Clinical trial NCT04418128: Clinical Efficacy of Nafamostat Mesylate for COVID-19 Pneumonia
Official title: Treatment Effect of Nafamostat Mesylate in Patients With COVID-19 Pneumonia: Open Labelled Randomized Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Corona Virus Infection
COVID-19
Keywords: Nafamostat
Pneumonia
TMPSS2
Serine protease inhibitor
Lead sponsor: Gyeongsang National University Hospital
Sponsor class: OTHER
First posted: 2020-06-05
Enrollment: 84
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: This study is an open-labelled, randomized clinical trial to evaluate the efficacy of nafamostate in patients with COVID-19 pneumonia.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: * 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

Primary outcomes:
measure: Proportion of patients with clinical improvement
timeFrame: Day 14 & Day 28
Secondary outcomes:
measure: Time to clinical improvement (TTCI)
timeFrame: up to 28 days
measure: Clinical status assessed by 7-category ordinal scale
timeFrame: days 7, 14, and 28
measure: Change in National Early Warning Score (NEWS)
timeFrame: Day 1 trough Day 28
measure: Time to National Early Warning Score (NEWS) of ≤ 2 and maintained for 24 hours
timeFrame: Day 1 through Day 28
measure: Duration of hospitalization
timeFrame: Day 1 through Day 28
measure: Duration of new non-invasive ventilation or high flow oxygen use
timeFrame: Day 1 through Day 28
measure: Incidence of new non-invasive ventilation or high flow oxygen use
timeFrame: Day 1 through Day 28
measure: Duration of new supplement oxygen use
timeFrame: Day 1 through Day 28
measure: Incidence of new supplement oxygen use
timeFrame: Day 1 through Day 28
measure: Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use
timeFrame: Day 1 through Day 28
measure: Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use
timeFrame: Day 1 through Day 28
measure: Mortality at day 28
timeFrame: Day 1 through Day 28
measure: Time (days) from treatment initiation to death
timeFrame: Day 1 through Day 28
measure: Proportions of patients with a negative nasopharyngeal swab and sputum sample for SARS-CoV-2 quantitative RT-PCR
timeFrame: days 3, 7, 10, 14, and 21
measure: Viral load change (log10 viral load) of nasopharyngeal swab and sputum sample for SARS-CoV-2 quantitative RT-PCR
timeFrame: days 3, 7, 10, 14, and 21
measure: Adverse events that occurred during treatment
timeFrame: Day 1 through Day 28
Other outcomes:
Locations:
Study officials:
affiliation: Gyeongsang National University Hospital
name: IN-GYU BAE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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):e01753-18. doi: 10.1128/mBio.01753-18.
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.
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 Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
citation: Hoffmann M, Schroeder S, Kleine-Weber H, Muller MA, Drosten C, Pohlmann S. Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19. Antimicrob Agents Chemother. 2020 May 21;64(6):e00754-20. doi: 10.1128/AAC.00754-20. Print 2020 May 21. No abstract available.
citation: Moon K, Hong KW, Bae IG. Treatment effect of nafamostat mesylate in patients with COVID-19 pneumonia: study protocol for a randomized controlled trial. Trials. 2021 Nov 23;22(1):832. doi: 10.1186/s13063-021-05760-1.