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Take a look at a selection of our recent media coverage:

Sabizabulin significantly reduces mortality in patients hospitalised with COVID-19

18th July 2022

Sabizabulin is an oral microtubule disruptor with anti-viral properties that significantly reduced death among patients with severe COVID-19

The oral microtubule disruptor, sabizabulin has been shown significantly reduce the risk of death among patients hospitalised with COVID-19 and with a high risk of acute respiratory distress syndrome according to the results of a randomised, placebo-controlled trial by an international group of researchers.

The cellular cytoskeleton represents a complex and dynamic network of interacting protein filaments with multiple roles in the functioning of cells and is composed of three major types of protein filaments: actin filaments, intermediate filaments, and microtubules. During an infection, once a virus enters a cell, it requires cytoplasmic transport to reach specific sub-cellular sites for replication and the microtubules of the cytoskeleton represent a heavily exploited network during viral infection. Sabizabulin is a novel agent that disrupts the microtubule and hence interferes with viral replication. Moreover, in vivo data suggests that sabizabulin can suppress some of the key cytokines involved in the development of acute respiratory distress syndrome.

To test the benefit in practice of the drug, researchers undertook the VERU-111 trial which was designed to test the efficacy of VERU-111 (sabizabulin) in the treatment of COVID-19 infection. Eligible patients were adults with a laboratory confirmed COVID-19 infection, a World Health Organisation (WHO) 9-point ordinal scale for clinical improvement score of at least 4 (i.e., oxygen mask or nasal prongs), an elevated body mass index (BMI) and a co-morbidity known to place the individual at a high risk of more severe disease (e.g., asthma, diabetes, hypertension etc). Participants were randomised 2:1 to receive sabizabulin 9 mg daily or matching placebo for 21 days or until hospital discharge. The researchers set the primary efficacy endpoint as the level of 60-day all-cause mortality whereas secondary endpoints included differences in intensive care unit (ICU) days, the number of days on mechanical ventilation and time spent in hospital.

Sabizabulin and COVID-19 mortality

A total of 150 patients with a median age of 64 years (68% male) were included and randomised to sabizabulin (98) or placebo. For the entire study cohort, the median BMI was 31.7 and the median WHO ordinal scale score was 5. In addition, diabetes and hypertension were present in 37.3% and 60% of patients respectively. Overall, 55.3% of participants had not been vaccinated against COVID-19.

The primary outcome occurred in 20.2% of those taking sabizabulin and 45.1% of placebo patients, which was significantly different (odds ratio, OR = 3.23, 95% CI 1.45 – 7.22, p = 0.0042). In fact, researchers observed how the benefits of treatment with sabizabulin were apparent after only 3 days and there were significant differences in mortality seen by day 15.

For the secondary endpoints and based on a relative risk reduction, treatment with sabizabulin led to a 43% lower number of ICU days (p = 0.0013), a 49% decrease in the number of days requiring mechanical ventilation (p = 0.0013) and a 26% decrease in the number of days spent in hospital (p = 0.00277).

Adverse events leading to discontinuation of treatment occurred in 4.7% and 5.9% of patients receiving sabizabulin and placebo respectively.

The authors concluded that sabizabulin was both effective at reducing mortality in patients with COVID-19 and had an acceptable safety profile.

Citation
Barnette KG et al. Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis New Eng J Med 2022

Intermediate dose LMW heparins best for venous thromboembolism prevention in acutely ill

12th July 2022

Intermediate dose LMW heparins offer the most favourable risk-benefit profile for preventing venous thromboembolism in acutely ill patients

A network meta-analysis by a collaborate team from the Netherlands, Denmark and the UK has suggested that intermediate dose low molecular weight (LMW) heparins offer the greatest balance of benefit and harm for the prevention of venous thromboembolism (VTE) in acute ill hospitalised patients.

Venous thromboembolism is not uncommon with one US study estimating that a VTE occurs in approximately 100 persons per 100,000 each year and that an estimated one third of these patients will also develop a pulmonary embolism. Furthermore, VTEs are commonly seen in those with limited movement as revealed in another study that observed how 59% of VTWs in the community could be attributed to institutionalisation such as current or recent hospitalisation or nursing home residence. Although any of the available anticoagulants such as intermediate dose LMW heparins, unfractionated heparin or even oral anticoagulants are effective for the prevention of a VTE, there are differences in the risk-benefit profile of each of the different agents leading to differences in guidance produced by national bodies. For example, in the UK, NICE advocates the use of LMW heparins as a first-line treatment for the prevention of venous thromboembolism in acutely ill patients. In contrast, the American Society for Haematology suggests that for acutely ill medical patients, clinicians can use unfractionated heparin, LMW heparins or fondaparinux. These slight differences have no doubt arise because to date, there is a lack of comparative data on the most appropriate anticoagulant type and dose for the management of VTE in acutely ill patients.

For the present study, researchers performed a systematic review and network meta-analysis to assess the benefits and harms of different types and doses of anticoagulant drugs for prevention of venous thromboembolism in acutely ill adults who have been admitted to hospital. To assess the effectiveness of different anticoagulants, they used a composite primary outcome of all-cause mortality, symptomatic venous thromboembolism, major bleeding and serious adverse events.

Intermediate dose LMW heparins and outcomes

A total of 44 randomised trials with 90,095 participants and a median age of 68.5 years (46.5% women) were included in the analysis.

Thirty-six trials reported on all-cause mortality but interestingly, none of the interventions reduced all-cause mortality in comparison to placebo. However, when compared to no intervention, intermediate dose low-molecular-weight heparins led to a significant reduction (odds ratio, OR = 0.79, 95% CI 0.61 to 0.96) as did pentasaccharides (OR = 0.44, 95% CI 0.20 to 0.92).

Intermediate dose LMW heparins were the only intervention to reduce the incidence of symptomatic venous thromboembolism compared to placebo (OR = 0.66, 95% CI 0.46 – 0.93) but all of the interventions were effective compared to no treatment.

Both intermediate dose unfractionated heparin and direct oral anticoagulants were the two groups of agents most likely to increase major bleeding though there were no apparent differences between the different interventions with respect to the incidence of major adverse effects.

Based on these findings, the authors concluded that intermediate dose LMW heparins conferred the best balance of benefits and harms for prevention of venous thromboembolism in acutely ill hospitalised patients. In contrast, unfractionated heparin, in particular the intermediate dose and direct oral anticoagulants had the least favourable profile.

Citation
Eck RJ et al. Anticoagulants for thrombosis prophylaxis in acutely ill patients admitted to hospital: systematic review and network meta-analysis BMJ 2022

Remdesivir use in COVID-19 patients requiring ventilator support confers no advantage over standard care

12th April 2022

A study found that remdesivir use among COVID-19 patients in need of ventilator support offers no advantage over standard care

Remdesivir use among patients hospitalised with COVID-19 requiring ventilator or oxygen support did not improve clinical outcomes after 15 days compared with standard care. This was the conclusion of a European, multi-centre, open label, randomised, controlled trial.

Remdesivir is a pro-drug that is converted into a nucleoside analog and incorporated by the RNA-dependent RNA polymerase of COVID-19 into the growing RNA product before RNA synthesis stalls. The drug was approved by the EMA in June 2020 for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. Moreover, early data on remdesivir was encouraging and in a study of over 1000 patients, those randomised to remdesivir use had a median recovery time of 10 days compared with 15 days in those who received placebo. In contrast, however, the World Health Organization (WHO) Solidarity Trial, concluded that remdesivir, along with hydroxychloroquine, lopinavir and interferon regimens, had little or no effect on hospitalised patients with COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. 

With such conflicting results, the European team undertook the DisCoVeRy trial and which was designed to evaluate the safety and efficacy of possible therapeutic agents in hospitalised adult patients diagnosed with COVID-19. Recruited patients were adults hospitalised with COVID-19 who presented with either evidence of rales/crackles on examination and a SpO2 < 94% on room air or had a requirement for supplemental oxygen, high flow oxygen devices, non-invasive ventilation and/or mechanical ventilation. Patients were randomised 1:1 to either remdesivir use (200 mg on day 1 followed by a 100 mg 1-hour infusion once daily for 10 days) or standard care, which included the use of corticosteroids and anticoagulants. The primary outcome was the patient’s clinical status at day 15 as recorded on the 7-point ordinal WHO scale. The scale, which represents increasingly severe disease, ranges from 1 represented those not hospitalised and with no limitation on activities, through 5 (hospitalised on non-invasive ventilation or high flow oxygen) and 6 (hospitalised on invasive mechanical ventilation or extracorporeal membrane oxygenation) and 7 (dead). Several secondary outcomes were also used including in-hospital mortality and 28-day mortality.

Remdesivir use and clinical outcomes

A total of 857 participants with a median age of 64 years (69.5% male) were randomised to remdesivir (420) or standard care and, at randomisation, 39.4% of individuals had severe COVID-19.

Overall, 73.6% of participants had at least one co-morbidity with the most frequent being obesity (34.1%), cardiac disease (28%) and diabetes (27%).

At day 15, a similar proportion of those assigned to remdesivir and standard care were categorised as 1 on the WHO scale (14.8% vs 17%, remdesivir vs standard care) and a similar proportion had died (5% vs 6%). Overall, there was no significant difference between those assigned to remdesivir use or standard care (odds ratio, OR = 1.02, 95% CI 0.62 – 1.70, p = 0.93). Additionally, there were no significant differences in the distribution of the 7-point scale at day 29 (OR = 1.11, 95% CI 0.87 – 1.43, p = 0.40).

Furthermore, there were no significant differences for each of the secondary outcomes or subgroup analyses according to age, sex, duration of symptoms prior to randomisation or in the level of detectable viral loads at each sampling time.

The authors therefore concluded that the remdesivir use had no impact on clinical outcomes compared with standard care at either day 15 or day 29.

Citation
Ader F et al. Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial MedRxiv 2022

Prone positioning of no value in non-critically ill patients with COVID-19

4th April 2022

Prone positioning can reduce respiratory failure risk but it is unclear whether this approach helps non-critically ill patients with COVID-19

The use of prone positioning (PP) in non-critically ill patients hospitalised with COVID-19 does not improve outcomes according to the results of a large, pragmatic trial by researchers from the Division of General Internal Medicine, Sinai Health, Toronto, Canada.

Prone positioning involves lying a patient face down onto their anterior chest and abdomen to take advantage of physiologic changes that can result in improved oxygenation through decreased ventilation/perfusion mismatch and potentially, decreased lung injury. Among patients with COVID-19, pneumonia is the most common reason for admission to hospital and severe pneumonia can result in acute hypoxic respiratory failure necessitating supplemental oxygen therapy or respiratory support with mechanical ventilation. Acute respiratory distress syndrome (ARDS) can be precipitated by a pneumonia and for patients with severe ARDS, there is a strong recommendation to use prone positioning for more than 12 hours per day. Some evidence from a meta-trial has suggested that awake prone positioning of patients with hypoxaemic respiratory failure caused by COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. This led the authors to concluded that their results support the routine use of awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula. However, whether this approach would benefit less severely ill patients, i.e., lead to a reduced risk of death or respiratory failure remains to be determined and was the subject of the present study by the Canadian team.

The trial recruited patients hospitalised with COVID-19 who required supplemental oxygen and who were independently able to adopt PP. Patients were randomised 1:1 to proning or standard of care, i.e., where there was no instruction to adopt a prone position. All participants were then followed until discharge from hospital or death or for 30 days. Among those randomised to PP, it was recommended that this position was used four times a day (2 hours per session) and participants were also asked to sleep overnight in this position. The primary outcome was a composite of in-hospital death, mechanical ventilation or worsening respiratory failure which was defined as the need for at least 60% fraction of inspired oxygen for more than 24 hours.

Prone positioning and outcomes

A total of 248 individuals with a median age of 56 years (36% female) were included in the analysis. Overall co-morbidities were hypertension (40%), diabetes (27%) and COPD or asthma (11%). The median time spent in PP during the first 72 hours was 6 hours and 0 hours in the control group.

The median time until the primary outcome was one day and occurred in 14% of those assigned to either group (odds ratio, OR = 0.92, 95% CI 0.44 – 1.92). There were also no differences in subgroup analyses based on age, or when stratified by baseline hypoxia.

The authors concluded that the use of prone positioning among hypoxic patients with COVID-19 did not improve clinical outcomes. However, they added that the wide confidence intervals precluded definitely ruling out benefit or harm.

Citation
Fralick M et al. Prone positioning of patients with moderate hypoxaemia due to covid-19: multicentre pragmatic randomised trial (COVID-PRONE) BMJ 2022

Empagliflozin effective for patients hospitalised with acute heart failure

14th March 2022

Empagliflozin given to patients with acute de novo and decompensated heart failure upon admission to hospital improves clinical outcomes

Empagliflozin administered to patients once hospitalised with either de novo or decompensated heart failure leads to a clinically significant benefit over the next 90 days. This was the finding of a randomised trial by researchers from the University of Groningen Department of Cardiology, Groningen, The Netherlands.

Among patients with type 2 diabetes, sodium–glucose cotransporter 2 inhibitors such as empagliflozin, have been shown to reduce the risk of hospitalisation for heart failure and the risk of serious adverse renal events. Although an anti-diabetic agent and based on several recent clinical trials, empagliflozin is now also indicated for the treatment of symptomatic chronic heart failure with a reduced ejection fraction.

However, whether the drug would still provide a clinical benefit to patients if given to those already admitted to hospital with heart failure is unknown. For the present study, the Dutch researchers were interested in exploring whether empagliflozin would be clinically advantageous for patients, not only hospitalisation with heart failure but also on reducing worsening heart failure events (HFEs) and on the improvement of symptoms. They performed the Oral EMPagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for acUte Heart faiLure (de Novo or Decompensated Chronic HF) Who Have Been StabilisEd or EMPULSE trial.

Included patients were those who had a primary diagnosis of acute de novo or decompensated chronic heart failure, irrespective of left ventricular ejection fraction. Individuals were randomised 1:1 to empagliflozin 10 mg or placebo and this occurred after at least 24 hours but no later than 5 days after admission, as early as possible after stabilisation and while still in hospital. The primary outcome of the study was the clinical benefit at 90 days, which was defined as a composite outcome of time to all-cause death, the number of HFEs, the time to the first HFE and a 5- point or greater difference in change from baseline in Kansas City Cardiomyopathy Questionnaire KCCQ after 90 days of treatment. The KCCQ is patient-reported outcome instrument that provides a measure of symptoms and physical limitations associated with heart failure. Assessments were based on the win ratio, which offers greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes.

Empagliflozin and clinical outcomes

A total of 530 patients with a median age of 71 years (34% women) were randomised to active treatment or placebo, within a median of 3 days after admission to hospital. The proportion of patients with diabetes ranged from 46.8% to 43.8%.

Overall, 33 (6.2%) of all patients died, 11 in the empagliflozin group and there were 67 patients assigned to empagliflozin who experienced at least one HFE. The adjusted mean change in KCCQ total score from baseline to 90 days was 36.2 in the empagliflozin group and 31.7 in the placebo arm. More patients taking empagliflozin had a clinical benefit compared to placebo (stratified win ratio = 1.36, 95% CI 1.09 – 1.68, p = 0.0054). This benefit was observed irrespective of the ejection fraction and for both de novo and decompensated heart failure in the presence or absence of diabetes.

The authors concluded that initiating empagliflozin as a component of usual clinical care for patients hospitalised with acute heart failure led to clinically meaningful benefits.

Citation
Voors AA et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med 2022

Vitamin D-deficient patients 14-times more likely to get severe COVID-19

7th February 2022

Vitamin D-deficient patients are more likely to get severe COVID-19 and die compared with those with sufficient levels of the vitamin

Vitamin D-deficient individuals have been shown to be much more likely to experience severe COVID-19 and die in comparison to those with normal or sufficient levels of the vitamin. This was an important finding by researchers from the Department of Otolaryngology, Head and Neck Surgery, Galilee Medical Center, Israel.

Previous research has shown how vitamin D has a protective effect against respiratory tract infections when taken as a once daily dosage. Moreover, a 2021 systematic review which included 46 randomised controlled trials with 48,488 individuals, re-affirmed the benefits of daily supplementation with 400 –1000 IU of vitamin D for reducing the risk of acute respiratory tract infections compared with placebo. Several studies undertaken during the COVID-19 pandemic have suggested that a vitamin D deficient status was associated with increased COVID-19 risk. Furthermore, other data has shown how the vitamin D level is markedly low in severe COVID-19 patients although this was measured once in hospital. However, what is less clear, is the extent to which pre-infection or baseline vitamin D levels, impact on the clinical outcomes once patients become infected with COVID-19.

For the present study, the Israeli team set out to determine whether COVID-19 disease severity correlated with patient’s most recent vitamin D levels as documented in their medical records. They undertook a retrospective study of hospitalised, adult patients with a PCR-confirmed COVID-19 infection. The team defined COVID-19 disease severity at the point of highest severity. For instance, if a patient was admitted with mild disease and which subsequently deteriorated, this would be categorised as a critical illness. They used the most recent medical record for vitamin D status and then categorised patients as vitamin D deficient (< 20 ng/ml), insufficient (20 – 29.9 ng/ml), adequate (30 – 39.9 ng/ml) and high-normal (40 ng/ml). They used multivariable analysis to examine the relationship between vitamin D status and COVID-19 disease severity.

Vitamin D deficient status and COVID-19 severity

A total of 253 individuals with a mean age of 63.3 years (56.9% female) were included in the analysis. Among the cohort, 52.5% were vitamin D-deficient, 14.2% had levels between 20 and 30ng/ml and 15.8% had a level of 40ng/ml or above.

Mortality from COVID-19 occurred in 2.3% of those with adequate vitamin D levels and 25.6% of individuals who were vitamin D deficient (p < 0.001). When stratifying COVID-19 disease severity with vitamin D status, among those with the lowest vitamin D levels, a higher proportion (87.4%) developed severe or critical COVID-19 compared to mild to moderate disease, 34.3% (p < 0.001). In regression analysis, patients with vitamin D deficiency compared to those with high-normal levels (40 ng/ml) were 14 times more likely to develop severe or critical illness (odds ratio, OR = 14, 95% CI 4 – 51, p < 0.001). Overall, when comparing pre-hospital vitamin D levels with COVID-19 disease severity, there was a clear inverse relationship such that as vitamin D levels reduced, COVID-19 disease severity increased.

Further analysis revealed that age was an independent risk factor for more severe disease and the strongest correlation between vitamin D status and COVID-19 severity occurred in those aged 50 years and over (r = – 0.74, p < 0.001). However, this correlation was still significant among those under 50 years of age (r = -0.66, p < 0.001).

The authors described how early on in the current pandemic, there was much debate on the role of vitamin D in protecting against COVID-19. They suggested that their study provided further evidence of how vitamin D deficient patients were at a much higher risk of more severe COVID-19 infection and called for further studies to investigate if and when vitamin D supplementing in those who are deficient, impacts on COVID-19-related outcomes.

Citation
Dror AA et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness PloS One 2022

Neurological manifestations seen in nearly half of children with COVID-19 and MIS-C

26th January 2022

Neurological manifestations have been found in nearly half of children hospitalised with COVID-19 or MIS-C according to a global study

A neurological manifestation has been found in 44% of children who had been hospitalised with either COVID-19 or multisystem inflammatory syndrome (MIS-C) according to researchers from the Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID). This multinational research collaborative initiative was established in April 2020 and designed to collect information on the prevalence and outcomes of neurological manifestations associated with both acute infection with COVID-19 and those with MIS-C and the equivalent adult condition.

Among adults with COVID-19, neurological problems are common and in one study, 82% of patients reported experiencing such problems. In contrast, a study of 27 children with COVID-19 MISC-C, found that only four, previously healthy children, had new-onset neurological symptoms including encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes. However, all four children were admitted to an intensive care unit.

The evidence of neurological manifestations in children to date is based on small samples. As a result, for the present study, the team made use of the GCS-NeuroCOVID) database and searched for children (i.e., those aged under 18 years of age) hospitalised with COVID-19 related condition which was either confirmed through testing or based on the presence of recognised clinical symptoms. The diagnosis of MIS-C was based on the Centers for Disease Control and Prevention (CDC) guidance. The primary outcome of the study was the frequency and type of neurological manifestations both overall, and due to COVID-19 and MIS-C.

Neurological manifestations identified

A total of 1,493 children with a median age of 8 (47% female) were included in the analysis, of whom 86% had COVID-19 and the remainder MIS-C.

Children with a pre-existing medical condition were more likely to become infected with COVID-19 than MIS-C (p < 0.001) although children with MIS-C were more likely to be admitted to intensive care units (69% vs 29%).

Overall, 44% of the whole cohort (40% of those with COVID-19 and 66% of those with MIS-C) had at least one neurological manifestation. The most common findings were headache (16% vs 47%, COVID-19 vs MIS-C) and acute encephalopathy (15% vs 22%) and for both conditions, this difference was statistically significant (p < 0.05). Other manifestations included seizures (8%), anosmia (4%) and ageusia (3.6%). Children with neurological manifestations were also more likely to require admission to ICU (51% vs 22%, p < 0.001).

Using regression analysis, the researchers identified that for the whole cohort, several factors including older age (adjusted odds ratio, aOR = 1.20, 95% CI 1.07 – 1.13), MIS-C (aOR = 2.16), neurologic (aOR = 3.48) and a pre-existing metabolic condition (aOR = 1.65) were all significantly (p < 0.05) associated with the presence of neurological manifestations.

Commenting on these results, the authors noted how the frequency of observed neurological manifestations in the cohort was fortunately much lower than that reported in adults, which was 80%. They concluded that neurological symptoms were a common problem in children hospitalised with COVID-19 and that the presence of such symptoms was much more likely in older children and those with pre-existing neurological and metabolic conditions.

Citation

Fink EL et al. Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C Pediatr Neurol 2022

Inhaled unfractionated heparin improves oxygenation in patients with COVID-19

24th January 2022

Inhaled unfractionated heparin appears safe and leads to an improvement in oxygenation among patients hospitalised with COVID-19

Inhaled unfractionated heparin can be safely used in hospitalised patients with COVID-19 and improves oxygenation according to a retrospective analysis by researchers from Saint George Hospital, Intensive Care Unit, Sydney, Australia.

There is a strong rational for the use of inhaled unfractionated heparin (IUH) in the treatment of patients with COVID-19, given the evidence that heparin blocks spike protein binding and/or infection by pseudo-typed virus and authentic COVID-19. Moreover, in a preliminary and pre-pandemic study, the use of IUH in patients with or at risk of acute respiratory distress syndrome, the drug was was well tolerated and there was less progression of lung injury and an earlier return home.

For the present study, the Australian team recruited hospitalised patients infected with COVID-19 and who had shown clinical deterioration despite standard of care and offered them treatment with IUH. The drug was nebulised and given at a dose of 5000IU every 8 hours or initially at 10,000 IU every four hours and if tolerated increased to 25,000 IU every six hours. The outcomes of interest were activated partial thromboplastin time (APTT) and the highest level achieved during treatment. Efficacy outcomes were oxygenation which was assessed by the ratio of oxygen saturation to the fraction of inspired oxygen (S/F ratio).

Findings

A total of 98 patients with an average age of 66 years (52% male) were enrolled in the study, 79 of whom were intubated and the median time from COVID-19 symptom onset to use of IUH was 6.7 days for non-intubated patients compared to 8 days among intubated patients.

In 3 patients on UFH, APTT levels did not significantly increase from a baseline of 72 to a peak of 84 seconds (p = 0.17).

The S/F ratio decreased by an average of 9.2 units each day prior to IUH, suggesting a deterioration of oxygenation although after commencement of therapy, this began to increase compared to baseline in all patients and for each of the doses used (p < 0.001) with intubated patients showing the greatest improvement.

In discussing these results, the authors noted that the use of IUH was associated with improved oxygenation. However, an important caveat was that the study did not have a control group and that IUH was administered at different doses and durations, together with the fact that COVID-19 severity was also not uniform. Nevertheless, they argued that this heterogeneity was a potential advantage, demonstrating that the use of IUH was safe across the COVID-19 disease spectrum. While based on a case series, the authors added that there are several ongoing trials examining the value of IUH in patients hospitalised with COVID-19 and which should report in the future.

Citation

van Haren FMP et al. Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID‐19: A multicentre case series of 98 patients Br J Clin Pharmacol 2022

Higher dexamethasone dose of no benefit in critically ill COVID-19 patients

28th October 2021

Doubling the dose of dexamethasone dose in COVID-19 patients hospitalised with severe hypoxia had no effect on 28-day mortality.

Increasing the dexamethasone dose from 6 mg to 12 mg/day in hospitalised patients with COVID-19 and severe hypoxia, has no effect on overall mortality. This was the conclusion of a randomised trial undertaken by researchers from the COVID STEROID 2 Trial group, Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark. The value of dexamethasone in hospitalised patients with COVID-19 was shown in an open-label trial published in February 2021, which found that dexamethasone 6mg/daily for 10 days, resulted in a lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen. Guidance from the World Health Organisation also recommends a dexamethasone dose of 6 mg/daily either orally or intravenously.

Whether a higher dexamethasone dose would be more beneficial to those with severe COVID-19 is uncertain. However, some evidence suggests that in patients with acute respiratory distress syndrome (which can be induced by infection with the virus) initial dexamethasone doses of 20 mg for five days, could reduce the duration of mechanical ventilation and overall mortality. Thus, the purpose of the COVID STEROID 2 trial was to evaluate the efficacy and safety of a higher dose of dexamethasone in hospitalised adult patients with COVID-19 and severe hypoxia. The researcher’s working hypothesis was that a higher dexamethasone dose would increase the number of days alive without life support. The study was conducted at 26 hospitals in four countries and included patients who required supplemental oxygen, and both non-invasive and invasive mechanical ventilation. Participants were randomised 1:1 to receive either 6 or 12 mg of dexamethasone daily as a bolus injection for up to 10 days after randomisation. Patients were assessed after 28 days with the primary outcome set as the number of days alive without life support (i.e., invasive mechanical ventilation, circulatory support or kidney replacement therapy) after 28 days. There were several secondary outcomes, including the number of days alive without life support at 90 days.

Findings

A total of 982 randomised patients were included in the final analysis with a median age of 65 years (31% female). The most common co-morbidities were diabetes (27% in the 12 mg dexamethasone group, 34% in the 6 mg group) and ischaemic heart disease or heart failure (14% in both groups). After 28 days, the median number of days alive without life support was 22 days in those with a dexamethasone dose of 12 mg and 20.5 days in the dexamethasone 6 mg group (adjusted mean difference, aMD  = 1.3 days, p = 0.07). The 28-day mortality was 27.1% and 32.3% (dexamethasone 12 mg vs 6 mg). Similarly after 90 days the corresponding number of days was 84 and 80 days (dexamethasone 12 mg vs 6 mg) and this difference was not statistically significant.

The authors concluded that doubling the dexamethasone dose did not improve the number of days alive but suggested that they trial might have been underpowered to identify a significant difference.

Citation

The COVID STEROID 2 Trial Group. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomised Trial. JAMA 2021

Molnupiravir halved risk of hospitalisation for patients with COVID-19

6th October 2021

Molnupiravir, an investigational anti-viral agent, has been shown to reduce hospitalisation in patients with COVID-19.

According to an interim analysis, Merck and Ridgeback’s investigational anti-viral drug, molnupiravir (MPV), halved the risk of hospitalisation in patients with mild-to-moderate COVID-19. MPV is a pro-drug that is incorporated by RNA polymerase into COVID-19 and which has been shown in preliminary studies, to reduce nasopharyngeal COVID-19 infectious virus and viral RNA.

The results come from the Phase III MOVe-OUT trial, designed to evaluate the safety, tolerability and efficacy of MPV in non-hospitalised patients with COVID-19. Enrolled patients had laboratory-confirmed mild-to-moderate COVID-19 and with an onset of symptoms within 5 days of study randomisation. In addition, all patients were required to have at least one risk factor associated with poor disease outcome. A second trial, examined the value of MPV in hospitalised patients although this was halted after it became apparent that molnupiravir was unlikely to demonstrate a clinical benefit in hospitalised patients.

MOVe-OUT is evaluating molnupiravir at a dose of 800mg twice daily and while the results are yet to be published, the interim analysis seems positive. According a joint press release from the companies, 7.3% (28/385) of patients receiving MPV were either hospitalised or died through to Day 29 following randomisation (28/385), compared with 14.1% (53/377) of placebo-treated (p=0.0012). In addition, after 29 days, there were no deaths were reported in patients who received MPV compared to 8 deaths in the placebo arm.

The incidence of drug-related adverse events was shown to be comparable (12% and 11% MPV vs placebo). Fewer subjects discontinued study therapy due to an adverse event in the molnupiravir group (1.3%) compared to the placebo group (3.4%).

Merck plans to submit an application for Emergency Use Authorisation (EUA) to the FDA as soon as possible and plans to submit marketing applications to other regulatory bodies worldwide.

Source: Merck and Ridgeback press release, October 2021