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

• ClinicalTrials.gov Identifier: NCT04352400
• Recruitment Status: Recruiting
• First Posted: April 20, 2020
• Last Update Posted: June 9, 2021
• Sponsor: University Hospital Padova
• Collaborators: Yokohama City University; University of Zurich
• Information provided by (Responsible Party): Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
COVID19	Drug: Nafamostat Mesilate; Drug: Placebo	Phase 2; Phase 3

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 256 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, double blind, placebo-controlled parallel-group trial, on top of best standard of care
• Masking: Double (Participant, Investigator)
• Masking Description: Randomization will be done with an algorithm tailored to the study design. Investigators and patients will be blinded to the treatment administered.
• Primary Purpose: Treatment
• Official Title: RAndomized Clinical Trial in COvid19 Patients to Assess the Efficacy of the Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor NAfamostat (RACONA Study)
• Actual Study Start Date: June 4, 2021
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Nafamostat; Nafamostat mesylate on top of best standard of care.	Drug: Nafamostat Mesilate; administered intravenously as a continuous infusion; Other Name: no alternative name. Commercial brands are available.
Placebo Comparator: Placebo; Placebo on top of best standard of care.	Drug: Placebo; administered intravenously as a continuous infusion; Other Name: no alternative name.

Outcome Measures

Primary Outcome Measures :

1. Time-to-clinical improvement [ Time Frame: day 1 until day 28 ]
   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.

Secondary Outcome Measures :

1. Responders [ Time Frame: day 1 until day 28 ]
   Rate of patients showing improvement of 2 points in 7 category ordinal scale (with 7 points the worst)(PubMed ID: 32187464)
2. Critical or dead patients [ Time Frame: day 1 until day 28 ]
   Proportion of patients who will progress to critical illness/death
3. pO2/FiO2 ratio [ Time Frame: day 1 until day 28 ]
   Change in pO2/FiO2 ratio over time
4. SOFA score over time [ Time Frame: day 1 until day 28 ]
   Change Sequential organ failure assessment score (SOFA score) over time. The Score ranges from 0 to 24 (with 24 the worst)(PubMed ID: 11594901)
5. Hospitalization [ Time Frame: day 1 until day 28 ]
   Duration of hospitalization in survivors (days)
6. Mechanical ventilation [ Time Frame: day 1 until day 28 ]
   Number of patients who require ventilation
7. Mechanical ventilation duration [ Time Frame: day 1 until day 28 ]
   Duration of ventilation (days)
8. Cardiovascular disease [ Time Frame: day 1 until day 28 ]
   Proportion of patients who develop arrhythmia, or myocardial infarction, or other cardiovascular disease not present at the baseline

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Gian Paolo Rossi, Prof.; 0039049821 ext 2279; gianpaolo.rossi@unipd.it

Locations

Italy

Azienda Ospedale Università di Padova; Recruiting

Padova, Italy, 35128

Contact: Gian Paolo Rossi, Prof.

Sub-Investigator: Andrea Vianello, MD

Sub-Investigator: Gabriella Guarnieri, MD

Sub-Investigator: Sara Lococo, MD

Sub-Investigator: Beatrice Molena, BSc

Principal Investigator: Paola Fioretto, MD

Sub-Investigator: Filippo Farnia, MD

Sub-Investigator: Federico Capone, MD

Principal Investigator: Annamaria Cattelan, MD

Sub-Investigator: Maria Mazzitelli, MD

Sponsors and Collaborators

University Hospital Padova

Yokohama City University

University of Zurich

Investigators

• Principal Investigator: Gian Paolo Rossi, Prof.; University of Padova, Italy

More Information

Study Data/Documents: Individual Participant Data Set 

Identifier: GPR (PI)
The link https://ncov.medsci.ox.ac.uk allows connection to EDCap database, a secure web platform for building and managing online databases and surveys. Data collection will use the WHO Case Record Form.

Publications of Results:

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 Assay. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6532-6539. doi: 10.1128/AAC.01043-16. Print 2016 Nov.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.

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 study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.

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, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.

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. Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies. Int J Hematol. 2019 Feb;109(2):141-146. doi: 10.1007/s12185-018-02567-w. Epub 2018 Dec 8.

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.

Ferreira FL, Bota DP, Bross A, Mélot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001 Oct 10;286(14):1754-8.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Flumignan RL, Civile VT, Tinôco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah ÁN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3:CD013739. doi: 10.1002/14651858.CD013739.pub2. Review.

Flumignan RL, Tinôco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah ÁN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10:CD013739. doi: 10.1002/14651858.CD013739. Update in: Cochrane Database Syst Rev. 2022 Mar 4;3:CD013739.

• Responsible Party: Gian Paolo Rossi, MD, FAHA, FACC, Prof., University Hospital Padova
• ClinicalTrials.gov Identifier: NCT04352400
• Other Study ID Numbers: RACONA Nafamostat
• First Posted: April 20, 2020
• Last Update Posted: June 9, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova:

Nafamostat; proteases; TMPRSS2; covid-19; coronavirus

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Nafamostat; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Anticoagulants; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Trypsin Inhibitors; Serine Proteinase Inhibitors; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors