TRPC6 inhibitor (BI 764198) to reduce risk and severity of ARDS due to COVID-19: a phase II randomised controlled trial

Ware et al., Thorax, doi:10.1136/thorax-2022-219668, NCT04604184, Apr 2023

https://c19early.org/ware2.html

RCT 129 hospitalized COVID-19 patients requiring non-invasive oxygen support showing no benefit and potential harm with BI 764198 (TRPC6 inhibitor). The study was terminated early due to lack of efficacy and an imbalance of fatal events (11 deaths vs 5 deaths in placebo group). Patients receiving BI 764198 had longer hospitalizations (+3.4 days), longer time to recovery, and longer oxygen use duration compared to placebo.

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risk of death, 116.6% higher, RR 2.17, p = 0.18, treatment 11 of 65 (16.9%), control 5 of 64 (7.8%), day 90.

risk of death, 96.9% higher, RR 1.97, p = 0.27, treatment 10 of 65 (15.4%), control 5 of 64 (7.8%), day 60.

risk of death, 57.5% higher, RR 1.58, p = 0.56, treatment 8 of 65 (12.3%), control 5 of 64 (7.8%), day 29.

risk of death, 293.8% higher, RR 3.94, p = 0.37, treatment 4 of 65 (6.2%), control 1 of 64 (1.6%), day 15.

risk of progression, 11.6% higher, RR 1.12, p = 0.84, treatment 17 of 65 (26.2%), control 15 of 64 (23.4%), death, ICU admission, or mechanical ventilation, day 29.

risk of no recovery, 42.2% higher, RR 1.42, p = 0.48, treatment 13 of 65 (20.0%), control 9 of 64 (14.1%), day 29.

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Ware et al., 6 Apr 2023, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, mean age 63.7, 10 authors, study period 12 November, 2020 - 24 February, 2021, average treatment delay 8.3 days, trial NCT04604184 (history).

This Paper BI 764198 All

TRPC6 inhibitor (BI 764198) to reduce risk and severity of ARDS due to COVID-19: a phase II randomised controlled trial

Dr Lorraine B Ware, Nima Soleymanlou, Danny Francis Mcauley, Vicente Estrada, George A Diaz, Peter Lacamera, Renee Kaste, Wansuk Choi, Abhya Gupta, Tobias Welte

Thorax, doi:10.1136/thorax-2022-219668

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 noninvasive, 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.

Respiratory infection 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. 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. Supplementary Methods Exclusion criteria The exclusion criteria included: pulmonary oedema/respiratory failure due to cardiogenic insult;..

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DOI record: { "DOI": "10.1136/thorax-2022-219668", "ISSN": [ "0040-6376", "1468-3296" ], "URL": "http://dx.doi.org/10.1136/thorax-2022-219668", "abstract": "BackgroundDespite 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).MethodsMulticentre, 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).ResultsNo 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).ConclusionsTRPC6 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 numberNCT04604184.", "accepted": { "date-parts": [ [ 2023, 1, 31 ] ] }, "alternative-id": [ "10.1136/thorax-2022-219668" ], "author": [ { "affiliation": [], "family": "Ware", "given": "Lorraine B", "sequence": "first" }, { "affiliation": [], "family": "Soleymanlou", "given": "Nima", "sequence": "additional" }, { "affiliation": [], "family": "McAuley", "given": "Danny Francis", "sequence": "additional" }, { "affiliation": [], "family": "Estrada", "given": "Vicente", "sequence": "additional" }, { "affiliation": [], "family": "Diaz", "given": "George A", "sequence": "additional" }, { "affiliation": [], "family": "Lacamera", "given": "Peter", "sequence": "additional" }, { "affiliation": [], "family": "Kaste", "given": "Renee", "sequence": "additional" }, { "affiliation": [], "family": "Choi", "given": "Wansuk", "sequence": "additional" }, { "affiliation": [], "family": "Gupta", "given": "Abhya", "sequence": "additional" }, { "affiliation": [], "family": "Welte", "given": "Tobias", "sequence": "additional" } ], "clinical-trial-number": [ { "clinical-trial-number": "nct04604184", "registry": "10.18810/clinical-trials-gov" }, { "clinical-trial-number": "nct03854552", "registry": "10.18810/clinical-trials-gov" }, { "clinical-trial-number": "nct04102462", "registry": "10.18810/clinical-trials-gov" } ], "container-title": "Thorax", "container-title-short": "Thorax", "content-domain": { "crossmark-restriction": true, "domain": [ "bmj.com" ] }, "created": { "date-parts": [ [ 2023, 4, 6 ] ], "date-time": "2023-04-06T15:05:13Z", "timestamp": 1680793513000 }, "deposited": { "date-parts": [ [ 2024, 5, 14 ] ], "date-time": "2024-05-14T03:53:08Z", "timestamp": 1715658788000 }, "funder": [ { "DOI": "10.13039/100001003", "award": [ "N/A" ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/100001003", "id-type": "DOI" } ], "name": "Boehringer Ingelheim" } ], "indexed": { "date-parts": [ [ 2025, 10, 21 ] ], "date-time": "2025-10-21T15:50:13Z", "timestamp": 1761061813516, "version": "3.37.3" }, "is-referenced-by-count": 6, "issue": "8", "issued": { "date-parts": [ [ 2023, 4, 6 ] ] }, "journal-issue": { "issue": "8", "published-online": { "date-parts": [ [ 2023, 7, 13 ] ] }, "published-print": { "date-parts": [ [ 2023, 8 ] ] } }, "language": "en", "license": [ { "URL": "http://creativecommons.org/licenses/by-nc/4.0/", "content-version": "unspecified", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 4, 6 ] ], "date-time": "2023-04-06T00:00:00Z", "timestamp": 1680739200000 } } ], "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1136/thorax-2022-219668", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "239", "original-title": [], "page": "816-824", "prefix": "10.1136", "published": { "date-parts": [ [ 2023, 4, 6 ] ] }, "published-online": { "date-parts": [ [ 2023, 4, 6 ] ] }, "published-print": { "date-parts": [ [ 2023, 8 ] ] }, "publisher": "BMJ", "reference": [ { "DOI": "10.1056/NEJMoa2002032", "doi-asserted-by": "publisher", "key": "2024051320382765000_78.8.816.1" }, { "DOI": "10.1183/16000617.0384-2020", "article-title": "Current evidence for COVID-19 therapies: a systematic literature review", "author": "Welte", "doi-asserted-by": "crossref", "journal-title": "Eur Respir Rev", "key": "2024051320382765000_78.8.816.2", "volume": "30", "year": "2021" }, { "key": "2024051320382765000_78.8.816.3", "unstructured": "Centers for Disease Control and Prevention (CDC) . 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COVID-19 treatment guidelines. Table 2c. Therapeutic management of adults hospitalized for COVID-19 based on disease severity. Available: https://www.covid19treatmentguidelines.nih.gov/tables/management-of-hospitalized-adults-summary [Accessed 4 Nov 2022]." }, { "key": "2024051320382765000_78.8.816.47", "unstructured": "U.S. Food & Drug Administration . Emergency use authorization 099 [press release]. 2021." } ], "reference-count": 49, "references-count": 49, "relation": {}, "resource": { "primary": { "URL": "https://thorax.bmj.com/lookup/doi/10.1136/thorax-2022-219668" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "TRPC6 inhibitor (BI 764198) to reduce risk and severity of ARDS due to COVID-19: a phase II randomised controlled trial", "type": "journal-article", "update-policy": "https://doi.org/10.1136/crossmarkpolicy", "volume": "78" }

Late treatment
is less effective

Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

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