Tag: covid treatment

High-dose Heparin Reduces Worsening in Moderate COVID

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Giving moderately ill hospitalised COVID patients a full-dose of heparin reduced the risk for organ support, and shortened hospital stays, a large clinical trial has found.

However, the use of this treatment strategy for critically ill COVID patients did not result in the same outcomes. 

“These results make for a compelling example of how important it is to stratify patients with different disease severity in clinical trials. What might help one subgroup of patients might be of no benefit, or even harmful, in another,” said NHLBI Director Gary H. Gibbons, M.D.

Researchers have observed that in some people who died from COVID, blood clots had formed throughout their bodies, even in their smallest blood vessels. Antithrombotics, which include blood thinners or anticoagulants, help prevent clot formation in certain diseases. It was not known which antithrombotic drug, what dose, and at what point during the course of COVID, antithrombotics might be effective. To answer these urgent questions, three international partners came together and harmonised their trial protocols to study the effects of using a full, or therapeutic dose, of heparin versus a low, or prophylactic dose, of heparin in moderately and critically ill patients hospitalised with COVID.

Moderately ill patients were defined as being hospitalised for COVID without needing organ support, and critically ill patients as hospitalised for COVID and needing intensive care level of support, including respiratory and/or cardiovascular organ support.

In April 2020, hospitalised COVID patients received either a low or full dose of heparin for up to 14 days after enrollment. By December 2020, interim results suggested that in critically ill patients, full-dose anticoagulation did not reduce the need for organ support and may even be harmful. However, one month later, results suggested full heparin doses likely benefited moderately ill patients.
“The formal conclusions from these studies suggest that initiating therapeutic anticoagulation is beneficial for moderately ill patients and once patients develop severe COVID-19, it may be too late for anticoagulation with heparin to alter the consequences of this disease,” said Judith Hochman, M.D., senior associate dean for Clinical Sciences at New York University, a corresponding author. “The medication evaluated in these trials is familiar to doctors around the world and is widely accessible, making the findings highly applicable to moderately ill COVID-19 patients.”

Fnal trial data analysis included 1098 critically ill and 2219 moderately ill patients. Among moderately ill patients, researchers found that the likelihood of full-dose heparin to reduce the need for organ support compared to those who received low-dose heparin was 99%. Major bleeding was rare. For critically ill patients, full-dose heparin also decreased the number of major thrombotic events, but it did not reduce the need for organ support or shorten hospital stay.

“More work needs to be done to continue to improve outcomes in patients with COVID-19,” said Matthew D. Neal, M.D., the Roberta G. Simmons Associate Professor of Surgery at the University of Pittsburgh, co-senior author. “Given what we know about the type of blood clots in patients with COVID-19, testing anti-platelet agents is a particularly exciting approach.”

Source: NIH

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

Could Nutritional Supplements Play a Role in Fighting COVID?

Photo by Diana Polekhina on Unsplash
Photo by Diana Polekhina on Unsplash

Researchers suggest that nutritional supplements such as Vitamin C do play a role in reinforcing the immune system against SARS-CoV-2.

An article in Advances in Experimental Medicine and Biology lays out the scientific rationale and possible benefits — as well as possible drawbacks — of several dietary supplements currently in clinical trials related to COVID-19 treatment. The article was written by Johns Hopkins Medicine gastroenterologist Gerard Mullin, MD, and colleagues.

Dr Mullin, associate professor of medicine at the Johns Hopkins University School of Medicine, and his colleagues shine a light on melatonin, vitamin C, vitamin D, zinc and several plant-based compounds, such as green tea and curcumin. For instance, the authors explained that vitamin C (ascorbic acid), “contributes to immune defense by supporting cell functions of both the innate and adaptive immune systems.”

The authors discuss in the journal article the mechanism of action of each of the supplements works, how each could benefit a patient with COVID.

Zinc is well tolerated, and well known for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral activities, the latter possibly mediated by its ability to inhibit RNA virus replication, thereby protecting cells from viral infection, oxidative damage, and dysfunction. It has been shown “to inhibit coronavirus RNA replication.” They also noted that, when administered at symptom onset, zinc “can reduce the duration of symptoms from illness attributed to more innocuous coronavirus infections, such as the common cold.”

Finally, Dr Mullin and colleagues gave short summaries of the clinical trials underway to test each supplement’s effectiveness in fighting COVID.

Regarding Vitamin D, which has received a lot of attention with regard to COVID outcomes, Dr Mullin said that, “to date, there are abundant data associating low vitamin D status to higher vulnerability to COVID-19 and poor clinical outcomes.”

The authors however struck a note of caution in that “any benefit of dietary supplements against COVID-19 depends on results of randomised controlled trials” and peer-reviewed literature.

Source: John Hopkins Medicine

Heparin Benefit Seen in Moderately Ill COVID Patients

Photo by Marcelo Leal on Unsplash
Photo by Marcelo Leal on Unsplash

New trial results show that early administration of the blood thinner heparin to moderately ill hospitalised COVID patients with could halt the thrombo-inflammation process, reducing the risk of severe disease and death.

COVID is characterised by inflammation and abnormal clotting in the blood vessels, especially the lungs, and is believed to contribute to progression to severe disease and death. 

The study is available as a preprint on MedRxiv and was led by investigators at St. Michael’s Hospital, a site of Unity Health Toronto, and the University of Vermont’s Larner College of Medicine.

Heparin, an anticoagulant, is indicated for both the prevention and treatment of thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism as well as atrial fibrillation. Heparin is also used to prevent excess coagulation during procedures such as cardiac surgery, extracorporeal circulation or dialysis. Heparin also has a wide range of off-label uses in hospitals. “This study was designed to detect a difference in the primary outcome that included ICU transfer, mechanical ventilation or death,” said study co-principal investigator  Mary Cushman, MD, MSc, professor of medicine at the UVM Larner College of Medicine.
The open-label randomised international multi-centre clinical RAPID Trial (also known as the RAPID COVID COAG – RAPID Trial) examined the benefits of administering a therapeutic full dose of heparin versus a prophylactic low dose to hospitalised patients with moderate COVID.

The primary outcome was a composite of ICU admission, mechanical ventilation, or death up to 28 days. Safety outcomes included major bleeding. Primary outcome occurred in 16.2% of patients with therapeutic full dose heparin, and 21.9% with low dose heparin (odds ratio [OR], 0.69). Four patients (1.8%) with therapeutic heparin died vs 7.6% with prophylactic heparin (OR, 0.22).

“While we found that therapeutic heparin didn’t statistically significantly lower incidence of the primary composite of death, mechanical ventilation or ICU admission compared with low dose heparin, the odds of all-cause death were significantly reduced by 78 percent with therapeutic heparin,” said first author and co-principal investigator Michelle Sholzberg, MDCM, MSc, Head of Division of Hematology-Oncology, medical director of the Coagulation Laboratory at St. Michael’s Hospital of Unity Health Toronto, and assistant professor at the University of Toronto.

Co-principal investigator Peter Jüni, MD, director of the Applied Health Research Centre (AHRC) at St. Michael’s, and professor of medicine at the University of Toronto, said that the researchers also presented a meta-analysis of randomised evidence (including data from a large multiplatform trial of ATTACC, ACTIV-4a and REMAP-CAP), which clearly indicated that therapeutic heparin is beneficial in moderately ill hospitalised COVID patients. He added that an additional meta-analysis presented in the preprint showed that therapeutic heparin is beneficial in moderately ill hospitalised patients but not in severely ill ICU patients.

Unusually, the RAPID Trial was funded through grassroots efforts from various institutions, grants and even a GoFundMe campaign.

“We called this trial ‘The Little Engine that Could,’ because of the sheer will of investigators around the world to conduct it,” said Cushman.

Sholzberg said, “We believe that the findings of our trial and the multiplatform trial taken together should result in a change in clinical practice for moderately ill ward patients with COVID.”

Source: University of Vermont

Journal information: Michelle Sholzberg et al, Heparin for Moderately Ill Patients with Covid-19, MedRxiv (2021). DOI: 10.1101/2021.07.08.21259351

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

Common Gut Bacteria Could Inhibit SARS-CoV-2

Bifidobacterium eriksonii, stained with fluorescent antibodies. Source: Public Health Image Library

South Korean researchers have found that certain common gut bacteria produce compounds that inhibit SARS-CoV-2. 

The research was presented on June 20 at World Microbe Forum, an online meeting of the American Society for Microbiology (ASM), the Federation of European Microbiological Societies (FEMS), and several other societies that taking place online June 20-24.

Previous clinical findings had shown that some patients with moderate to severe COVID experience gastrointestinal symptoms, while others show signs of infection in the lungs only.

“We wondered whether gut resident bacteria could protect the intestine from invasion of the virus,” said Mohammed Ali, a PhD student in Medicine at Yonsei University in South Korea.

To investigate this hypothesis, the researchers screened dominant bacteria inhabiting the gut for activity against SARS-CoV-2. Their efforts revealed that Bifidobacteria, already shown to suppress other bacteria such as H. pylori and have proven active against irritable bowel syndrome, had such activity, said Ali. Bifidobacteria are common in the guts of breast fed infants, which is partly driven by the bifidogenic activities of specific mother milk-derived oligosaccharides

The researchers also searched for potential illness-fighting compounds in databases containing microbially produced molecules, and discovered some that might also be useful against SARS-CoV-2. “To train our model we leveraged previous coronavirus datasets in which several compounds were tested against targets from coronaviruses,” explained Ali. “This approach seems to be significant as those targets share features in common with SARS-CoV-2.”

Ali emphasised the ecological nature of his approach to this work, pointing out that numerous existing antibiotics and cancer therapies are themselves compounds that bacteria use to compete with each other within the gastrointestinal tract, and that these were initially purified from microbial secretions.

“Finding microbes that secrete anti-coronavirus molecules will be a promising method to develop natural or engineered probiotics to expand our therapeutics prevention techniques, to provide a more sustainable way to combat the viral infection,” said Ali.

Source: American Society for Microbiology

Inhaled Corticosteroid Could Shorten Moderate COVID

Source: Pixabay

Early treatment with inhaled budesonide shortens recovery time by a median of three days in community-treated patients with COVID who are at higher risk of more severe illness, according to preliminary results from an Oxford University trial.

Inhaled budesonide is a safe, fairly cheap and readily available corticosteroid commonly used in inhalers for the treatment of asthma and chronic obstructive pulmonary disease

Based on an interim analysis using the latest data from 25th March 2021, the results showed the estimated median time to self-reported recovery for inhaled budesonide was three days shorter compared to usual care, with a high probability of being superior to the usual standard of care. Of those taking inhaled budesonide, 32% recovered within the first 14 days and stayed well until the 28 day endpoint, compared to 22% receiving usual care. Budesonide group participants also reported greater wellbeing after two weeks. 

Among patients who had completed the study, 8.5% (59/692) in the budesonide group were hospitalised with COVID compared with 10.3% (100/968) in the usual care group, with an estimated percentage benefit of 2.1%. However as fewer than expected people were admitted to hospital in the trial, and with COVID cases falling in the UK, it is not clear from this interim analysis whether budesonide reduces hospitalisations.

Patients with COVID symptoms that started within 14 days and who are at higher risk of a poor outcome from the illness were eligible to join the trial and those who tested positive for SARS-CoV-2 were included in the main analysis. Patients receiving inhaled budesonide were asked to inhale 800 micrograms twice a day for 14 days, with a 28 day follow-up.

Joint Chief Investigator, Professor Chris Butler, a South Wales GP and Professor of Primary Care from the University of Oxford’s Nuffield Department of Primary Care Health Sciences, said, “PRINCIPLE, the world’s largest platform trial of community-based treatments for COVID-19, has found evidence that a relatively cheap, widely available drug with very few side effects helps people at higher risk of worse outcomes from COVID recover quicker, stay better once they feel recovered, and improves their wellbeing. We therefore anticipate that medical practitioners around the world caring for people with COVID in the community may wish to consider this evidence when making treatment decisions, as it should help people with COVID recover quicker.”

When the data has been obtained and analysed, detailed results on time to recovery and hospitalisations will be published. The full pre-print is available on the MedRxiv server.

Source: University of Oxford

Molnupiravir Performs Well Versus COVID in Early Trials

Pharmaceutical giant announced on Saturday that its antiviral drug molnupiravir significantly reduced viral load in COVID patients.

Delivering the information to infectious disease experts, the company said that the drug caused the drop in viral loads five days after administration to COVID patients.

“At a time where there is unmet need for antiviral treatments against SARS-CoV-2, we are encouraged by these preliminary data,” said Wendy Painter, chief medical officer of the US firm, Ridgeback Biotherapeutics, which developed the drug in concert with Merck.

Merck had stopped development of two vaccine candidates earlier on, but has been pressing ahead with two possible treatments for COVID.

The experimental drug, also known as EIDD-2801, is currently in its Phase 2a trials. It would need to complete the third phase trials to gain approval. Molnupiravir was originally developed to treat influenza viruses, and its mechanism of action is thought to be through inducing RNA transcription errors in viruses, leading to a transcription catastrophe. This mechanism also inherently creates a significant barrier for viral escape from the drug.

The clinical trials enrolled 202 participants with COVID, who were not hospitalised. There were no safety alerts for the drug, and the four serious adverse events that did occur were not considered to be associated with the drug, Ms Painter said.

William Fischer, lead investigator of the study and a professor of medicine at the University of North Carolina said that these were promising results, adding: “If supported by additional studies, (they) could have important public health implications, particularly as the SARS-CoV-2 virus continues to spread and evolve globally.”

The company is testing another drug in clinical trials, MK-711, preliminary results for which have indicated a 50% drop in viral load in mild and severe COVID patients.

Source: Medical Xpress

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.

COVID Antibody Drugs Work Best with Immune Cells

Research into the current antibody-based drugs for COVID treatment shows that they need to be designed to work in concert with immune cells to be effective.

Three drugs using monoclonal antibodies are approved by the FDA to treat COVID, which provide the patient’s body with ready-made antibodies faster than can be produced by their own immune systems.

The distinctive Y shape of antibodies comes from their two short arms, which latch on to foreign molecules to clear them out, and a long effector arm which interacts with immune cells, inducing them to attack infected cells and release molecules that modulate the immune response.

In antibody-dependent enhancement, the long arm of antibodies can interfere with immune cells, such as in tropical dengue fever. Immunity against one strain against dengue fever causes life-threatening illness if infected with the other strain.

To investigate the possibility of this in COVID, some companies altered the long arm of their antibodies to prevent interaction with immune cells. Other companies took the opposite approach and strengthened antibody effector functions to boost the potency of their drugs.

“Some of the companies removed the effector functions from their antibodies, and other companies are trying to optimise the effector functions,” said senior author Michael S Diamond, MD, PhD, the Herbert S Gasser Professor of Medicine. “Neither of these strategies is backed by data in the context of SARS-CoV-2 infections. Based on our findings, if you have a potently neutralising antibody without effector functions and you give it before infection, as a preventive, it will probably work. But if you give it after infection, it won’t work well; you need to optimise effector functions to get maximal benefit.”

“‘Effector functions’ refers to a complex set of interactions between antibodies and other elements of the immune system,” said Prof Diamond, who also is a professor of molecular microbiology and of pathology and immunology. “You can introduce different point mutations to augment certain kinds of effector functions, and some might be harmful to the immune response while others might be beneficial. There’s a lot of nuance. We are still learning how to harness effector functions so you get what you want but not what you don’t want.”

To find how antibody effectors work with COVID, the researchers took an antibody which was known to be effective against the virus and disabled the effector so it could not interact with immune cells.

They administered the original antibodies, the disabled antibodies and placebo antibodies each to a different group of mice, which were infected a day later with SARS-CoV-2. Both normal and disabled effector antibodies were able to protect against the disease. There were no signs of antibody enhancement of the disease, fortunately.

To find out whether the effector function was needed for treatment after infection, they infected mice with SARS-CoV-2 and administered one of the three sets of antibodies to mice  one, two or three days later. Only the original antibodies protected the mice from the disease. The tests were run in hamsters with the same results.

The researchers discovered in the study that losing effector functions changed the types of immune cells recruited to fight the COVID infection and the way they behaved.

Source: Medical Xpress

Journal information: Emma S. Winkler et al, Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection, Cell (2021). DOI: 10.1016/j.cell.2021.02.026