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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04352400
Recruitment Status : Not yet recruiting
First Posted : April 20, 2020
Last Update Posted : April 20, 2020
Sponsor:
Collaborators:
Yokohama City University
University of Zurich
Information provided by (Responsible Party):
Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova

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.

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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)
Estimated Study Start Date : April 2020
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

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.




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



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04352400


Contacts
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Contact: Gian Paolo Rossi 00390498217821 ext 2279 gianpaolo.rossi@unipd.it
Contact: Gian Paolo Rossi, Prof. 00390498217821 ext 2279 gianpaolo.rossi@unipd.it

Sponsors and Collaborators
University Hospital Padova
Yokohama City University
University of Zurich
Investigators
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Principal Investigator: Gian Paolo Rossi, Prof. University of Padova, Italy
Study Data/Documents: Individual Participant Data Set  This link exits the ClinicalTrials.gov site
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:

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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    Key Record Dates
Last Update Posted: April 20, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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