Efficacy of Nafamostat in Covid-19 Patients (RACONA Study)

COVID19 Clinical Trial

— RACONA  

Official title:

RAndomized Clinical Trial in COvid19 Patients to Assess the Efficacy of the Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor NAfamostat (RACONA Study)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04352400
• Other study ID #: RACONA Nafamostat
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: June 4, 2021
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: University Hospital Padova
• Contact: Gian Paolo Rossi, Prof.
• Phone: 0039049821
• Email: gianpaolo.rossi[@]unipd.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RACONA is a prospective trial that will test the hypothesis that nafamostat can lower lung function deterioration and need for intensive care admission in COVID-19 patients.

Design: Adult hospitalized COVID-19 patients will be randomized in a prospective double-blind randomized placebo-controlled study to test the clinical efficacy of nafamostat mesylate (administered intravenously) on top of best standard of care.

Primary outcome measures: the time-to-clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven category ordinal scale or live discharge from the hospital, whichever comes first.

Description:

Purpose: SARS-Cov-2 enters the lung cells by binding to ACE-2 and activating the protease TMPRSS2, which, therefore, can be a target for antiviral treatment. Accordingly, TMPRSS2 inhibitors prevent SARS-CoV cell entry in vitro. The most potent such inhibitors, nafamostat is being used as anticoagulant and anti-pancreatitis agent, and is approved for the treatment of cystic fibrosis as its mucolytic action can prevent lung function deterioration by owering airways infections.

RACONA study will test the hypothesize that nafamostat is useful in COVID-19 lung involvement because COVID-19 entails activation of the coagulation cascade, pulmonary embolism, and bacterial superinfections.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 256
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Hospitalized, COVID-19 positive, between 18 and = 85 years of age;

• Signed Inform Consent Form;

• Body temperature > 37.3 ?;

• Oxygenation criterion (any of the following): i) Oxygen saturation =94% on Room Air; ii) PaO2/FiO2 ratio =300 mmHg but > 100 mmHg, if patient on supplemental oxygen; iii) SpO2/FiO2<200 if no arterial blood gas available;

• Respiratory rate (RR) = 25 beats/min.

Exclusion Criteria:

• Pregnant or lactating females;

• Unwillingness or inability to complete the study.

• Rapidly deteriorating clinical condition or low likelihood to complete the study according to the investigator;

• eGFR < 30 ml/min/m2 assessed with CKD EPI formula;

• Current or chronic history of liver disease (Child Pugh score = 10), or known hepatic or biliary abnormalities;

• Participation in a clinical trial with an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer);

• Patients requiring high doses of loop diuretics (i.e. > 240 mg furosemide daily) with significant intravascular volume depletion, as assessed clinically;

• History of allergy;

• History of sensitivity to heparin or heparin-induced thrombocytopenia;

• Unstable hemodynamics in the preceding 4 hours (SBP < 90 mmHg, and/or vasoactive agents required);

• Hemoglobin < 7 at time of drug infusion. Transfusion is allowed to increase hemoglobin levels before entry into the study;

• Malignancy or any other condition for which estimated 6-month mortality >50%;

• Arterial blood pH less than 7.2;

• Known evidence of chronic interstitial infiltration at imaging;

• Known hospitalization within the past six months for respiratory failure (PaCO2 > 50 mmHg or PaO2 < 55 mmHg, or oxygen saturation <88% on FiO2 = 0.21);

• Known chronic vascular disease resulting in severe exercise restriction (i.e. unable to perform household duties);

• Known secondary polycythemia, severe pulmonary hypertension, or ventilator dependency;

• Known vasculitis with diffuse alveolar hemorrhage;.

• Pre-existing renal failure on hemodialysis or peritoneal dialysis requiring renal replacement therapy;

• Extracorporeal membrane oxygenation (ECMO);

• Immunosuppressive treatment;

• Patient in trials for COVID-19 within 30 days before;

• Unstable hemodynamics in the preceding 4 hours (MAP = 65 mmHg, or SAP < 90 mmHg, DAP < 60 mmHg, and vasoactive agents required);

• Hyperkalemia , i.e. serum K+ levels > 5.0 mEq/L;

• Severe active bleeding;

• Any other uncontrolled comorbidities that increase the risks associated with the study drug administration, as assessed by the medical expert team.

Related Conditions & MeSH terms

• COVID-19
• COVID19

Intervention

Drug:
• Nafamostat Mesilate
administered intravenously as a continuous infusion
• Placebo
administered intravenously as a continuous infusion

Locations

Country	Name	City	State
Italy	Azienda Ospedale Università di Padova	Padova

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital Padova	University of Zurich, Yokohama City University

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L — View Citation

Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001 Oct 10;286(14):1754-8. doi: 10.1001/jama.286.14.1754. — View Citation

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibi — View Citation

Minakata D, Fujiwara SI, Ikeda T, Kawaguchi SI, Toda Y, Ito S, Ochi SI, Nagayama T, Mashima K, Umino K, Nakano H, Yamasaki R, Morita K, Kawasaki Y, Sugimoto M, Yamamoto C, Ashizawa M, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Ohmori T, Kanda Y. Compariso — View Citation

Yamamoto M, Matsuyama S, Li X, Takeda M, Kawaguchi Y, Inoue JI, Matsuda Z. Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion — View Citation

Yu G, Li S, Wan R, Wang X, Hu G. Nafamostat mesilate for prevention of post-ERCP pancreatitis: a meta-analysis of prospective, randomized, controlled trials. Pancreas. 2015 May;44(4):561-9. doi: 10.1097/MPA.0000000000000310. — View Citation

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time-to-clinical improvement	Time-to-clinical improvement (time from randomization to an improvement of two points (from the status at randomization) on a 7 category ordinal scale or live discharge from the hospital, whichever came first.	day 1 until day 28
Secondary	Responders	Rate of patients showing improvement of 2 points in 7 category ordinal scale (with 7 points the worst)(PubMed ID: 32187464)	day 1 until day 28
Secondary	Critical or dead patients	Proportion of patients who will progress to critical illness/death	day 1 until day 28
Secondary	pO2/FiO2 ratio	Change in pO2/FiO2 ratio over time	day 1 until day 28
Secondary	SOFA score over time	Change Sequential organ failure assessment score (SOFA score) over time. The Score ranges from 0 to 24 (with 24 the worst)(PubMed ID: 11594901)	day 1 until day 28
Secondary	Hospitalization	Duration of hospitalization in survivors (days)	day 1 until day 28
Secondary	Mechanical ventilation	Number of patients who require ventilation	day 1 until day 28
Secondary	Mechanical ventilation duration	Duration of ventilation (days)	day 1 until day 28
Secondary	Cardiovascular disease	Proportion of patients who develop arrhythmia, or myocardial infarction, or other cardiovascular disease not present at the baseline	day 1 until day 28