Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study. (preprint)

There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted hospital in Brazil. One hundred patients were planned to be randomised to either “standard of care” (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 hrs of randomisation. In the ITT population (n=75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p=0.24. In the mITT population, nebulised UFH reduced mortality (OR 0.2, p=0.035).

Statistical analysis plan for the INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) meta-trial (preprint)

The INHALE-HEP meta-trial is a prospective collaborative individual participant data meta-analysis of randomised controlled trials and early phase studies, to evaluate whether inhaled nebulised UFH in hospitalised patients with COVID-19 who do not require immediate invasive mechanical ventilation, significantly reduces intubation (or death, for patients who died before intubation) at day 28 compared to standard care alone. Objective: In keeping with best practice and with the published protocol, a pre-specified statistical analysis plan has been described and made public before completion of patient recruitment and data collection into the INHALE-HEP meta-trial. Methods: Our statistical analysis plan was designed by the INHALE-HEP executive committee and statisticians and approved by the INHALE-HEP steering committee. We reviewed the data collected as specified in the meta-trial protocol and collected in individual contributing studies. We present information pertaining to data collection, pre-specified subgroups, and study outcomes. Primary and secondary outcomes are defined, and additional subgroup analyses of pre-defined variables are described. Results: We have described our methods for presenting the trial profile and baseline characteristics, as well as our Bayesian approach to monitoring and meta-analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. Conclusion: To minimise analytical bias, we have developed a statistical analysis plan and made this available to the public domain before completion of patient recruitment and data collection into the INHALE-HEP meta-trial.

Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge (preprint)

To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.

INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and Statistical Analysis Plan for an investigator-initiated international meta-trial of randomised studies (preprint)

Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anti-coagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. Methods and intervention The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) meta-trial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the meta-trial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. Analysis We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. Trial registration, ethics and dissemination The meta-trial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board.

INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol for an investigator-initiated international meta-trial of randomised studies (preprint)

Introduction: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential for COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anti-coagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. Methods and intervention This meta-trial is a prospective collaborative individual patient data meta-analysis of randomised controlled trials and early phase studies. Individual studies are conducted in multiple countries. Adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, are randomised to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome is intubation (or death, for patients who died before intubation) at day 28, assessed in a time-to-event analysis. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have specific outcome measures in addition to the core set. Ethics and dissemination: The meta-trial is registered at ClinicalTrials.gov, ID NCT04635241. Results of this study will be shared with the WHO, published in scientific journals and presented at scientific meetings.

Accuracy of Rapid Point-of-Care Antibody Test in patients with suspected or confirmed COVID-19 (preprint)

ObjectivesTo assess the real-world diagnostic accuracy of the Livzon point-of-care rapid test for antibodies to SARS-COV-2 DesignProspective cohort study SettingDistrict general hospital in England Participants173 Patients and 224 hospital staff with a history of COVID-19 symptoms, and who underwent PCR and/or reference antibody testing for COVID-19. InterventionsThe Livzon point-of-care (POC) lateral flow immunoassay rapid antibody test (IgM and IgG) was conducted at least 7 days after onset of symptoms and compared to the composite reference standard of PCR for SARS-COV-2 plus reference laboratory testing for antibodies to SARS-COV-2. The SARS-CoV-2 RT-PCR was tested using the available molecular technology during the study time (PHE laboratories, GeneXpert(R) system Xpert, Xpress SARS-CoV-2 and Source bioscience laboratory). All molecular platforms/assays were PHE/NHSE approved. The reference antibody test was the Elecsys Anti-SARS-CoV-2 assay (Roche diagnostics GmBH). Main outcome measuresSensitivity and specificity of the rapid antibody test ResultsThe reference antibody test was positive in 190/268 (70.9%) of participants with a history of symptoms suggestive of COVID-19; in the majority (n=312) the POC test was taken 35 days or more after onset of symptoms. The POC antibody test had an overall sensitivity of 90.1% (292/328, 95% CI 86.3 - 93.1) and specificity of 100% (68/68, 95% CI 94.7 - 100) for confirming prior SARS-CoV-2 infection when compared to the composite reference standard. Sensitivity was 97.8% (89/92, 95% CI 92.3% to 99.7%) in participants who had been admitted to hospital and 84.4% (124/147, 95% CI 77.5% to 89.8%) in those with milder illness who had never been seen in hospital. ConclusionsThe Livzon point-of-care antibody test had comparable sensitivity and specificity to the reference laboratory antibody test, so could be used in clinical settings to support decision-making about patients presenting with more than 10 days of symptoms of COVID-19. What is already known on this topic- Presence of IgG and IgM antibodies to SARS-COV-2 indicates that the person was infected at least 7 days previously and is usually no longer infectious. - Rapid point-of-care tests for antibodies to SARS-COV-2 are widely available, cheap and easy to use - Preliminary evaluations suggested that rapid antibody tests may have insufficient accuracy to be useful for testing individual patients. What this study adds- The rapid point-of-care test for antibodies to SARS-COV-2 was 90.1% sensitive and 100% specific compared to reference standards for prior infection with COVID-19. - This is comparable to reference antibody tests - The point-of-care test evaluated in this study could be used to support clinical decision-making in real time, for patients presenting with symptoms of possible COVID-19 with at least 10 days of symptoms.