ivermectin arm of the trial that had not clinically deteriorated at day 7 were not offered any further treatment - because we believe that single dose ivermectin is not optimal, treatment failures beyond day 7 would not be unexpected in this group. Another important issue in this study was the high rate of non-compliance in the benzyl benzoate group, with 28% and 25% of patients failing to comply with one and two initial applications of benzyl benzoate respectively, compared to just 6% in the ivermectin group. It is our experience that benzyl benzoate can cause considerable skin irritation as was reported in 18% of this group with irritant dermatitis compared to 4% of gastrointestinal side-effects in the ivermectin group. Benzyl benzoate is often very poorly tolerated as was indicated by the high rates of non-compliance. A further concern was that the number of family contacts included in the study that were given the same treatment as the index case was not provided, yet the number of family members not included in the study that were given benzyl benzoate was stated. This made it difficult to compare the number of family members given benzyl benzoate compared to ivermectin. If more family members with scabies were given a single dose of ivermectin that is known to be subtherapeutic for its effectiveness on scabies eggs, then this would bias the results towards benzyl benzoate as re-infection would be more likely in the ivermectin treated family contacts (unmeasured confounder). Our last concern with the study relates to observer bias. There was no blinding of outcome assessment and no evaluation of inter-rater reliability. This may suggest a leaning towards benzyl benzoate and raises concern about bias with outcome assessment. Taken together, the issues outlined above raise concerns about the external validity of the study by Ly et al. We believe that optimally dosed ivermectin is worthy of further investigation in resource-poor settings with endemic scabies infestation. ■

Impact of seven rounds of mass administration of diethylcarbamazine and ivermectin on prevalence of chronic lymphatic filariasis in south India

To evaluate the impact of seven rounds of mass administration of diethylcarbamazine (DEC) and ivermectin on the prevalence of chronic lymphatic filariasis and to compare it with that observed in a placebo arm in a community-level trial. Cross-sectional clinical surveys were carried out before and after seven rounds of mass drug administration (MDA). About 54-75% of the target population were treated at each round of MDA. After seven rounds, the hydrocele prevalence had declined from the pre-intervention level of 20.5-5.1% (P < 0.05) in the DEC arm, from 23.9% to 10.4% (P < 0.05) in the ivermectin arm and from 20.4% to 10.9% (P < 0.05) in the placebo arm, equivalent to reductions of 75.3%, 56.6% and 46.6%, respectively. The lymphoedema/elephantiasis prevalence declined only marginally and without statistical significance from 3.7% to 3.2%, 4.6% to 3.9% and 2.9% to 2.3% in the DEC, ivermectin and placebo arm. After the seventh MDA, none of the sampled people in the 0-20 age group was found with hydrocele and there was a statistically significant decline in hydrocele prevalence in all other age groups in the communities treated with DEC, the drug known to have macrofilaricidal effect. The impact was relatively less in ivermectin arm. Repeated DEC administration has the potential to prevent incidence of new hydrocele cases and may resolve the manifestation at least in a proportion of affected people. Apart from reducing the microfilaraemia prevalence and transmission of infection, MDA also results in significant public health benefits by reducing the burden of hydrocele in treated communities.

Impact of 10 years of diethylcarbamazine and ivermectin mass administration on infection and transmission of lymphatic filariasis

The potential of repeated mass administration of diethylcarbamazine (DEC) and ivermectin to eliminate lymphatic filariasis has been examined in a study implemented in 10 villages with a population of 18415 in south India. During ten rounds of mass drug administration, 49-84% of the eligible population received treatment in different villages. Ten rounds of mass administration of DEC alone reduced the microfilaria (mf) prevalence and intensity by 93% and 97%, respectively, and the vector infection and infectivity rates by 91% and 89%, respectively. The corresponding figures with nine rounds of administration of ivermectin alone were 83%, 90%, 89% and 79%. Out of five villages in each treatment arm, the mf rate declined to <or=1% in four villages in the DEC arm and two villages in the ivermectin arm. No mosquitoes with infective-stage larvae were found in three of five villages in the DEC arm and two of five villages in the ivermectin arm. None of the children (n=130) were found to be positive for mf in either treatment arm. None of the 40 sampled children were found to be positive for circulating filarial antigenaemia in villages with lower endemicity in the DEC arm. The results suggest that ten rounds of DEC mass administration have the potential to interrupt transmission of infection in the majority of communities. The outcome was relatively less remarkable with ivermectin.

Pattern of community compliance with spaced, single-dose, mass administrations of diethylcarbamazine or ivermectin, for the elimination of lymphatic filariasis from rural areas of southern India

Current programmes to eliminate lymphatic filariasis (LF) are largely based on annual mass administrations of single doses of antifilarial drugs. The level and pattern of compliance by the target population are important determinants of the success of such mass drug administrations (MDA). Community compliance was therefore investigated during a study in southern India of the effects, on Wuchereria bancrofti microfilaraemia and transmission, of spaced MDA based on diethylcarbamazine (DEC) or ivermectin (IVM). During six rounds of MDA, the frequency of compliance in the target populations, in the five study villages given DEC and the five given IVM, ranged from 55%-77%. Analysis of the relevant cohort data indicated that about 30% of the villagers had complied with treatment during all six rounds, but 3.5% of those in the DEC arm and 4.0% of those in the IVM arm had never complied with treatment. Most of the villagers (>90%) had received treatment at least once, however, and >60% had each received treatment in at least four of the six rounds. Overall, there was a significant negative correlation (r=-0.78; P=0.008) between the size of the village, in terms of the number of villagers, and the mean frequency of compliance over the six rounds of MDA. The pattern of community compliance was found to be 'semi-systematic', laying between random and systematic. In terms of the elimination of LF, a semi-systematic pattern of compliance is worse than random compliance but better than systematic. The relevance of the levels and patterns of compliance to LF control or elimination is discussed.