Clinical trial NCT04352400: Efficacy of Nafamostat in Covid-19 Patients (RACONA Study)
Official title: RAndomized Clinical Trial in COvid19 Patients to Assess the Efficacy of the Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor NAfamostat (RACONA Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: COVID19
Keywords: Nafamostat
proteases
TMPRSS2
covid-19
coronavirus
Lead sponsor: University Hospital Padova
Sponsor class: OTHER
Collaborators: name: Yokohama City University
name: University of Zurich
First posted: 2020-04-20
Enrollment: 256
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double blind, placebo-controlled parallel-group trial, on top of best standard of care
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Time-to-clinical improvement
timeFrame: day 1 until day 28
Secondary outcomes:
measure: Responders
timeFrame: day 1 until day 28
measure: Critical or dead patients
timeFrame: day 1 until day 28
measure: pO2/FiO2 ratio
timeFrame: day 1 until day 28
measure: SOFA score over time
timeFrame: day 1 until day 28
measure: Hospitalization
timeFrame: day 1 until day 28
measure: Mechanical ventilation
timeFrame: day 1 until day 28
measure: Mechanical ventilation duration
timeFrame: day 1 until day 28
measure: Cardiovascular disease
timeFrame: day 1 until day 28
Other outcomes:
Locations:
city: Padova
country: Italy
facility: Azienda Ospedale Università di Padova
Study officials:
affiliation: University of Padova, Italy
name: Gian Paolo Rossi, Prof.
role: PRINCIPAL_INVESTIGATOR
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