Clinical Efficacy of Nafamostat Mesylate for COVID-19 Pneumonia

COVID-19 Clinical Trial

Official title:

Treatment Effect of Nafamostat Mesylate in Patients With COVID-19 Pneumonia: Open Labelled Randomized Controlled Clinical Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04418128
• Other study ID #: 2020-04-012
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: June 10, 2020
• Est. completion date: April 30, 2021

Study information

• Verified date: June 2020
• Source: Gyeongsang National University Hospital
• Contact: IN-GYU BAE, MD
• Phone: +82-55-750-8055
• Email: ttezebae[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In-vitro studies revealed that nafamostat mesylate has antiviral activity against Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti-inflammatory and anti-coagulation effect. However, there is no clinical studies on the efficacy of nafamostat in patients with COVID-19.

This study is conducted to evaluate the clinical efficacy of nafamostate mesylate in adult patients hospitalized with COVID-19 pneumonia.

Description:

• The COVID-19 epidemic expanded to the whole world since it started from the Wuhan area in China in Dec. 2019. The Republic of Korea experiences a sharp increase in the patient since 24th Feb. 2020. An analysis of more than 70,000 patients in China, about 15% of them cause severe pneumonia, 5% require treatment in the intensive care unit, half of them die of the disease.

• There is no proven therapeutics for COVID-19 patients yet. Currently, the treatment with Kaletra, Hydroxychloroquine, etc. did not show apparent effect, and there are no other drugs that can apply to patients who get worse even with those drugs or severe.

• There are research reports that defective innate immunity and accelerated activation of the complement cascade, caused by the SARS-CoV-2, induce rapidly progressing pneumonitis.

• Action mechanism of Nafamostat mesilate A. Show anti-viral effect by an inhibition serine protease, which is required for the host membrane fusion of viral envelop protein. In vitro experiments showed that the drug is effective in MERS-CoV, Influenza virus, and SARS-CoV-2.

B. Show anti-inflammatory effect by inhibition of the complement pathway, and inhibition of cytokine production.

This study is conducted to evaluate the clinical efficacy of nafamostate mesylate in adult patients hospitalized with COVID-19 pneumonia.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 84
• Est. completion date: April 30, 2021
• Est. primary completion date: March 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

• Inclusion Criteria:

1. 18 years old or older

2. Patients who have been confirmed of COVID-19 infection and has evidence for pneumonia

• Confirmation of COVID-19 infection by RT-PCR of SARS-CoV-2

• Definite diagnosis of new infiltration of the lungs by chest CT scan of chest radiographic inspection

3. Patients who are within 72 hours of COVID-19 pneumonia confirmation

4. Patients with 3(hospitalization, not requiring supplemental oxygen) or higher in seven-category ordinal scale of clinical status

• Seven-category ordinal scale of clinical status

1. not hospitalized with resumption of normal activities;

2. not hospitalized, but unable to resume normal activities;

3. hospitalization, not requiring supplemental oxygen;

4. hospitalization, requiring supplemental oxygen;

5. hospitalization, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation;

6. hospitalization, requiring extracorporeal membrane oxygenation and/or invasive mechanical ventilation;

7. death.

5. Patients who are eligible for diagnosis/evaluation to chest CT scan and related to it

6. Patients should be able to understand the essence of the clinical trial and to submit a written consent document. For the patients who can understand the nature of the research but cannot sign the document, a relative can agree to the study.

• Exclusion Criteria:

1. Patients who have a record of HIV or AIDS

2. Female patients, either who are pregnant within 6 months before the investigation, who breast-fed babies within 3 months before the investigation, or who may get pregnant or breast-feed within 1 month after the investigation is over

3. Patients at high risk of death within 3 days of randomized assignment, by the judge of the investigator

4. Patients with liver cirrhosis whose Child-Puch score is B or C

5. Patients who have liver disease abnormalities with ALT or AST > 5 times ULN

6. Patients who can be in danger or who shows clinically-important other conditions which may interfere with the evaluation or completion of the test procedure, as the investigator's opinion

7. Patients who are not appropriate for the test, as the investigator's opinion

8. Patients who have hypersensitivity to the investigational drug

Related Conditions & MeSH terms

• Corona Virus Infection
• Coronavirus Infections
• COVID-19
• Pneumonia
• Severe Acute Respiratory Syndrome

Intervention

Drug:
• Nafamostat Mesylate
The Nafamostat mesilate group received continuous intravenous infusion of 0.1-0.2 mg/kg/h of nafamostat mesilate mixed with 5% DW.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gyeongsang National University Hospital

References & Publications (4)

Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, Whitmore A, Heise MT, Baric RS. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio. 2018 Oct 9;9(5). pii: e01753-18. doi: 10.1128/mBio.01753-18. — View Citation

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 Inhibi — View Citation

Hoffmann M, Schroeder S, Kleine-Weber H, Müller MA, Drosten C, Pöhlmann S. Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19. Antimicrob Agents Chemother. 2020 May 21;64(6). pii: e00754-20. doi: 10.1128/AAC.00754-20. P — View Citation

Yamaya M, Shimotai Y, Hatachi Y, Lusamba Kalonji N, Tando Y, Kitajima Y, Matsuo K, Kubo H, Nagatomi R, Hongo S, Homma M, Nishimura H. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther. 2015 Aug;33:66-74. doi: 10.1016/j.pupt.2015.07.001. Epub 2015 Jul 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients with clinical improvement	Proportion of patients with clinical improvement as defined by live discharge from hospital or a decline of 2 categories on the seven-category ordinal scale of clinical status.; * Seven-category ordinal scale of clinical status; not hospitalized with resumption of normal activities; not hospitalized, but unable to resume normal activities; hospitalization, not requiring supplemental oxygen; hospitalization, requiring supplemental oxygen; hospitalization, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation; hospitalization, requiring extracorporeal membrane oxygenation and/or invasive mechanical ventilation; death.	Day 14 & Day 28
Secondary	Time to clinical improvement (TTCI)	Time to clinical improvement (TTCI) was defined as time from randomization to a decline of 2 categories on the seven-category ordinal scale of clinical status or live discharge from the hospital, whichever came first.	up to 28 days
Secondary	Clinical status assessed by 7-category ordinal scale	* Seven-category ordinal scale of clinical status; not hospitalized with resumption of normal activities; not hospitalized, but unable to resume normal activities; hospitalization, not requiring supplemental oxygen; hospitalization, requiring supplemental oxygen; hospitalization, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation; hospitalization, requiring extracorporeal membrane oxygenation and/or invasive mechanical ventilation; death.; Higher scores of Seven-category ordinal scale mean serious clinical status.	days 7, 14, and 28
Secondary	Change in National Early Warning Score (NEWS)	The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The range of NEW score is from zero to 23. Higher scores of NEWS mean the higher risk of poor outcomes. The NEW Score is being used as an efficacy measure.	Day 1 trough Day 28
Secondary	Time to National Early Warning Score (NEWS) of = 2 and maintained for 24 hours		Day 1 through Day 28
Secondary	Duration of hospitalization		Day 1 through Day 28
Secondary	Duration of new non-invasive ventilation or high flow oxygen use		Day 1 through Day 28
Secondary	Incidence of new non-invasive ventilation or high flow oxygen use		Day 1 through Day 28
Secondary	Duration of new supplement oxygen use		Day 1 through Day 28
Secondary	Incidence of new supplement oxygen use		Day 1 through Day 28
Secondary	Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use		Day 1 through Day 28
Secondary	Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use		Day 1 through Day 28
Secondary	Mortality at day 28		Day 1 through Day 28
Secondary	Time (days) from treatment initiation to death		Day 1 through Day 28
Secondary	Proportions of patients with a negative nasopharyngeal swab and sputum sample for SARS-CoV-2 quantitative RT-PCR		days 3, 7, 10, 14, and 21
Secondary	Viral load change (log10 viral load) of nasopharyngeal swab and sputum sample for SARS-CoV-2 quantitative RT-PCR		days 3, 7, 10, 14, and 21
Secondary	Adverse events that occurred during treatment		Day 1 through Day 28