COVID-19 patients treated with the controversially repurposed drug Ivermectin in a randomised Colombian trial did no better than a placebo group, reports MedicalBrief. However, the study had several flaws and was not definitive, observers have noted.
The findings don’t support the use of Ivermectin for treatment of mild COVID-19, although larger trials may be needed, the researchers concluded. There has been, both internationally and in South Africa, considerable buzz around the use of Ivermectin, an anti-parasitic, to treat COVID-19, with several countries including it in their guidelines.
At present, the US National Institutes of Health COVID-19 guidelines cited "insufficient data" to either recommend for or against use of Ivermectin, and called for more research and clinical trials on the subject. In South Africa, the drug has been made available for use on "compassionate grounds', via application to the medicines regulator.
GroundUp's Elsabe Brits writes that the results of what it describes as "the first peer-reviewed large clinical trial of the drug … in a prestigious medical journal", will boost the defence of South Africa Health Products Regulatory Authority (SAHPRA) against four court cases that have been launched against it, to compel SAHPRA to make Ivermectin available for the treatment of COVID-19, "even though there is no compelling evidence of the drug’s benefit". Among those seeking a court order are AfriForum and and the African Christian Democratic Party.
But, MedPage Today reports, the trial was "far from perfect". Limitations to the study, observers have noted, included:
That it was not conducted or completed according to the original design;
That it may have been underpowered to detect a smaller, clinically meaningful reduction in the primary endpoint. Few patients reached the initial primary outcome in the expected time, meaning the sample size needed to maintain sufficient power was "unattainable".
That virological assessments were not included, only clinical characteristics;
And that a labelling error occurred where Ivermectin was given to all patients for two weeks, meaning that the protocol and to be amended and these patients were excluded from the primary analysis. Additional patients were then recruited to retain the originally calculated study power.
Median time to recovery among mild COVID-19 patients in the Ivermectin group was 10 days versus 12 days among those receiving placebo, and rates of symptom resolution at day 21 were about equal, reported Dr Eduardo López-Medina, of Centro de Estudios en Infectología Pediátrica, and colleagues.
The trial was a randomised, double-blind, single-centre study conducted from 15 July to 21 December 2020. Patients were eligible if they were non-pregnant or breastfeeding adults with mild disease, defined as a positive RT-PCR or antigen test for SARS-CoV-2, and if they were at home or hospitalised, but not receiving high-flow mechanical ventilation.
Patients were assigned 1:1 to receive 300 μg/kg of body weight per day of Ivermectin or placebo, for 5 days orally. They were instructed to take it on an empty stomach, except the first day, when it was administered following screening and randomisation. Patients were then followed up on days 2, 5, 8, 11, 15, and 21.
Primary outcome was complete resolution of symptoms within the 21-day period, using an eight-category ordinal scale, ranging from 0 (no clinical evidence of infection) to 7 (death). Time to recovery was counted as the first day during the 21-day period when patients reported a score of 0.
Overall, 476 patients were randomised, including those excluded on account of the dosing error (they remained in the as-treated population).
Patient median age was 37, and 58% were women. Almost 80% had no comorbidities at baseline. Over three-quarters of patients reported myalgia and headache, and 56% reported loss of smell.
There was no significant difference in time to resolution of symptoms between groups (HR 1.07, 95% CI 0.87-1.32, P=0.53). In addition, symptoms resolved in 82% of the ivermectin group and 79% of the placebo group by 21 days.
Few patients in either group experienced clinical deterioration of more than two points on the ordinal scale (2% in Ivermectin vs 3.5% in placebo), and odds of improving score in the ordinal scale were not significantly different between groups either. There was also no significant difference in the proportion of patients requiring escalation of care in both groups (2% vs 5%, respectively).
Adverse events were reported in the majority of both groups (77% vs 81.3%) between randomisation and day 21, leading to discontinuation in 15 patients in the Ivermectin group and five in the placebo. There were four serious adverse events (two apiece in each group), but none were judged to be related to the study medication.
The researchers noted that the failure to show a clinical benefit contrasts with the previously published ICON study (see MedicalBrief archives list, below) which, using logistic regression and propensity matching, showed a single 200 μg/kg dose of Ivermectin to improve survival in patients hospitalized with Covid-19.
"The contrast with the findings in this trial may be related to differences in patient characteristics, exposures and outcomes that were measured, or unmeasured confounders in the observational study,” Lopez-Medina et al wrote. “To our knowledge, preliminary reports of other randomised trials of Ivermectin as a treatment for COVID-19 with positive results have not yet been published in peer-reviewed journals.”
The researchers conclude: "However, the relatively young and healthy study population [average age of 37] rarely developed complications, rendering the study underpowered to detect such effects. Therefore, the ability of Ivermectin to prevent the progression of mild Covid-19 to more severe stages would need to be assessed in larger trials."
Andy Gray, senior lecturer in the Division of Division of Pharmacology at University of KwaZulu-Natal, told GroundUp that it should be noted that the cases were all symptomatic, and the endpoint was the time to those symptoms being reported by patients as resolved. After 21 days 82% of the patients who received Ivermectin had no symptoms and 79% of those who received the placebo were symptom free. Average time till symptoms alleviated was ten days in the Ivermectin group versus 12 in the placebo one. These results are not statistically significant and could also be a result of the placebo group having more participants over 65 and more males. There were also no significant differences in the medical care the two groups needed, or who needed more serious medical intervention.
Gray added that one of the key issues with Ivermectin has been the lack of clarity about the dose to be used. Doses in various studies have varied from 200‐600 μg/kg, or clinicians have used multiples of the 3mg dosage from 6‐12mg. The dose interval also varies: from a daily dose to once every ten days; so does the duration: from a single day to 10 days. The dose used in this study is not the highest or the lowest used, but somewhere in the middle, he said.
Gray explained: “The initial [laboratory] work indicated that far higher doses than had previously been used in humans (for other indications) would be needed to reach the concentrations associated with antiviral activity. However, there were also claims of other possible mechanisms of action. The clinical trial does, however, seem to support a lack of a clinically relevant antiviral effect at the dose used, when initiated in mild cases (mostly outside of hospital).”
GroundUp's Brits writes: "The authors wrote that ivermectin did not significantly affect the course of Covid-19, and this is consistent with models showing that even at ten times the approved dose the amount of ivermectin is insufficient to make a big enough difference against the virus.
"As the court cases proceed there is still no compelling evidence that Ivermectin has any efficacy for COVID-19 or any answers to these questions: What dose of Ivermectin would be effective? For how many days? And at what stage of COVID-19 disease?"
Study details
Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19 – A Randomized Clinical Trial
Eduardo López-Medina; Pío López; Isabel C Hurtado; Diana M Dávalos; Oscar Ramirez; Ernesto Martínez; Jesus A Díazgranados; José M Oñate; Hector Chavarriaga; Sócrates Herrera; Beatriz Parra; Gerardo Libreros; Roberto Jaramillo; Ana C Avendaño; Dilian F Toro; Miyerlandi Torres; Maria C Lesmes; Carlos A Rios; Isabella Caicedo
Published in JAMA on 4 March 2021
Abstract
Importance
Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit.
Objective
To determine whether ivermectin is an efficacious treatment for mild COVID-19.
Design, Setting, and Participants
Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state’s health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020.
Intervention
Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).
Main Outcomes and Measures
Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected.
Results
Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).
Conclusion and Relevance
Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.
[link url="https://jamanetwork.com/journals/jama/fullarticle/2777389"]JAMA study[/link]
[link url="https://www.groundup.org.za/article/ivermectin-study-result-boosts-regulators-court-defence/"]GroundUp report (Open access)[/link]
[link url="https://www.medpagetoday.com/infectiousdisease/covid19/91479?"]Full MedPage Today report (Restricted access)[/link]
See also MedicalBrief archives:
[link url="https://www.medicalbrief.co.za/archives/sa-experts-scoff-at-the-flimsy-evidence-for-ivermectin-to-treat-covid-19/"]SA experts scoff at the ‘flimsy’ evidence for Ivermectin to treat COVID-19[/link]
[link url="https://www.medicalbrief.co.za/archives/university-of-free-state-clinical-trial-on-ivermectin-for-covid-19/"]University of Free State: Clinical trial on Ivermectin for COVID-19[/link]
[link url="https://www.medicalbrief.co.za/archives/iranian-trial-of-efficacy-and-safety-of-ivermectin-in-patients-with-mild-and-moderate-covid-19/"]Iranian trial of efficacy and safety of Ivermectin in patients with mild and moderate COVID-19[/link]
[link url="https://www.medicalbrief.co.za/archives/lower-mortality-for-hospitalised-covid-19-patients-taking-ivermectin-icon-study/"]Lower mortality for hospitalised COVID-19 patients taking Ivermectin – ICON study[/link]
[link url="https://www.medicalbrief.co.za/archives/ivermectin-stops-sars-cov-2-virus-growing-in-cell-culture-within-48-hours/"]Ivermectin stops SARS-CoV-2 virus growing in cell culture within 48 hours[/link]
[link url="https://www.medicalbrief.co.za/archives/sahpra-error-means-ivermectin-has-been-legal-for-30-years/"]SAHPRA ‘error’ means Ivermectin ‘has been legal for 30 years’[/link]
[link url="https://www.medicalbrief.co.za/archives/significant-risk-to-dispensing-sas-unregistered-ivermectin/"]‘Significant’ risk to dispensing SA’s unregistered Ivermectin[/link]
[link url="https://www.medicalbrief.co.za/archives/merck-warns-on-ivermectin-for-covid-no-evidence-of-efficacy-and-safety/"]Merck warns on Ivermectin for COVID: No evidence of efficacy and safety[/link]
[link url="https://www.medicalbrief.co.za/archives/sahpra-shifts-responsibility-for-ivermectin-use-to-doctors/"]SAHPRA shifts responsibility for Ivermectin use to doctors[/link]
[link url="https://www.medicalbrief.co.za/archives/sahpra-guidelines-on-accessing-ivermectin-compassionate-use-programme/"]SAHPRA: Guidelines on accessing Ivermectin Compassionate Use Programme[/link]
[link url="https://www.medicalbrief.co.za/archives/fact-file-making-sense-of-the-ivermectin-controversy/"]Fact File: Making sense of the Ivermectin controversy[/link]