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Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID Pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics (preprint)

Young, Irene, Russell, Kay, Scholefield, Emma, Nimmo, Alastair F.1, Islom B. Nazarov2, Grant C. Churchill2, James S. O. McCullagh2, Kourosh H. Ebrahimi3, Anthony, Daniel, Dear, James, Hirani, Nik, Dhaliwal, Kev4 •
University of Edinburgh1, University of Oxford2, King's College London3, NHS Lothian4
07 Oct 2021-medRxiv (Cold Spring Harbor Laboratory Press)-
TL;DR: In this paper, the authors present the findings of a phase Ib/II open label, platform randomised controlled trial of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis.
Abstract: Background: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is Nafamostat Mesylate. Methods: We present the findings of a phase Ib/II open label, platform randomised controlled trial of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2mg/kg/hour for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. Results: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. 78% of Nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The Nafamostat group developed significantly higher plasma creatinine levels and had a lower number of oxygen free days (posterior mean difference 10.57 micromol/L, 95% HPD interval 2.43 - 18.92, rate ratio 0.55- 95% HPD interval 0.31- 0.99 respectively). There were no other statistically significant differences in endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D-Dimers. Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Further evaluation of Nafamostat delivered via a different route may be warranted. Clinical Trial Registration Details: This trial has been registered on ISRCTN (https://www.isrctn.com/) ISRCTN14212905, and Clinicaltrials.gov (https://www.clinicaltrials.gov/) NCT04473053. Funding Information: DEFINE was funded by LifeArc (an independent medical research charity under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230). Declaration of Interests: The authors report no conflict of interests. Ethics Approval Statement: The DEFINE trial has received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian. Written informed consent was taken by trial clinicians prior to any trial procedures being performed. If a patient lacked capacity, consent could be provided by their next of kin.

Summary (4 min read)

Jump to: [INTRODUCTION] – [Trial design and participants] – [Endpoints] – [Interventions] – [Clinical and laboratory monitoring] – [Pharmacokinetics] – [Viral Load] – [Cytokine analysis] – [Flow cytometry] – [Statistics] – [Participants] – [Adverse events] – [Clinical endpoints] – [Viral data] – [Thromboelastometry] – [Peripheral blood immunophenotyping] and [DISCUSSION]

INTRODUCTION

  • COVID-19, caused by the coronavirus SARS-CoV-2, was declared a global pandemic on the 11th of March 2020 [1] and an ongoing global health, social and economic crisis has ensued.
  • At the time of writing, dexamethasone and interleukin-6 receptor antagonists [2] are the only effective treatments available for COVID-19 [3] [4], however, the mortality rate of unvaccinated COVID-19 in hospitalised patients remains high at 22.9% [2].
  • In addition to the potential antiviral effects, Nafamostat inhibits platelet aggregation, inhibits thrombin, kallikrein, plasmin and other complement factors and reduces endothelial activation [9].
  • The authors report the first detailed assessment of safety, PK/PD; immunology and coagulation effects of the drug at the recommended dose and route, using a platform RCT.

Trial design and participants

  • The DEFINE trial is a platform, multicentre, randomised controlled open label trial.
  • Here the authors report the finding for the Nafamostat arm compared to SoC.
  • The trial protocol has been reported previously. [10].
  • A current or recent history of severe uncontrolled cardiac disease, diabetes mellitus, renal impairment or hepatic impairment, anaemia, thrombocytopaenia, hyponatraemia or hyperkalaemia, were also exclusion criteria (see pre-print protocol with full inclusion/exclusion criteria [10]).
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Endpoints

  • The primary endpoint was to evaluate the safety and tolerability of intravenous Nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis.
  • Secondary endpoints were to explore the Pharmacokinetics/Pharmacodynamics (PK/PD) of Nafamostat; assess the response of key biomarkers during the treatment period; evaluate SARS-CoV-2 viral load over time.
  • Clinical secondary endpoints included oxygen free days; the change in the oxygen saturations and fraction of inspired oxygen concentration (SpO2/FiO2 ratio); time to discharge; the use of kidney replacement therapy.

Interventions

  • Participants randomised to intravenous Nafamostat were administered the drug as a continuous infusion at a dose of 0.2 mg/kg/hr through a dedicated intravenous cannula.
  • The infusion was prepared as per local guidelines and changed every 24 hours for a total of 7 days, or until discharge or withdrawal.
  • In the event of biochemical side effects, namely clinically significant hyperkalaemia or hyponatraemia, treatment was ceased.
  • Treatment was also terminated if there was a clotting event requiring anticoagulation or antiplatelet therapy, but trial participants continued to provide daily bloods, ECG and clinical assessments despite no longer receiving a trial medication.
  • SoC included all appropriate supportive measures for SARS-CoV-2 and approved therapies as per national guidance at the time including dexamethasone, remdesivir and tocilizumab as per NHS guidelines.

Clinical and laboratory monitoring

  • Nursing and medical staff visited patients daily until discharge, withdrawal, or day 16 of participation.
  • A list of daily observations and blood parameters recorded are listed in Table 3 (supplementary material).
  • Symptoms were elicited from patients and recorded as adverse events (AE) if indicated.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprint this version posted October 7, 2021.

Pharmacokinetics

  • Blood samples for the analysis of plasma Nafamostat levels and its breakdown metabolite (4-GBA) were obtained.
  • To determine Nafamostat breakdown products, levels of 4-GBA were measured pre-infusion .
  • 4-GBA was undetectable in the pre-infusion samples confirming no intrinsic 4-GBA.
  • Following Nafamostat administration, 4-GBA was detected at elevated levels in plasma .
  • Taken together, this suggests in hospitalised patients with COVID19 pneumonitis, there is rapid breakdown of intravenous Nafamostat to its inactive metabolite, 4- GBA, resulting in very low levels of circulating Nafamostat, and intravenous Nafamostat therefore had unfavourable PK characteristics in this cohort of patients.

Viral Load

  • Qualitative and quantitative polymerase chain reaction (PCR) of oropharyngeal/nasal measurements for SARS-CoV-2 were taken from the final 37 participants in the trial.
  • A volume of 110μL of eluate containing purified RNA was obtained following automated extraction carried out on the NucliSENS® easyMag® using an ‘off-board’ extraction where 200μL of the sample was added to 2ml of easyMAG lysis buffer.
  • Nasopharygeal and saliva samples were then tested using the Altona RealTime PCR kit (Hamburg, Germany).
  • Ct values were converted to copies per mL by relating values to a standard linearity panel with values in copies/mL derived by digital droplet PCR (Quality Control for Molecular Diagnostics, Glasgow).
  • Measurements of anticoagulation effect, clot strength and antifibrinolytic effect were executed.

Cytokine analysis

  • Samples were frozen on dry-ice in aliquots and stored at -80°C and assayed at the end of the trial using the ELLA platform (Simple protein, Bio-Techne, R&D, USA).
  • Results beyond the limit of detection and .
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprint this version posted October 7, 2021.

Flow cytometry

  • All staining and processing were performed in an MSCII biosafety cabinet with centrifugation steps using capped tubes in the biosafety bucket which were loaded and unloaded within the MSCII Peripheral blood was taken for detailed immunophenotyping.
  • Red blood cells were lysed using BD FACS lyse.
  • 5 minutes later, 50 µl of antibody staining cocktail (prepared in FACS staining buffer (PBS 2% FCS (Gibco)) containing 10% Brilliant violet plus buffer (BD 566385)) was added to each tube and then incubated in the dark, at room temperature for 20 minutes and washed twice in staining buffer before fixation (Biolegend Fixation buffer).
  • After 20 minutes, fixed samples were moved from the MSCII to cold storage.
  • Freshly prepared 8 peak calibration beads were run daily prior to sample collection.

Statistics

  • The analysis population consisted of (i) all patients randomised to Nafamostat who received any dose of the trial drug and (ii) all patients randomised to the control arm (SoC) who would also have been eligible to receive Nafamostat.
  • Therefore, any patients who were randomised to Nafamostat but did not receive the trial drug were excluded.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The authors also separately analysed the outcome of “at least one AE during follow-up” using a Bayesian logistic regression model, with trial arm as the only explanatory variable.
  • The cytokine data were presented as means and 95% confidence intervals with best-fit line by linear regression and comparing intercepts and slopes.

Participants

  • Amongst 299 individuals screened, 66 met eligibility criteria and were randomised.
  • 44 participants were enrolled to the Nafamostat vs SoC comparison reported here.
  • There were no baseline differences between Nafamostat and SoC groups .

Adverse events

  • Patients’ clinical course, in-hospital AE occurrence and time in the trial are summarised for each arm in Figure 2A and Table 6.
  • The Nafamostat group experienced more AEs compared to SoC (n=50 vs n=35), with 78% of Nafamostat-treated patients experiencing at least one AE compared to 57% of the SoC group.
  • There were no serious adverse events (SAEs) in either group.
  • Other than clinical deterioration, hyperkalaemia was the most common reason for early cessation (6/21), although there were no related complications.
  • One patient developed a pulmonary embolism, and one patient suffered an ischaemic CVA whilst on Nafamostat .

Clinical endpoints

  • A Kaplan-Meier plot of duration of hospital stay is shown in Figure 2B, with an average longer hospital stay in Nafamostat patients (Table 2).
  • Nafamostat-treated patients were on oxygen for a median of 2 days more than SoC patients (Table 2) and there were a significantly lower number of oxygen free days for those on Nafamostat (rate ratio 0.55- 95% HPD interval 0.31- 0.99).
  • There were no other statistically significant differences regarding primary endpoints.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Viral data

  • Nasopharyngeal and saliva samples were taken at baseline, day 3 and day 5 for RT PCR analysis.
  • Viral load decreased over time in both groups, with no difference observed between the Nafamostat and SoC groups .

Thromboelastometry

  • In most patients receiving intravenous Nafamostat, little or no anticoagulant effect was evident .
  • An antifibrinolytic effect was seen in patients receiving Nafamostat .
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • A similar trend was seen with Protein C .

Peripheral blood immunophenotyping

  • To assess immune perturbations associated with COVID-19 infection, and whether kinetic changes in the immune response correlated with treatment, flow cytometry was used to characterise peripheral blood leukocytes on entry to the trial (pre-treatment), and on day four and day seven whilst hospitalised.
  • Evidence of activation of the adaptive immune response during COVID-19 infection was seen as the presence of HLA-DR+CD38+ activated T cells and CD19+CD27+CD38+ antibody secreting cells (ASC) .
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • In summary, Nafamostat did not influence the rate of change in any immune parameters . .
  • The copyright holder for this preprint this version posted October 7, 2021.

DISCUSSION

  • Nafamostat was delivered at its recommended dose for its licenced indication.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprint this version posted October 7, 2021.
  • This experimental medicine trial with extensive phenotyping of PK and PD, does not support the use of intravenous Nafamostat in hospitalised COVID-19 patients.
  • The authors thank Nichi-Iko for kindly supplying Futhan (intravenous Nafamostat) for the trial;.

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Figures (8)

Content maybe subject to copyright    Report

TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis:
Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics
Tom M. Quinn
#1,2
, Erin E. Gaughan
#1,2
, Annya Bruce
1
, Jean Antonelli
1
, Richard O’Connor
1
, Feng Li
1
,
Sarah McNamara
1
, Oliver Koch
3
, Claire MacIntosh
3
, David Dockrell
1,3
, Timothy Walsh
1,2
, Kevin G.
Blyth
4
, Colin Church
5
, Jürgen Schwarze
1
, Cecilia Boz
1
, Asta Valanciute
1
, Matthew Burgess
1
, Philip
Emanuel
1
, Bethany Mills
1
, Giulia Rinaldi
1
, Gareth Hardisty
1
, Ross Mills
1
, Emily Findlay
1
, Sunny
Jabbal
2
, Andrew Duncan
3
, Sinéad Plant
3
, Adam D. L. Marshall
1,2
, Irene Young
1
, Kay Russell
1
, Emma
Scholefield
1
, Alastair F. Nimmo
2
, Islom B. Nazarov
6,7
, Grant C. Churchill
7
, James S.O. McCullagh
9
,
Kourosh H. Ebrahimi
13
, Colin Ferrett
8
, Kate Templeton
2
, Steve Rannard
10
, Andrew Owen
10
, Anne
Moore
1
, Keith Finlayson
1
, Manu Shankar-Hari
1
, John Norrie
11
, Richard A. Parker
11
, Ahsan R.
Akram
1,2
, Daniel C. Anthony
7
, James W. Dear
2,12
, Nik Hirani
1,2
, Kevin Dhaliwal*
1,2
#
contributed equally
*Correspondence to Kev.Dhaliwal@ed.ac.uk
1
Centre for Inflammation Research, Queen’s Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh,
UK
2
Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh
3
Regional Infectious Disease Unit, NHS Lothian
4
Institute of Cancer Sciences, University of Glasgow
5
Department of Respiratory Medicine, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde Health
Board, Glasgow, UK
6
Latus Therapeutics, Oxford, UK
7
Department of Pharmacology, University of Oxford, Oxford, UK
8
Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
9
Department of Chemistry, University of Oxford, Oxford, UK
10
Centre of Excellence for Long-acting Therapeutics, Materials Innovation Factory & Department of Pharmacology and
Therapeutics, University of Liverpool
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
11
Edinburgh Clinical Trials Unit (ECTU), Usher Institute, University of Edinburgh, Edinburgh, UK
12
Centre for Cardiovascular Science, Queen’s Medical Research Institute, Bioquarter, University of Edinburgh, Edinburgh,
UK
13
Institute of Pharmaceutical Science, King's College London, UK
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis:
Phase 2A Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics
ABSTRACT
Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a
global health problem and further chemotherapeutics are required. Many repurposed drugs have
progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics
(PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate
(Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory
properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-
2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell
entry.
Methods:
We present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT),
exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19
pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative
therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and
clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell
flow cytometry and viral load.
Results:
Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous
Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more
adverse events and a lower number of oxygen free days. There were no other statistically significant
differences in the primary or secondary endpoints between Nafamostat and SoC. PK data
demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We
observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no
differences in cytokine profile and immune cell phenotype and viral loads between the groups.
Conclusion
In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory,
anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials
with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to
selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat
delivered via a different route may be warranted. This trial demonstrates the importance of
experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
INTRODUCTION
COVID-19, caused by the coronavirus SARS-CoV-2, was declared a global pandemic on the 11
th
of
March 2020 [1] and an ongoing global health, social and economic crisis has ensued. Vaccination
programmes are at varying stages globally, with concerns in vaccinated populations regarding
resistant strains ever-present. Identifying effective treatments for preventing clinical deterioration is
therefore of paramount importance. At the time of writing, dexamethasone and interleukin-6 receptor
antagonists [2] are the only effective treatments available for COVID-19 [3] [4], however, the
mortality rate of unvaccinated COVID-19 in hospitalised patients remains high at 22.9% [2].
Further chemotherapeutics are therefore required, with the repurposing of pre-existing drugs, quicker
and more cost-effective than the development of new medications.
Nafamostat Mesylate (Nafamostat) is a synthetic protease inhibitor and directly inhibits the
transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry of MERS-CoV,
therefore, blocking human cell entry [5]. This method of cell entry is shared by other coronaviruses
including SARS-CoV-2, and in-vitro studies have confirmed activity against SARS-CoV-2 [6, 7].
Nafamostat has shown to significantly reduce weight loss and lung tissue SARS-CoV-2 titres in
murine models [8]. Nafamostat has a short half-life and poor oral bioavailability, which necessitates
intravenous administration, limiting the potential use of the current formulation outside of a hospital
setting. It has been used to treat disseminated intravascular coagulation (DIC), acute pancreatitis, and
as an anticoagulant in extracorporeal hemofiltration and dialysis since the 1980s. In addition to the
potential antiviral effects, Nafamostat inhibits platelet aggregation, inhibits thrombin, kallikrein,
plasmin and other complement factors and reduces endothelial activation [9]. Given the prominent
activation of thrombotic pathways and endothelial inflammation in COVID-19 immunopathogenesis,
these are potentially beneficial attributes.
In this context Nafamostat is a drug highlighted as a potential target due to its antiviral,
immunomodulatory and anticoagulant effects. Nine trials are ongoing without testing whether at the
current recommended dose and route of administration, it has the expected PK/PD and safety profile.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
Citations
More filters
Journal Article•DOI•
Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles: A Systematic Review.

[...]

Anthony D. Bai, Yunbo Jiang, David L Nguyen, Carson K L Lo, Isabella Stefanova, Kevin H Guo, Frank Wang, Cindy Zhang, Kyle Sayeau, Akhil Garg, Mark Loeb 
03 Jan 2023-JAMA network open
TL;DR: In this paper , the authors used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021.
Abstract: Importance Randomized clinical trials (RCTs) on COVID-19 are increasingly being posted as preprints before publication in a scientific, peer-reviewed journal. Objective To assess time to journal publication for COVID-19 RCT preprints and to compare differences between pairs of preprints and corresponding journal articles. Evidence Review This systematic review used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021. This review included RCTs with human participants and research questions regarding the treatment or prevention of COVID-19. For each preprint, a literature search was done to locate the corresponding journal article. Two independent reviewers read the full text, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Time to publication was analyzed using a Cox proportional hazards regression model. Differences between preprint and journal article pairs in terms of outcomes, analyses, results, or conclusions were described. Statistical analysis was performed on October 17, 2022. Findings This study included 152 preprints. As of October 1, 2022, 119 of 152 preprints (78.3%) had been published in journals. The median time to publication was 186 days (range, 17-407 days). In a multivariable model, larger sample size and low risk of bias were associated with journal publication. With a sample size of less than 200 as the reference, sample sizes of 201 to 1000 and greater than 1000 had hazard ratios (HRs) of 1.23 (95% CI, 0.80-1.91) and 2.19 (95% CI, 1.36-3.53) for publication, respectively. With high risk of bias as the reference, medium-risk articles with some concerns for bias had an HR of 1.77 (95% CI, 1.02-3.09); those with a low risk of bias had an HR of 3.01 (95% CI, 1.71-5.30). Of the 119 published preprints, there were differences in terms of outcomes, analyses, results, or conclusions in 65 studies (54.6%). The main conclusion in the preprint contradicted the conclusion in the journal article for 2 studies (1.7%). Conclusions and Relevance These findings suggest that there is a substantial time lag from preprint posting to journal publication. Preprints with smaller sample sizes and high risk of bias were less likely to be published. Finally, although differences in terms of outcomes, analyses, results, or conclusions were observed for preprint and journal article pairs in most studies, the main conclusion remained consistent for the majority of studies.
References
More filters
Journal Article•DOI•
Functional testing of tranexamic acid effects in patients undergoing elective orthopaedic surgery.

[...]

Philipp Groene1, Sophia R. Sappel1, Thomas Saller1, Tobias Nitschke1, Paula A. Sa, Alexander C. Paulus1, Daniel Chappell1, Simon T. Schäfer1 •
Ludwig Maximilian University of Munich1
01 May 2021-Journal of Thrombosis and Thrombolysis
TL;DR: This prospective observational study evaluated and correlated TXA plasma concentrations (cTXA) following intravenous and oral administration in patients undergoing elective orthopaedic surgery with lysis variables of TPA-test and correlated with cTXA.
Abstract: Tranexamic acid (TXA) can reduce blood loss and transfusion rates in orthopaedic surgery. In this regard, a new viscoelastometric test (TPA-test, ClotPro), enables the monitoring of TXA effects. This prospective observational study evaluated and correlated TXA plasma concentrations (cTXA) following intravenous and oral administration in patients undergoing elective orthopaedic surgery with lysis variables of TPA-test. Blood samples of 42 patients were evaluated before TXA application and 2, 6, 12, 24 and 48 h afterwards. TPA-test was used to determine lysis time (LT) as well as maximum lysis (ML) and cTXA was measured using Ultra-High-Performance-Liquid-Chromatography/Mass-Spectrometry. Data are presented as median (min–max). LTTPA-test and MLTPA-test correlated with cTXA (r = 0.9456/r = 0.5362; p < 0.0001). 2 h after intravenous TXA administration all samples showed complete lysis inhibition (LTTPA-test prolongation: T1: 217 s (161–529) vs. T2: 4500 s (4500–4500);p < 0.0001), whereas after oral application high intraindividual variability was observed as some samples showed only moderate changes in LTTPA-test (T1: 236 s (180–360) vs. T2: 4500 s (460–4500); p < 0.0001). Nevertheless, statistically LTTPA-test did not differ between groups. MLTPA-test differed 2 h after application (i.v.: 9.0% (5–14) vs. oral: 31% (8–97); p = 0.0081). In 17/21 samples after oral and 0/21 samples after intravenous administration cTXA was < 10 µg ml−1 2 h after application. TPA-test correlated with cTXA. MLTPA-test differed between intravenous and oral application 2 h after application. Most patients with oral application had TXA plasma concentration < 10 µg ml−1. The duration of action did not differ between intravenous and oral application. Additional studies evaluating clinical outcomes and side-effects based on individualized TXA prophylaxis/therapy are required.

12 citations

Posted Content•DOI•
Evaluation of nafamostat mesylate safety and inhibition of SARS-CoV-2 replication using a 3-dimensional human airway epithelia model

[...]

D. Lynn Kirkpatrick, Jeffrey Millard
16 Sep 2020-bioRxiv
TL;DR: Using a human airway model, study demonstrates the powerful inhibitory effect of nafamostat on SARS-CoV-2 genome copy detection when applied apically and confirms the relevance of this model for the preclinical evaluation of safety and efficacy of antiviral candidates.
Abstract: In the current COVID-19 pandemic context, Ensysce and its subsidiary Covistat have been working to repurpose nafamostat mesylate as an effective oral and inhalation treatment against SARS-CoV-2 infection. Prior reports used cell lines to demonstrate the antiviral potential of nafamostat against coronaviral infections and determined its mechanism of action through inhibition of transmembrane protease serine 2 (TMPRSS2). We selected a biologically relevant pre-clinical experimental model of SARS-CoV-2 lung infection using a 3D human reconstituted airway epithelial model of nasal origin to characterize the effects of nafamostat on tissue-level cellular ultrastructure and viral infection kinetics. Our results confirm the not only the relevance of this model for the preclinical evaluation of safety and efficacy of antiviral candidates, but also the highly potent nature of nafamostat SARS-CoV-2 antiviral activity. The studies described herein provided evidence demonstrating the therapeutic potential of nafamostat against COVID-19, as well as its safety upon exposure to lung airway cellular. One Sentence Summary Using a human airway model, study demonstrates the powerful inhibitory effect of nafamostat on SARS-CoV-2 genome copy detection when applied apically.

5 citations

Posted Content•DOI•
DEFINE: A Phase IIa Randomised Controlled Trial to Evaluate Repurposed Treatments for COVID-19

[...]

Erin Gaughan1, Tom Quinn1, Annya Bruce1, Jean Antonelli1, Vikki Young1, Joanne Mair1, Ahsan R. Akram1, Nikhil Hirani1, Oliver Koch2, Claire Mackintosh2, John Norrie1, James W. Dear1, Kevin Dhaliwal1 •
University of Edinburgh1, NHS Lothian2
23 May 2021-medRxiv
TL;DR: DEFINE as mentioned in this paper is an exploratory multicentre platform, open label, randomised study for COVID-19 positive patients, which is designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy.
Abstract: IntroductionCOVID-19 (Coronavirus Disease 2019) is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). At present there are few proven effective treatments. This early phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients. Methods and analysisDEFINE is an ongoing exploratory multicentre platform, open label, randomised study. COVID-19 positive patients will be recruited from the following cohorts; a) community cases b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised patients requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action. The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19. Safety will be assessed usingO_LIHaematological and biochemical safety laboratory investigations. C_LIO_LIPhysical examination C_LIO_LIVital signs (blood pressure/heart rate/temperature and respiratory rate) C_LIO_LIDaily electrocardiogram (ECG) readings C_LIO_LIAdverse events C_LI The analysis population will consist of (i) all patients randomised to a treatment arm who receive any dose of the study drug and (ii) all patients randomised to the control arm who would also have been eligible to receive a study drug. Secondary analysis will assess the following variables during treatment period 1) the response of key exploratory biomarkers 2) change in WHO ordinal scale and NEWS2 score 3) oxygen requirements 4) viral load 5) duration of hospital stay 6) PK/PD and 7) changes in key coagulation pathways. Ethics and disseminationThe DEFINE trial platform and its initial two treatment and standard of care arms have received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian and NHS Greater Glasgow and Clyde. The results of each study arm will be published as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including RECOVERY, and to other partners for rapid roll out in larger patient cohorts. Registration detailsThe DEFINE protocol has been registered on ISRCTN (https://www.isrctn.com/) and Clinicaltrials.gov(https://www.clinicaltrials.gov/). ClinicalTrials.gov Identifier: NCT04473053 ISRCTN Identifier: ISRCTN14212905 Strengths and limitations of this studyO_LIThe trial is as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges. C_LIO_LIThe team are collecting real world data of medications at an early stage of their use in COVID-19 across the full spectrum of disease; allowing the administration of different treatment formulations (inhaled vs oral vs intravenous). C_LIO_LIThe simultaneous collection of clinical outcomes as well as exploratory endpoints including clinical biomarkers, flow cytometry, PK/PD and thromboelastography allows further characterisation and elucidation of the temporal immuno-inflammatory cascade in COVID-19 to inform on future therapy selection. C_LIO_LIThis is a Phase 1b/IIa platform study and thus the primary end point is clinical safety therefore our anticipated numbers will be too small to allow for definitive data on efficacy. C_LIO_LIDEFINE is an experimental medicine platform, currently restricted to three clinical sites and so the generation of data will be slower than that of larger platforms with access to a greater number of patients. C_LI

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Nafamostat Mesylate ( NafAmostat ) is a synthetic protease inhibitor and directly inhibits the transmembrane protease serine 2 ( TMPRSS2 ) dependent stage of host cell entry this paper.