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Abstract
Background Despite the availability of COVID-19 vaccinations, there remains a need to investigate treatments to reduce the risk or severity of potentially fatal complications of COVID-19, such as acute respiratory distress syndrome (ARDS). This study evaluated the efficacy and safety of the transient receptor potential channel C6 (TRPC6) inhibitor, BI 764198, in reducing the risk and/or severity of ARDS in patients hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen support (oxygen by mask or nasal prongs, oxygen by non-invasive ventilation or high-flow nasal oxygen).
Methods Multicentre, double-blind, randomised phase II trial comparing once-daily oral BI 764198 (n=65) with placebo (n=64) for 28 days (+2-month follow-up). Primary endpoint: proportion of patients alive and free of mechanical ventilation at day 29. Secondary endpoints: proportion of patients alive and discharged without oxygen (day 29); occurrence of either in-hospital mortality, intensive care unit admission or mechanical ventilation (day 29); time to first response (clinical improvement/recovery); ventilator-free days (day 29); and mortality (days 15, 29, 60 and 90).
Results No difference was observed for the primary endpoint: BI 764198 (83.1%) versus placebo (87.5%) (estimated risk difference –5.39%; 95% CI –16.08 to 5.30; p=0.323). For secondary endpoints, a longer time to first response (rate ratio 0.67; 95% CI 0.46 to 0.99; p=0.045) and longer hospitalisation (+3.41 days; 95% CI 0.49 to 6.34; p=0.023) for BI 764198 versus placebo was observed; no other significant differences were observed. On-treatment adverse events were similar between trial arms and more fatal events were reported for BI 764198 (n=7) versus placebo (n=2). Treatment was stopped early based on an interim observation of a lack of efficacy and an imbalance of fatal events (Data Monitoring Committee recommendation).
Conclusions TRPC6 inhibition was not effective in reducing the risk and/or severity of ARDS in patients with COVID-19 requiring non-invasive, supplemental oxygen support.
Trial registration number NCT04604184.
- ARDS
- ambulatory oxygen therapy
- assisted ventilation
- critical care
- emergency medicine
- non-invasive ventilation
Data availability statement
Data are available upon reasonable request. To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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- ARDS
- ambulatory oxygen therapy
- assisted ventilation
- critical care
- emergency medicine
- non-invasive ventilation
WHAT IS ALREADY KNOWN ON THIS TOPIC
Over 40% of patients hospitalised for COVID-19 develop acute respiratory distress syndrome (ARDS).
Therefore, there is a significant unmet need for a safe and effective treatment that reduces the risk and severity of ARDS in patients with severe COVID-19.
WHAT THIS STUDY ADDS
This is the first evaluation of TRPC6 inhibition as a potential treatment to reduce the risk and/or severity of ARDS in patients with COVID-19 requiring non-invasive, supplemental oxygen support.
BI 764198 did not improve outcomes in hospitalised patients and prolonged the duration of hospitalisation and recovery.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Despite promising preclinical and phase I findings, further clinical trials of BI 764198 for the treatment of ARDS in COVID-19 are not justified based on the results of this study.
Introduction
COVID-19 is associated with a wide spectrum of symptoms of varying intensity, most notably affecting the respiratory system.1 Studies estimate that up to 20% of COVID-19 cases are severe enough to warrant hospitalisation2 and that 26%–32% of patients hospitalised with COVID-19 require medical care in an intensive care unit (ICU).3
At the time of this study, between 3% and 17% of all patients with COVID-19 developed acute respiratory distress syndrome (ARDS), a potentially deadly complication of severe COVID-19.3 This figure increased to 42% among hospitalised patients, and between 61% and 85% among patients admitted to an ICU.3–6 Therefore, preventing progression of COVID-19 to ARDS was of significant medical importance. Treatments available for patients hospitalised with COVID-19 included remdesivir, immunomodulators and corticosteroids.7 Corticosteroids, such as dexamethasone, and interleukin (IL)-6 antagonists, such as tocilizumab, had been shown to improve outcomes in patients with COVID-19.8–10 Janus kinase inhibitors such as baricitinib had also shown favourable outcomes but not a significant reduction in the development of ARDS in patients with COVID-19.11–13 Since this trial, emergency use authorisation has been granted for several monoclonal antibody/antibody combinations14–16 and two antiviral treatments17 18; these treatments have been authorised for patients with mild to moderate COVID-19 who are at high risk of progressing to severe COVID-19, but not for patients already hospitalised with COVID-19. In addition, numerous vaccines have been approved and are in use around the world.19 Vaccinations reduce rates of infection as well as the intensity and adverse outcomes of infection, should it occur. However, breakthrough infections can occur in fully vaccinated individuals and in those who have received booster vaccines. New variants of concern, such as the Omicron variant (B.1.1.529) and the subvariant B.1.1.529.2 (BA.2), may present further challenges to vaccine-induced immune protection, highlighting the ongoing need for therapeutic options.20 21
The pathophysiology of developing ARDS in COVID-19 is heterogeneous and complex, involving various molecular pathways and a general imbalance between injurious and reparative mechanisms.22 23 Endothelial injury can cause increased lung endothelial and alveolar epithelial permeability and a subsequent accumulation of pulmonary oedema fluid within the interstitium and alveolus.22 In addition, injury to the lung epithelium facilitates leucocyte migration, reduces surfactant production and inhibits clearance of pulmonary oedema fluid. Other mechanisms, including deleterious effects of proinflammatory cytokines, oxidants and hypoxia, have also been identified as factors that can impair alveolar fluid clearance in ARDS.22
Transient receptor potential channel C6 (TRPC6) is highly expressed in human epithelial and endothelial cells within the lung24 and is indirectly activated by hypoxia and reactive oxygen species; this results in calcium influx, leading to smooth muscle contraction and increased endothelial cell damage, which in turn increases endothelial permeability and oedema.25 TRPC6 knockdown prevents thrombin-induced actin stress fibre formation and interendothelial junctional gap formation in human pulmonary arterial endothelial cells.26
BI 764198, a novel, potent, oral, small-molecule inhibitor of TRPC6, is being developed for the treatment of chronic kidney disease and has been shown to be well tolerated (data on file) in phase I studies in healthy adults.27 28
Due to the potential effect of TRPC6 inhibition in reducing lung oedema, the efficacy and safety of BI 764198 was investigated in a proof-of-concept phase II trial for the treatment of patients hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen support.
Methods
Trial design and participants
This parallel-group, randomised, double-blind, placebo-controlled, phase II trial was conducted across 25 trial sites in the USA, Brazil, Chile, Mexico and Spain (online supplemental table 1).
Supplemental material
Eligible patients were aged ≥50 years old, hospitalised for COVID-19 (SARS-CoV-2 infection confirmed by PCR or approved point-of-care test) with a clinical score of 5 (hospitalised; oxygen by mask or nasal prongs) or 6 (hospitalised; oxygen by non-invasive ventilation or high-flow nasal oxygen (HFNO)), as defined on the WHO Clinical Progression Scale at the time of study screening.29 Other scores were not eligible for inclusion. Patients were not vaccinated against SARS-CoV-2. Patients aged 50 years and older were included in this trial as these patients are at a higher risk of developing severe lung complications as a result of SARS-CoV-2 infection, and as such, are clinically important. Additionally, patients with a WHO Clinical Progression Scale score of 5 or 6 were included as, at the time of screening, there was a lack of physiological differentiation between the two scores as well as variability in local clinical decision-making regarding the choice between oxygen by mask (clinical score of 5) or HFNO (clinical score of 6). The inclusion of patients with a clinical score of 5 or 6 was also consistent with regulatory agency guidance at the time of screening.
An independent and unblinded Data Monitoring Committee (DMC; composed of field experts and supported by an independent statistician) with full access to efficacy and safety data oversaw conduct of the trial; they reviewed data snapshots at frequent intervals and provided recommendations on trial continuation, modification or termination.
Procedures
Eligible patients were randomised 1:1 to receive once-daily BI 764198 or placebo orally, or by nasogastric tube, for up to 28 days. Patients were hospitalised during the duration of treatment (up to 28 days). If a patient was well enough to be discharged from the hospital, treatment was stopped prior to the maximum treatment period of 28 days. Patients were followed up for 90 days from randomisation.
Trial medication was added on to COVID-19 standard of care according to local COVID-19 treatment guidelines at the time of trial conduct.30–32 Patients were excluded if they had received experimental, or off-label usage of, medicinal products for COVID-19.
Outcomes
The primary endpoint was the proportion of patients alive and free of mechanical ventilation at day 29. Secondary endpoints included (1) proportion of patients alive and discharged without supplemental oxygen at day 29; (2) proportion of patients with occurrence of any component of a composite of in-hospital mortality, ICU admission or mechanical ventilation at day 29; (3) time to response, defined as 2-point decrease in score (from randomisation) on the WHO Clinical Progression Scale, discharge from the hospital or being considered fit for discharge (score of 0, 1, 2 or 3 on the Clinical Progression Scale), whichever comes first, by day 29; (4) number of ventilator-free days by day 29; and (5) mortality at days 15, 29, 60 and 90.
Safety and tolerability assessments were based on occurrence of on-treatment (defined as start of drug treatment to 4 days after last drug treatment – the residual effect time) adverse events (AEs), safety laboratory parameters, physical examination, vital sign measurements and 12-lead ECG.
Randomisation, blinding and sample size
Patients were block randomised (block size: 4) in a 1:1 ratio to double-blind treatment and stratified by baseline disease severity (WHO Clinical Progression Score 5 vs 6). The trial sponsor was responsible for arranging the randomisation, packaging and labelling of the trial medication, and the randomisation list was generated using a pseudorandom number generator to ensure reproducibility and non-predictability. Access to the randomisation codes was restricted to keep the investigators, patients, reviewers and any other individuals involved in conducting the trial blinded to the treatment allocation, with the exception of the independent DMC.
The proportion of patients assumed to be alive and free of mechanical ventilation at day 29 in the placebo group was expected to be ~81%. Assuming BI 764198 would increase this proportion by 9%, the probability of observing ≥5% improvement in the primary endpoint would be 72% if 130 patients were randomised (online supplemental table 2).
Further details on exclusion criteria, dosage, clinical, physiology and AE monitoring, statistical analyses and sample size determination are provided in the online supplemental file 1.
Results
Trial population
Patient recruitment opened on 3 November 2020; the first patient was screened and randomised on 12 November 2020, and recruitment ended on 24 February 2021. The trial ended on 31 May 2021.
This trial screened a total of 151 patients; of these, 133 patients were eligible, consented to being involved in the trial and were enrolled (figure 1). Patients were randomised to receive either BI 764198 once daily (n=67) or placebo once daily (n=66). Four patients, two in each treatment group, were not treated due to withdrawal (n=1, BI 764198; n=1, placebo), meeting an exclusion criterion (n=1, BI 764198) or clinical worsening (n=1, placebo). The total number of patients enrolled and included in the full analysis set was 65 in the BI 764198 group and 64 in the placebo group.
Patient flow diagram. *Patients completed visits through end of trial (day 90). qd, once daily.
In the BI 764198 and placebo groups, 52 and 56 patients, respectively, completed the trial. In both groups, the main reason for discontinuation was death (n=11, BI 764198; n=5, placebo). Five patients (two in the BI 764198 group and three in the placebo group) missed one dose of treatment and an additional patient in the BI 764198 group missed two consecutive doses. Although the trial completed enrolment, based on advice from the DMC (following their periodic review of unblinded safety and efficacy data), treatment was discontinued early for patients receiving ongoing treatment when the trial was terminated by the DMC. This included nine patients in the BI 764198 group and seven in the placebo group. Further details are provided in the DMC section.
Patient baseline characteristics are shown in table 1. Overall, baseline characteristics, medical history and standard of care received were well balanced between treatment groups. The majority of patients were white (77.5%) and over half were from North America. Diabetes was the most common comorbidity (31.8%), followed by chronic cardiac disease (10.9%) and asthma (8.5%). About 91% of patients were prescribed corticosteroid treatment for COVID-19. Specifically, 76% were prescribed dexamethasone. Remdesivir and tocilizumab were used in 44% and 3% of patients, respectively.
Demographics and clinical characteristics at baseline
Efficacy
There was no statistically significant difference in the proportion of patients alive and free of mechanical ventilation at day 29 (figure 2A) between active and placebo treatment arms (83.1% vs 87.5%; estimated risk difference –5.39%; 95% CI –16.08 to 5.30; p=0.323). This result was consistent across a number of sensitivity analyses (online supplemental figure 1) and subgroup analyses based on WHO Clinical Progression Scale score at baseline (5 vs 6; p value for interaction 0.942) and time from first symptom onset to first drug intake (<7 days vs ≥7 days; p value for interaction 0.169) (online supplemental figure 2). Of the patients receiving corticosteroids as standard of care (BI 764198: n=58; placebo: n=59), 47 patients in the BI 764198 group (81.0%) and 51 patients in the placebo group (86.4%) met the primary endpoint.
Key efficacy results for patients treated with BI 764198 versus placebo. The following endpoints are presented: (A) patients alive and free of mechanical ventilation and patients alive and discharged free of oxygen free of oxygen; (B) patients with occurrence of any component of a composite of in-hospital mortality, ICU admission or mechanical ventilation; (C) clinical improvement or recovery; (D) duration of mechanical ventilation, ICU stay and hospitalisation; (E) and ventilator-free days. *Sensitivity analyses support these data. †The logistic regression model includes treatment, severity grade at baseline, age, creatinine at baseline and duration of symptoms before hospitalisation as covariates. ‡Covariates in the Cox model are treatment, severity grade at baseline, age, creatinine at baseline and duration of symptoms before hospitalisation; first response of clinical improvement or recovery defined as a 2-point decrease in score (from randomisation) on the WHO Clinical Progression Scale, discharge from the hospital, or considered fit for discharge (scores of 0, 1, 2 or 3), whichever comes first, by day 29. §Patients analysed using analysis of covariance with fixed effects of treatment, severity grade at baseline, age, creatinine at baseline and duration of symptoms before hospitalisation as covariates. ICU, intensive care unit.
No statistically significant difference was observed either in the proportion of patients alive and discharged free of oxygen (75.4% vs 82.8%; estimated risk difference –9.86; 95% CI −22.54 to 2.82; p=0.127) (figure 2A) or the proportion of patients with occurrence of any one of: hospital mortality, ICU admission or mechanical ventilation at day 29 (26.2% vs 23.4%; estimated risk difference 2.66; 95% CI –10.11 to 15.43; p=0.683) (figure 2B).
Patients treated with active treatment had a longer time to recovery than patients treated with placebo (rate ratio 0.67; 95% CI 0.46 to 0.99; p=0.045) (figure 2C and online supplemental figure 3).
Treatment with BI 764198 versus placebo increased the duration of hospitalisation by 3.4±1.5 days (95% CI 0.49 to 6.34; p=0.023) (figure 2D) and increased the duration of oxygen use up to day 29 after treatment start by 3.4±1.7 days (95% CI 0.13 to 6.76; p=0.042) (online supplemental table 3). There were numeric but not significant differences in the duration of mechanical ventilation and stay in an ICU at day 29 (figure 2D). The difference in number of ventilator-free days by day 29 was also not significantly different between treatment groups (figure 2E).
By days 15, 29, 60 and 90, the number of deaths was numerically higher in patients treated with BI 764198 compared with placebo (day 29: BI 764198: n=8; placebo: n=5) (table 2). All 16 patients who died during the study period were receiving corticosteroids as standard of care.
Mortality by days 15, 29, 60 and 90
Safety
The frequency of patients with any AE was similar between the two treatment groups (46.2% in the BI 764198 group vs 54.7% in the placebo group) (table 3).
Adverse events
The frequency of patients with serious AEs—with the exception of fatal events—was also similar between treatment arms (23.1% in the BI 764198 group vs 25.0% in the placebo group) (table 3). The most common on-treatment AEs were respiratory, thoracic and mediastinal disorders (22.5%), metabolism and nutrition disorders (17.8%) and gastrointestinal disorders (15.5%).
In total, there were 16 deaths due to fatal AEs during the trial (11 in the BI 764198 group vs five in the placebo group). Infections (six in the BI 764198 group vs two in the placebo group), as well as respiratory, thoracic and mediastinal disorders (four in the BI 764198 group vs three in the placebo group), were the most common fatal AEs. With regard to fatal AEs, there were nine patients with onset of AEs leading to death during the treatment period (seven in the BI 764198 group vs two in the placebo group) (table 3). After treatment, there were eight patients with an onset of AEs leading to death (five in the BI 764198 group vs three in the placebo group) (table 3). One patient had fatal AEs with an onset during treatment and after treatment (table 4).
On-treatment and post-treatment serious AEs with a fatal outcome
Cause of death and clinical characteristics are shown in online supplemental table 4. Fatal events were typically directly related to the deterioration of COVID-19 culminating in respiratory failure.
DMC
Based on the DMC’s fourth unblinded snapshot data review (inclusive of 101 patients with eight fatal events), a recommendation was made to the sponsor to stop enrolment, discontinue administration of trial drug and continue blinded evaluation of patients already enrolled in the trial.
Following this recommendation, the sponsor advised that the trial sites immediately implement the DMC recommendations as a result of the lack of efficacy (with regard to primary and secondary endpoints) and numerical imbalance of fatal events (although not statistically significant) between the active treatment and placebo groups. As there was a lag time from the fourth data snapshot being captured to review of data by the DMC, an additional five patients were randomised and treated after the fourth data snapshot (22 February 2021). At the time the recommendation was implemented, treatment had not been completed in all patients and was discontinued in those receiving ongoing treatment and in the additional five patients randomised/treated on or after 22 February 2021 (nine patients in the BI 764198 group and seven in the placebo group were discontinued due to the sponsor’s decision). Further details of the treatment status of patients at the time of study discontinuation are provided in online supplemental table 5.
Discussion
This phase II proof-of-concept clinical trial investigated the efficacy and safety of a TRPC6 inhibitor aimed at reducing the risk and/or severity of ARDS associated with severe COVID-19.
The trial did not meet any of its primary or secondary endpoints, and the TRPC6 inhibitor (BI 764198) did not reduce the risk or severity of ARDS associated with severe COVID-19. In general, patients had a trend towards worse outcomes with active therapy. At day 29, no statistically significant difference was observed in the proportion of patients alive and free of mechanical ventilation, alive and discharged free of oxygen, or with any one of a composite of in-hospital mortality, ICU admission or mechanical ventilation. Compared with BI 764198, more patients in the placebo group achieved clinical improvement or recovery. In addition, for patients treated with BI 764198 versus placebo, both the duration of hospitalisation and the duration of oxygen use were longer by an average of approximately 3 days.
In terms of safety, the number of patients with on-treatment AEs and serious AEs were similar in both treatment arms; however, more patients treated with BI 764198 had fatal AEs compared with placebo. The safety monitoring of the trial worked as planned, with close monitoring by the DMC resulting in an immediate early stop in enrolment and treatment of patients when signals pointed towards potential worsening under treatment.
Although this trial did not meet its primary or secondary endpoints, it was initiated on the basis of strong scientific rationale. The therapeutic premise for this study in terms of TRP channel involvement in acute lung injury and potentially COVID-19 has been previously postulated.33 34 Inhibition of TRPC6 has been studied in detail as a potential mechanism to reduce pulmonary oedema25 35 36 and was supported by preclinical findings of TRPC6 inhibition in mouse models of lung injury wherein TRPC6 inhibition led to marked reduction in alveolar leakage, endothelial cellular damage and apoptosis (data not shown). Additionally, in phase I studies, BI 764198 was well tolerated by healthy adults (data on file). This is not the first time that strong evidence for reduction in inflammation and oedema from preclinical models has not been replicated in the clinic. There was preclinical evidence that the bradykinin inhibitor BI 1026706 reduced lung inflammation.37–39 However, clinical studies went on to show numerical signs of increased inflammation or oedema in chronic obstructive pulmonary disease and a human pulmonary endotoxin challenge model in early exploratory studies.40 41
The trial was designed in response to an unprecedented unmet need to find a safe and effective treatment to reduce the risk and severity of ARDS in patients hospitalised for severe COVID-19. In patients hospitalised with COVID-19, up to 42% are reported to develop ARDS.3 At the time of the trial, there were no validated and effective treatments recommended for the management of ARDS in patients with COVID-19.42–44 Treatments shown to be effective in patients hospitalised for COVID-19 included immune modulators, namely, corticosteroids (eg, dexamethasone) and anti-inflammatories (eg, tocilizumab).45 Good clinical management, adequate ventilatory support and the use of systemic corticosteroids were considered the most effective methods to reduce mortality and duration of hospitalisation at the time this trial was conducted.43 As of September 2022, the National Institutes of Health (NIH) COVID-19 Treatment Guidelines46 recommend the use of dexamethasone plus the antiviral remdesivir for most patients that are hospitalised and require oxygen supplementation, replacing antivirals with anti-inflammatory antibody-based treatment as oxygen supplementation needs become more invasive with disease progression. This phase II proof-of-concept study was initiated in November 2020 and was terminated in February 2021, before the NIH recommendations. Even then, only a small fraction of patients (~10%) did not receive corticosteroids.
The scope of this trial was exploratory in nature, and it was conducted in a relatively small number of participants. The main objective was to assess if TRPC6 inhibition, based on promising preclinical findings, could improve outcomes in patients aged ≥50 years, hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen at the time of trial inclusion. The clear lack of benefit with BI 764198 treatment relative to placebo in this patient population cannot be fully explained given the supportive preclinical data. The patient numbers were relatively small, with only 106 patients completing the trial. However, it is not expected that a larger or longer duration trial would have demonstrated a different outcome given the relative consistency of results towards worsening of outcome.
The time point of administration of treatment and the disease severity of the patients recruited (including their inflammatory status) could have resulted in the lack of efficacy observed with BI 764198. COVID-19 infection may be broadly considered in terms of two stages: the first, early stage, in which viral load plays the major role and antiviral therapies are generally effective; and the second, later stage, dominated by the immune response (in particular, the hyperinflammatory response) and for which dexamethasone is the current standard of care.2 Particularly for this latter stage, the time point of administration of anti-inflammatory therapies is critical.2 In this trial, patients were recruited later on in the disease course (WHO Clinical Scale 5 and 6 at the time of screening), at which point they were already hypoxaemic and likely to have had damage to their lung endothelial barrier. Therefore, it may have been too late for BI 764198 to be effective. Earlier intervention might have been more effective but would be challenging to study, particularly given the outcome of the current trial.
Another potential variable was the standard of care patients received. In terms of concomitant treatments permitted during the trial, medications prescribed to patients were consistent with the Infectious Diseases Society of America-recommended guidelines for standard of care30 and over 90% of patients were receiving corticosteroids at baseline. However, concomitant medications were generally well balanced, with the exception that more patients in the BI 764198 arm received anti-IL-6 blockade than in the placebo arm (4 vs 0, respectively). All four patients were receiving tocilizumab; emergency use authorisation had not yet been granted when the trial was conducted, thus accounting for the low number of patients on this treatment.47 All four patients were alive and free of mechanical ventilation at day 29.
A limitation of the trial was the fact that only a single dose of active treatment was investigated; therefore, the evaluation of a dose range was not feasible in the context of this accelerated development.
Patients who had been enrolled in vaccine studies were excluded from this trial as their course of disease was expected to be modified based on vaccination, a finding now scientifically well established. As patient enrolment began before COVID-19 vaccinations were approved or widely used in the study countries, none of the patients in this trial were vaccinated for COVID-19 on a post-release basis.
In conclusion, this is the first time that inhibition of TRPC6 has been evaluated as a potential treatment modality with an aim to reduce the risk and/or severity of ARDS secondary to COVID-19 requiring hospitalisation and receiving non-invasive, supplemental oxygen. Despite promising preclinical data and a sound mechanistic treatment rationale, BI 764198 did not improve outcomes in patients hospitalised for COVID-19 and prolonged the duration of hospitalisation and recovery.
Data availability statement
Data are available upon reasonable request. To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.
Ethics statements
Patient consent for publication
Ethics approval
This has been uploaded as a supplemental file named "TRPC6i in COVID-19 IRB approval list". Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors would like to acknowledge Professor Roy Brower (Johns Hopkins Hospital, Baltimore, Maryland, USA) for his contributions towards the trial design; sponsor representatives Dr Ulrich Bothner and Dr Veronika Kohlbrenner for their roles in ensuring patient safety and pharmacovigilance; and sponsor representative Dr Thierry Bouyssou for the generation of supportive preclinical data. The oversight of the trial by the independent DMC (Dr Anne Elizabeth O'Donnell, Dr Scott S. Emerson, Dr Edward S. Schulman and Dr Karl Gallegos) is greatly appreciated. We sincerely thank all trial research centres and investigators (online supplemental table 1) for their dedicated work in this trial. A special recognition goes to all patients and their families for their invaluable time and participation which made the conduct of this trial possible. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for the development of the manuscript. Shivani Singh, PhD, of Meditech Media, provided writing assistance, which was contracted and funded by Boehringer Ingelheim. Boehringer Ingelheim were given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The study was supported and funded by Boehringer Ingelheim.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Correction notice This article has been corrected since it was published Online First. An author name has been amended.
Contributors Conception and design: LW, NS, DFM, RK, WC, AG and TW. Acquisition of data/design of data acquisition platform: LW, NS, VE, GAD, PL, RK, WC and AG. Principal investigators at study sites: VE, GAD and PL. Statistical analysis: NS, RK, WC and AG. Data interpretation, edited and reviewed the manuscript, and approved the final version of the manuscript: LW, NS, DFM, VE, GAD, PL, RK, WC, AG and TW. LW accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding This work was supported by Boehringer Ingelheim International GmbH.
Competing interests LW reports receipt of research support from Boehringer Ingelheim, Genentech and CSL Behring and consulting fees from Merck, Citius, Foresee and Quark. NS, WC and AG are employees of Boehringer Ingelheim. DFM reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim, Bayer, Novartis, SOBI and Eli Lilly, and from sitting on Data Monitoring and Ethics Committees for trials undertaken by Vir Biotechnology and Faron Pharmaceuticals. DFM’s institution has received funds from grants from the NIHR Wellcome Trust, MRC, Innovate UK and NIHSC R&D, and others for studies in patients with ARDS and COVID-19; he also has a patent (US8962032) issued to his institution for a treatment for inflammatory disease. DFM is the MRC/NIHR EME Programme Director; DFM’s spouse is joint Editor-in-Chief for Thorax. VE reports clinical trial support and consulting fees from Gilead. GAD reports receipt of clinical trial research support from Boehringer Ingelheim, Edesa Biotech, Gilead Sciences, Regeneron and Roche, and scientific advisory board membership for Safeology.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.