Tag: ivermectin

Large Ivermectin Study Retracted Due to Data Problems Ethical Concerns

Photo by Markus Winkler on Unsplash

MedPage Today reports that a large ivermectin study has been retracted over concerns of plagiarism and serious problems with their raw data.

Michele Avissar-Whiting, PhD, editor-in-chief of the preprint server Research Square, wrote in a July 14 statement that the study was retracted “because we were presented with evidence of both plagiarism and anomalies in the dataset associated with the study, neither of which could reasonably be addressed by the author issuing a revised version of the paper.”

Dr Avissar-Whiting noted that the concerns were first raised by Jack Lawrence, a British medical student, according to The Guardian.

“Based on what Jack found, we have reason to believe the preprint’s conclusions are compromised, so the withdrawal was done to stop its propagation as sound science,” she said. “This is the strategy employed by a number of preprint servers, per best practice guidance.”

The 400-patient Egyptian trial, from Ahmed Elgazzar, MD, of Benha University, and colleagues, had been included in two recent meta-analyses (Bryant et al. and Hill et al.) which drew significant attention for their positive results — especially the much-anticipated Hill review. Two ivermectin proponent groups, the Front Line COVID-19 Critical Care Alliance (FLCCC) and the British Ivermectin Recommendation Development Group (BIRD), released a statement saying that removing the Algazzar data from the two studies did not change their overall positive result.

In an email to MedPage Today, lead author Andrew Hill, PhD, of the University of Liverpool in England, said  that his team will be “re-running our analysis with the Elgazzar trial removed.”

Dr Hill added that the analysis would also be updated with a recent 500-patient randomised controlled trial from Argentina, which found no effect for ivermectin in terms of preventing hospitalisation in patients with COVID. The study also fiend that patients receiving ivermectin required invasive ventilation sooner than those on placebo.

“In our published paper, we emphasised the preliminary nature of our results and the need to continue more definitive studies,” Hill wrote in his email.

The Elgazzar study’s main findings have already been cited by other publications: Hospitalised patients with COVID who were treated with ivermectin were 90% less likely to die than those who didn’t receive the drug. 

Lawrence had taken on an assignment for medical school which had prompted a deeper look at the paper, coming across plagiarism with entire paragraphs copied from other sources.

Additionally, the raw data, which can be purchased online, contradicted the study in several instances. Gideon Meyerowitz-Katz, an epidemiologist from the University of Wollongong in Australia, highlighted some of those discrepancies in a Medium post.

“For example, the study reports getting ethical approval and beginning on the 8th of June, 2020, but in the data file uploaded by the authors onto the website of the preprint fully 1/3 of the people who died from COVID were already dead when the researchers started to recruit their patients,” Meyerowitz-Katz wrote.

“Moreover, about 25% of the entire group of patients who were recruited for this supposedly prospective randomised trial appear to have been hospitalised before the study even started, which is either a mind-boggling breach of ethics or a very bad sign of potential fraud,” he continued.
Other phase III randomised clinical trials continue to investigate ivermectin for COVID such as the PRINCIPLE trial which seeks 1500 participants for its ivermectin arm.

Source: MedPage Today

Positives as Well as Criticism for Ivermectin Review

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An eagerly awaited review and meta-analysis on ivermectin for COVID has arrived, however while it seems positive there are many shortcomings and unanswered questions. 

The findings of the study, led by Andrew Hill, PhD, of the University of Liverpool, were published in Open Forum Infectious Diseases. The review and meta-analysis was conducted as part of the International Ivermectin Project Team from December 2020 to May 2021. Ivermectin proponents alleged that Dr Hill was conducting the analysis for the WHO, but MedPage Today was not able to make a confirmation of this. A separate review published on June 28 in the journal Clinical Infectious Diseases found no benefits for ivermectin use in COVID.

Dr Hill and colleagues assessed 24 randomised trials enrolling a total of 3328 patients that involved some type of control, whether it was standard of care or some other therapy. Sample sizes ranged from 24 to 400 participants. Of these, eight were published studies.

In the 11 trials with 2127 patients that focused on moderate or severe infection, a 56% reduction in mortality was seen (P=0.004), with 3% of patients on ivermectin dying compared with 9% of controls.

However, the researchers noted that the total number of deaths was small (128) and in the subgroup with severe disease, there was no difference between ivermectin and controls. As for moderate disease, they reported a 70% improvement in survival with ivermectin (P=0.0004).
Compared with controls, ivermectin use was also associated with a reduction in time to recovery of 1.58 days (P=0.01) and with a shorter duration of hospitalisation of 4.27 days (P=0.05).

However, the drug was not associated with a lower risk of hospitalisation, though a sensitivity analysis that included any hospitalizations within 12 hours of taking the drug did show a reduction with ivermectin (RR 0.32, 95% CI 0.13-0.80, P=0.01).

A key limitation was the lack of peer review for many studies included in the analysis; there was also wide variation in terms of dosage, treatment duration, and inclusion criteria. There were also many different comparators, including hydroxychloroquine, lopinavir/ritonavir, standard of care, and placebo.

The authors concluded that their results “need to be validated in larger confirmatory trials”. David Boulware, MD, MPH, of the University of Minnesota, agreed with this. Dr Boulware has been interested in evaluating ivermectin for COVID outpatients, agreed with. On Twitter, he noted that no mention was made of whether patients used steroids, which could seriously confound results.

Only two of seven trials showed a reduction in symptom duration in outpatient trials. No analysis was done to see if early treatment cut hospitalisation risk.

He tweeted that there was a need for phase III randomised clinical trials “in order to delineate what is the clinical benefit of early treatment”, such as quicker resolution and fewer symptoms. He would have also liked to see more distinction between outpatient and in-hospital therapy.

“Of course, rolling out vaccination as quickly and widespread as possible would negate the need to use ivermectin as a treatment,” he added. “So big picture, vaccines are the better solution.”

There are multiple ongoing phase III randomised controlled trials “which will provide definitive results,” Boulware noted. These include the UK-based PRINCIPLE outpatient trial which has a target of 1500 patients for its ivermectin arm.

Source: MedPage Today

Indian States Turn to Ivermectin Amid COVID Crisis

Image by Steve Buissinne from Pixabay

Two Indian states have decided to distribute the controversial anti-parasitic drug ivermectin as a preventative measure, MedPage Today reports.

Goa, on the west coast, and Uttarakhand, a northern state in the Himalayas, will give the anti-parasitic to wide swaths of their population as a preventative measure in hopes of preventing future outbreaks.

Leaders of both states insisted that their recommendations were evidence-based. “An expert medical panel has recommended this,” Om Prakash, chief secretary of Uttarakhand, told Reuters. Vishwajit Rane, health minister of Goa, also said an expert panel from Europe found the drug shortened recovery time and reduced the risk of death, the news agency reported.

Yet no large randomised controlled trial has proven the drug’s efficacy against COVID, and no prominent health group — the NIH and the WHO among them — has recommended the drug in treatment or prophylaxis.

The use of ivermectin for COVID has been the subject of bitter debate in South Africa, and human administration of ivermectin was approved for compassionate use with guidelines released in January. Following a court order, pharmacists and doctors in South Africa are allowed to make up small batches of medicines containing Ivermectin on prescription by a doctor and in small quantities, and can be used.

Madhu Pai, MD, PhD, professor of epidemiology and global health at McGill University in Montreal, tweeted a link to guidelines developed by collaborators in the UK and India, led by Cochrane and Christian Medical College Vellore in the southern state of Tamil Nadu.

On May 15, the group updated their guidance to state that it recommends “against using ivermectin for treatment of patients with any severity of COVID-19. Ivermectin should only be used in the context of a randomized controlled trial.”

Officials in Goa said the state will give ivermectin tablets to anyone aged 18 or over. Through most of the recent COVID surge, the popular tourist destination has remained open to holidaymakers, only imposing a 15-day lockdown last week.

Meanwhile, Uttarakhand plans to distribute the drug even more widely, giving it to anyone over age 2, with the exception of pregnant and lactating women, according. The state has been struggling with high caseloads, which rose from under 300 a day in early April to more than 7000 a day last week, Reuters reported.

The state recently hosted Kumbh Mela, a huge festival which drew millions of people from across the country for a two week long celebration including bathing in the river Ganges. Reports indicated many people did not wear masks and were closely packed. This became a massive superspreader event, with cases all over India being traced to it. Some districts of Madhya Pradesh reported that 20% of cases were festival returnees.

Goa and Uttarakhand’s moves have not gone unnoticed by ivermectin advocates. The Front Line COVID-19 Critical Care Alliance, a long time champion of the drug, paid scant attention to the difference between causation and correlation in a recent tweet on the issue: “Case counts and deaths are falling in India! A close look … shows that the declines occurred as the Health Ministry [sic] began its widespread distribution of #ivermectin.”

Source: MedPage Today

Clinical Trial for Ivermectin Delivers Disappointing Results

A randomised clinical trial in Colombia for ivermectin treatment in mild COVID returned disappointing results.

An anti-parasitic normally used for livestock, ivermectin has gathered considerable attention as a possible COVID treatment in recent months, especially locally, with stocks containing the product depleted in the last month. There are no ivermectin-containing products in South Africa for human use. The South African Health Products Regulatory Authority is of the view that the evidence for ivermectin is currently inconclusive.

“To our knowledge, preliminary reports of other randomized trials of ivermectin as treatment for COVID-19 with positive results have not yet been published in peer-reviewed journals,” the researchers wrote.

  The randomised, double-blind, single-center study took place from July 15 to December 21, 2020. Patients were assigned to either receive an oral dose of 300 μg/kg of body weight per day of ivermectin or placebo, for five days. Follow-up took place on days 2, 5, 8, 11, 15, and 21. The primary trial outcome was resolution of symptoms within 21 days.  

However, the study was not without its share of problems. The initial primary outcome was time from randomisation until worsening of symptoms by two points on an ordinal scale, but few patients reached this endpoint in the expected time. This meant the sample size needed to maintain sufficient power was “unattainable.” To accommodate this, the primary endpoint was changed to time from randomisation to symptom resolution by day 21, retaining the original sample size.

To make matters worse, a labelling error occurred, where ivermectin was mistakenly given to all patients from September 29 to October 15, so the protocol was amended, with these patients excluded from the primary analysis. The researchers then recruited more patients to retain the originally calculated study power.

Despite these problems, the researchers said the findings remained valid within the confines of its other limitations. Limitations to the study, the researchers said, 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; and virological assessments were not included, only clinical characteristics.

Larger trials would be needed “to understand the effects of ivermectin on other clinically relevant outcomes,” concluded the researchers.

Source: MedPage Today

Journal information: López-Medina E, et al “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19 — A Randomized Clinical Trial” JAMA 2021; DOI: 10.1001/jama.2031.3071.

Ivermectin Approved to Treat COVID in SA on Limited Basis

Ivermectin, which has some reports of high effectiveness in limited studies, has received approval from the SA government to be used under strict control for compassionate use.  

Dr Boitumelo Semete-Makokotlela, head of the South African Health Products Regulatory Authority (SAHPRA), said that practitioners applying to use the drug will be considered case-by-case.

Ivermectin has a long history of use as an antiparasitic treatment in animals, while in humans it’s used as an anthelmintic drug that is usually indicated for filarial and resistant scabies infections. While the World Health Organization has suggested the drug has encouraging effects on coronavirus, although it hasn’t been properly evaluated yet.

“We absolutely share everyone’s desperation at this point,” said Helen Rees, SAHPRA chairwoman. “So the question about ivermectin and self-medication goes back to what everyone in the scientific community is saying. And that is, we don’t know if it works and we don’t know if it doesn’t work. That’s why we need to get data.”

Physicians in Zimbabwe are reportedly treating COVID with ivermectin in combination with silver nanoparticles – normally used as an algaecide – to great success.

Rees, however, warned South Africans that people self-medicating “need to be very careful because we don’t have any information about the quality of what you’re taking.”

Dr Semete-Makokotlela said that clear guidelines for the rollout would be given tomorrow. She added that SAHPRA granted the health department permission to distribute the Oxford/AstraZeneca COVID vaccine, the first one for SA. It is also currently reviewing applications from Johnson & Johnson and Pfizer, but has yet to receive an application from Moderna, she said.

Source: BusinessTech