Summary of COVID-19 TMPRSS2 inhibitor studies

50 patient bromhexine prophylaxis RCT: 91% fewer symptomatic cases (p=0.05) and 71% fewer cases (p=0.14).
Small prophylaxis RCT with 25 treatment and 25 control health care workers, showing lower PCR+, symptomatic cases, and hospitalization with treatment, although not statistically significant with the small sample size.
Mar 2021, Interdisciplinary Perspectives on Infectious Diseases, https://www.hindawi.com/journals/ipid/2022/4693121/, https://c19p.org/mikhaylov

2. Karolyi et al., Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19—Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT)

201 patient camostat late treatment RCT: 72% lower mortality (p=0.1), 70% lower ventilation (p=0.02), 60% lower combined mortality/intubation (p=0.04), and 18% faster recovery (p=0.005).
RCT 201 hospitalized COVID-19 patients showing faster clinical improvement, less progression to mechanical ventilation or death, and shorter hospital stay with camostat mesylate compared to lopinavir/ritonavir. There was also a trend towards lower 29-day mortality with camostat. Authors note that the lopinavir/ritonavir dose likely did not reach effective levels, so it may be considered similar to a placebo group.
Jul 2022, Frontiers in Pharmacology, https://www.frontiersin.org/articles/10.3389/fphar.2022.870493/full, https://c19p.org/karolyi

3. Vila Méndez et al., Efficacy of Bromhexine versus Standard of Care in Reducing Viral Load in Patients with Mild-to-Moderate COVID-19 Disease Attended in Primary Care: A Randomized Open-Label Trial

191 patient bromhexine early treatment RCT: 67% lower hospitalization (p=0.49) and 7% worse viral clearance (p=0.82).
RCT 191 low risk (no mortality) outpatients in Spain, showing no significant differences with bromhexine. Authors note that "statistical differences between the study groups were observed in the percentage of patients treated with bronchodilators (p = 0.033) and receiving symptomatic treatment (p = 0.034), which were higher in the SOC alone group", but do not provide details or perform adjustments. There were more moderate/severe cases in the treatment group (9 vs. 5). Many results appear to be missing including: reduction in the severity of each symptom (0–10 NRS score) at days 4, 7, 14, and 28 as compared with baseline; proportion of patients with clinical improvement and time to clinical improvement; proportion of patients with disappearance of each symptom at days 4, 7, 14, and 28, and time to disappearance; proportion of asymptomatic patients at days 4, 7, 14, and 28. Bromhexine 48 mg/day for seven days. SOC included acetaminophen.
Dec 2022, J. Clinical Medicine, https://www.mdpi.com/2077-0383/12/1/142, https://c19p.org/vilamendez

4. Zhuravel et al., Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial

102 patient nafamostat late treatment RCT: 76% lower mortality (p=0.2), 42% greater improvement (p=0.28), and 42% improved recovery (p=0.28).
RCT 104 hospitalized patients with moderate to severe COVID-19 pneumonia showing no significant difference in the primary endpoint of time to clinical improvement with nafamostat. However, in patients with baseline National Early Warning Score (NEWS) ≥7, nafamostat treatment significantly shortened time to clinical improvement and recovery. Patients in the nafamostat group with NEWS ≥7 also had higher recovery rates and significantly reduced NEWS scores by day 11.
Nov 2021, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537021004491, https://c19p.org/zhuravel

5. Ansarin et al., Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial

78 patient bromhexine early treatment RCT: 91% lower mortality (p=0.05), 89% lower ventilation (p=0.01), and 82% lower ICU admission (p=0.01).
RCT with 39 bromhexine and 39 control patients showing lower mortality, intubation, and ICU admission with treatment. The treatment group received bromhexine hydrochloride 8 mg three times a day for two weeks. All patients received SOC including HCQ.
Jul 2020, Bioimpacts, https://bi.tbzmed.ac.ir/Article/bi-23240, https://c19p.org/ansarin

6. Okugawa et al., Antiviral effect and safety of nafamostat mesilate in patients with mild early-onset COVID-19: An exploratory multicentre randomized controlled clinical trial

29 patient nafamostat early treatment RCT: 33% improved viral clearance (p=0.007).
RCT 30 early-onset COVID-19 patients showing significantly improved viral load reduction with nafamostat.
Sep 2023, Int. J. Antimicrobial Agents, https://www.sciencedirect.com/science/article/pii/S0924857923002017, https://c19p.org/okugawa

7. Morpeth et al., A Randomized Trial of Nafamostat for Covid-19

155 patient nafamostat late treatment RCT: 55% lower ventilation (p=0.23), 57% lower progression (p=0.14), and 28% improved recovery (p=0.36).
RCT 160 hospitalized non-critically ill COVID-19 patients showing a 93% posterior probability that nafamostat reduced the odds of death or receipt of ventilatory or vasopressor support by day 28 compared to usual care. Nafamostat, a TMPRSS2 inhibitor with potent in vitro antiviral activity against SARS-CoV-2, was administered as a continuous intravenous infusion for up to 7 days. The trial was conducted across 21 hospitals in Australia, New Zealand, and Nepal. Despite promising results, the trial was stopped early due to slowing recruitment, low event rates, and funding constraints, limiting definitive conclusions. Authors note that the posterior probability of effectiveness was higher among those with earlier disease onset, but lower during the Omicron era when variants were less dependent on the TMPRSS2 pathway.
Oct 2023, NEJM Evidence, https://evidence.nejm.org/doi/10.1056/EVIDoa2300132, https://c19p.org/morpeth

8. Seccia et al., RAndomized Clinical Trial Of NAfamostat Mesylate, A Potent Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor, in Patients with COVID-19 Pneumonia

14 patient nafamostat late treatment RCT: 67% lower mortality (p=1) and 20% improved recovery (p=1).
RCT 15 hospitalized COVID-19 patients showing a positive safety profile with nafamostat mesylate treatment. While the study was underpowered to detect differences in efficacy, Bayesian analysis suggested a signal for potential benefit (69-88% probability that nafamostat is effective depending on prior assumptions). Authors note that nafamostat, as a potent TMPRSS2 inhibitor with anticoagulant properties, could theoretically prevent virus entry into cells and complications like disseminated intravascular coagulation in COVID-19 patients. The study was significantly limited by small sample size due to recruitment challenges.
Oct 2023, J. Clinical Medicine, https://www.mdpi.com/2077-0383/12/20/6618, https://c19p.org/seccia

9. Li et al., Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID-19: An Open-Label Randomized Controlled Pilot Study

18 patient bromhexine late treatment RCT: 75% higher hospital discharge (p=0.11) and 3% slower recovery.
Tiny RCT with 12 bromhexine and 6 control patients showing non-statistically significant improvements in chest CT, need for oxygen therapy, and discharge rate within 20 days. Authors recommend a larger scale trial.
Sep 2020, Clinical and Translational Science, https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12881, https://c19p.org/li5

10. Terada et al., Favipiravir, camostat, and ciclesonide combination therapy in patients with moderate COVID-19 pneumonia with/without oxygen therapy: An open-label, single-center phase 3 randomized clinical trial

117 patient camostat late treatment RCT: 8% lower progression (p=1) and 40% higher hospital discharge (p=0.04).
RCT 117 hospitalized patients with moderate COVID-19 pneumonia in Japan, showing a shorter time to discharge with favipiravir, camostat, and ciclesonide combination therapy compared to favipiravir monotherapy. Subgroup analysis showed greater benefit in patients ≤60 years old and those with less severe disease not requiring oxygen. There were no significant differences between groups in clinical findings, laboratory values, or adverse events. The mortality numbers in the main results table and the text are different, without explanation.
Jun 2022, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537022002140, https://c19p.org/terada

11. Kinoshita et al., A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study)

155 patient camostat early treatment RCT: 67% lower progression (p=1), 50% lower need for oxygen therapy (p=0.37), 1% worse recovery (p=1), and 1% worse viral clearance (p=0.97).
RCT 155 hospitalized patients showing no significant differences with camostat.
Sep 2022, BMC Medicine, https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02518-7, https://c19p.org/kinoshita

12. Sakr et al., Camostat mesylate therapy in critically ill patients with COVID-19 pneumonia

122 patient camostat late treatment PSM study: 69% lower mortality (p=0.001), 10% lower ventilation (p=1), and 17% longer hospitalization (p=0.35).
Retrospective 371 critically ill COVID-19 patients showing lower mortality with camostat mesylate treatment.
Apr 2021, Intensive Care Medicine, https://link.springer.com/10.1007/s00134-021-06395-1, https://c19p.org/sakr

13. Gunst et al., Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial

205 patient camostat late treatment RCT: 18% lower mortality (p=0.75), 31% lower ventilation (p=0.65), 20% lower ICU admission (p=0.61), and 15% improved recovery (p=0.28).
RCT 205 hospitalized patients showing no significant benefit with camostat. There was a trend towards lower risk of ICU admission or death in the camostat group (10% vs. 18% for placebo), but the study was not powered for this endpoint. Viral load and inflammatory markers were not significantly different between groups. The study was underpowered due to faster than expected clinical improvement.
May 2021, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537021001292, https://c19p.org/gunst

14. Tolouian et al., Bromhexine, for Post Exposure COVID-19 Prophylaxis: A Randomized, Double-Blind, Placebo Control Trial

372 patient bromhexine prophylaxis RCT: 70% lower hospitalization (p=0.15), 53% fewer symptomatic cases (p=0.007), and 50% fewer cases (p=0.03).
PEP RCT with 372 close contacts of COVID+ patients, 187 treated with bromhexine, showing significantly lower cases with treatment. IRCT20120703010178N22.
Dec 2021, SSRN, https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3989849, https://c19p.org/tolouian2

15. Mareev et al., Results of Open-Label non-Randomized Comparative Clinical Trial: “BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)

66 patient bromhexine late treatment RCT: 11% improved recovery (p=0.47), 8% shorter hospitalization (p=0.35), and 87% improved viral clearance (p=0.08).
Prospective 103 PCR+ patients in Russia, 33 treated with bromexhine+spironolactone, showing lower PCR+ at day 10 or hospitalization >10 days with treatment. Bromhexine 8mg 4 times daily, spironolactone 25-50 mg/day for 10 days.
Dec 2020, Кардиология, https://lib.ossn.ru/jour/article/view/1440, https://c19p.org/mareev

16. Tare et al., The DAWN antivirals trial: process evaluation of a COVID-19 trial in general practice

36 patient camostat early treatment RCT: 33% improved recovery (p=0.7).
Small early terminated RCT showing better recovery with camostat treatment, without statistical significance.
Nov 2023, BJGP Open, http://bjgpopen.org/lookup/doi/10.3399/BJGPO.2023.0109, https://c19p.org/tarecm

17. Tolouian et al., Effect of bromhexine in hospitalized patients with COVID-19

100 patient bromhexine late treatment RCT: 76% lower mortality (p=0.43), 76% greater improvement (p=0.43), and 75% worse viral clearance (p=0.02).
Small RCT with 100 patients, 48 with bromhexine added to SOC, showing slower viral- conversion but lower mortality and greater clinical improvement with bromhexine (not statistically significant with few deaths and very high recovery). The very large difference between unadjusted and adjusted results is due to much higher risk for patients with renal disease and the much higher prevalence of renal disease in the bromhexine group. The study also shows 90% of patients in the control group had BMI>=30 compared to 0% in the treatment group, suggesting a possible problem with randomization. Due to the imbalance between groups, results were adjusted for BMI>30, smoking, and renal disease. 11 patients were lost to followup in the treatment group compared to zero in the control group, perhaps in part due to faster recovery in the treatment group. 9 patients were excluded from the treatment group because they did not want to take bromhexine after discharge. Therefore up to 29% of treatment..
Mar 2021, J. Investig. Med., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970656/, https://c19p.org/tolouian

18. Bryce et al., RECOVER: Phase 2 Randomized, Double-Blind Trial TREating Hospitalized Patients With COVID-19 With Camostat MesilatE, a TMPRSS2 Inhibitor

100 patient camostat late treatment RCT: 25% lower mortality (p=1).
RCT 100 patients showing no significant difference with camostat. Results are currently unclear - different mortality numbers were provided for all-cause mortality and mortality rate (2/50 vs. 3/46 for the treatment group at 28 days, with the 28 day all-cause mortality result removed in an updated submission). The main outcome measures appear to be different due to only including patients that submitted day 28 outcome data.
Mar 2024, NCT04470544, https://clinicaltrials.gov/study/NCT04470544, https://c19p.org/bryce

19. Chupp et al., A Phase 2 Randomized, Double-Blind, Placebo-controlled Trial of Oral Camostat Mesylate for Early Treatment of COVID-19 Outpatients Showed Shorter Illness Course and Attenuation of Loss of Smell and Taste

70 patient camostat early treatment RCT: 37% improved recovery (p=0.15).
RCT 70 outpatients showing significantly lower symptom scores at day 6, faster recovery, and improved taste/smell, and fatigue with camostat treatment. There was no significant difference for viral load. The recovery result is from [bmcinfectdis.biomedcentral.com].
Jan 2022, medRxiv, https://www.medrxiv.org/content/10.1101/2022.01.28.22270035, https://c19p.org/chupp

20. Soma et al., Nafamostat Mesylate Monotherapy in Patients with Moderate COVID-19: a Single-Center, Retrospective Study

64 patient nafamostat late treatment study: 80% lower mortality (p=0.49) and 6% higher severe cases (p=1).
Retrospective 64 hospitalized patients with moderate COVID-19 showing no significant difference in clinical outcomes with nafamostat mesylate.
Sep 2022, Japanese J. Infectious Diseases, https://www.jstage.jst.go.jp/article/yoken/75/5/75_JJID.2021.699/_article, https://c19p.org/soma

21. Dhaliwal et al., A Randomised Phase II Trial in Early COVID-19, Assessing Use of Camostat by Blocking SARS-CoV-2 Spike Protein-initiated Membrane Fusion

34 patient camostat early treatment RCT: 14% lower hospitalization (p=1).
Early terminated RCT with 34 patients showing no significant differences with camostat treatment.
Mar 2022, NCT04455815, https://clinicaltrials.gov/study/NCT04455815, https://c19p.org/dhaliwal

22. Kim et al., A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19

323 patient camostat early treatment RCT: 8% faster recovery (p=0.54).
Double-blind RCT with 342 mild to moderate COVID-19 outpatients in South Korea, showing no significant difference in time to clinical improvement with camostat mesylate. In a post-hoc subgroup analysis of high-risk patients, there were non-statistically significant trends towards faster improvement in ordinal scale scores and subjective symptom scores at day 7 with treatment. Viral cultures suggested faster viral clearance with treatment, without statistical significance.
Jan 2023, Antimicrobial Agents and Chemotherapy, https://journals.asm.org/doi/10.1128/aac.00452-22, https://c19p.org/kim19

23. Quinn et al., Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics

42 patient nafamostat late treatment RCT: 48% longer hospitalization (p=0.21).
RCT 42 hospitalized patients with COVID-19 pneumonitis showing no benefit with intravenous nafamostat mesylate.
Feb 2022, eBioMedicine, https://www.sciencedirect.com/science/article/pii/S2352396422000408, https://c19p.org/quinn

24. Parsonnet et al., A Phase 2 Randomized, Double Blinded, Placebo Controlled Study of Oral Camostat Mesilate Compared to Standard of Care in Subjects With Mild-Moderate COVID-19

49 patient camostat early treatment RCT: 35% improved recovery (p=0.24), 86% improvement (p=0.11), and 41% improved viral clearance (p=0.24).
RCT 49 outpatients in the USA, showing no significant differences with camostat treatment.
May 2021, NCT04524663, https://clinicaltrials.gov/study/NCT04524663, https://c19p.org/parsonnet

25. Inokuchi et al., Association between Nafamostat Mesylate and In-Hospital Mortality in Patients with Coronavirus Disease 2019: A Multicenter Observational Study

15,859 patient nafamostat late treatment study: 27% higher mortality (p=0.52).
Retrospective multicenter observational study of 15,859 hospitalized COVID-19 patients in Japan showing no significant difference in in-hospital mortality with nafamostat mesylate. Very few patients received treatment and they had more severe disease on average. There may be significant residual confounding by indication.
Dec 2021, J. Clinical Medicine, https://www.mdpi.com/2077-0383/11/1/116, https://c19p.org/inokuchi2

26. Huh et al., Association of prescribed medications with the risk of COVID-19 infection and severity among adults in South Korea

44,046 patient camostat prophylaxis study: 14% more cases (p=0.84).
Retrospective database analysis showing no significant differences with camostat use.
Dec 2020, Int. J. Infectious Diseases, https://www.sciencedirect.com/science/article/pii/S1201971220325650, https://c19p.org/huh2cm

27. Tobback et al., Efficacy and safety of camostat mesylate in early COVID-19 disease in an ambulatory setting: a randomized placebo-controlled phase II trial

96 patient camostat early treatment RCT: 36% higher hospitalization (p=1) and 8% improved recovery (p=0.84).
RCT 90 outpatients showing no significant difference in viral load or time to clinical improvement with camostat mesylate. The trial was discontinued early and did not reach the intended sample size. Authors note that combining camostat with a cathepsin inhibitor may improve efficacy.
Sep 2022, Int. J. Infectious Diseases, https://www.sciencedirect.com/science/article/pii/S1201971222003885, https://c19p.org/tobback

28. Sagent Pharmaceuticals et al., A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Efficacy of Camostat Mesilate for Treatment of COVID-19 in Outpatients

295 patient camostat early treatment RCT: 152% higher mortality (p=1), 13% lower progression (p=0.79), and 16% improved viral clearance (p=0.36).
RCT 295 outpatients in the USA, showing no significant differences with camostat.
Mar 2021, Sagent Pharmaceuticals, NCT04583592, https://clinicaltrials.gov/study/NCT04583592, https://c19p.org/sagent

29. Jilg et al., One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019 (COVID-19): A Randomized Controlled Phase 2 Trial

216 patient camostat late treatment RCT: 198% higher mortality (p=1), 18% higher hospitalization (p=1), and no change in recovery (p=0.99).
RCT 216 patients, 55% >5 days from symptom onset, showing no significant difference with camostat treatment.
Jun 2023, Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad342/7190261, https://c19p.org/jilg

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