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Japanese, multicenter, phase II trial of combination therapy with favipiravir and corticosteroids for coronavirus disease 2019 (COVID-19) patients with mild respiratory failure (J-CRITICAL trial)

Phase II trial of combination therapy with favipiravir and corticosteroids for COVID-19 (J-CRITICAL trial)

69

Inclusion Criteria Gender does not matter 1. Patients who developed pneumonia* and need inpatient treatment (*pneumonia is defined as the presence of a new infiltrate on a chest radiograph or a computed tomography scan in addition to at least one of the following: new or increased cough or sputum production, new pleuritic chest pain, new or increased dyspnea, fever (temperature >= 37.5 degrees) or hypothermia (temperature <35.0 degrees), leukocytosis [white blood cell count (WBC) >=10,000/mm3] or leukopenia (WBC <4,000/mm3), elevated level of CRP value (exceed the upper threshold of each study institution), or new hypoxemia or deterioration of hypoxemia) 2. Positive PCR or antigen testing of SARS-CoV-2 3. Within 12 days of onset of symptoms 4. Patients with hypoxemia who need oxygen therapy (who meet one of the following: SpO2 =< 93% on room air; arterial oxygen partial pressure (PaO2) =< 60 mmHg or PaO2/ fraction of inspired oxygen (FiO2) < 300; or AaDO2 >= 40) 5. Age >= 20 years old 6. Informed consent must be obtained prior to participation in this study 7. Patients who were registered in observational registry studies organized by National Center for Global Health and Medicine or Fujita Health University. Exclusion Criteria 1. Patients who meet the criteria of tracheal intubation (at least one of the following: 5 L/min or more of oxygen flux; unstable circulatory dynamics; or consciousness disturbance) 2. Intubated or tracheostomy was performed at time of initiation of treatment 3. Patients who need vasopressor(s) at time of initiation of treatment 4. Patients who are receiving systemic corticosteroids or immunosuppressive agents including biological ones at time of initiation of treatment 5. Patients with HIV or immunodeficiency disorders 6. Respiratory failure due to cardiac pulmonary edema 7. Apparent asthma attack 8. Apparent pulmonary embolism 9. Chronic pulmonary diseases (e.g., interstitial pneumonia and severe COPD) which potentially affect assessment of the efficacy of study treatment 10. Long term oxygen therapy 11. Malignant diseases which potentially affect assessment of the efficacy of study treatment 12. Complicating pneumonia due to apparent bacterial infection or aspiration 13. Patients who are receiving anti-SARS-CoV-2 agents (e.g., favipiravir, lopinavir/ritonavir, remdesivir, ciclesonide, etc.) 14. Patients who need to receive medications that affect the effect of corticosteroids (e.g., rifampicin, phenobarbital, phenytoin, and ephedrine) 15. Contraindication for use of favipiravir or corticosteroids (e.g., allergy to them) 16. Pregnant women and women suspected of being pregnant 17. Women who are not able to give informed consent regarding protected sexual intercourse from the initiation of favipiravir to 90 days after the end of its administration 18. Men or their partners who are not able to give informed consent regarding protected sexual intercourse from the initiation of favipiravir to 90 days after the end of its administration 19. Patients who may have difficulty receiving efficacy assessment due to dementia or mental disorders 20. Patients who are participating in other clinical studies which do not allow use of corticosteroids or those who are expected to participate in them 21. Patients in whom physicians in charge judged inappropriate for registration A total of 69 patients with confirmed COVID-19 diagnosis by SARS-CoV-2 PCR testing or its antigen test were enrolled in the study and underwent the study treatment. The mean age of the enrolled patients was 64.6 years and 34.8% of them were women. In terms of activities of daily living before the onset of COVID-19, all patients were self-reliant. The percentages of patients with chronic lung diseases and diabetes were 11.6% and 20.3%, respectively, and 58.0% (40/69) had a history of smoking. The mean lymphocyte count was 1067/mm3. Regarding radiological findings, bilateral lesions were observed in 97.1% of the patients, and the main chest computed tomography findings were peripheral predominant distribution and ground-glass opacity. As for the A-DROP severity class, 72.5% of the patients were classified into moderate to severe.

From July 1, 2020 through September 12, 2020, in the midst of the second wave of COVID-19 in Japan, 69 patients with confirmed COVID-19 diagnosis by SARS-CoV-2 PCR testing or its antigen test were enrolled in the study and underwent the study treatment. All of the patients were evaluable for treatment efficacy and safety.

The most common grade 3-4 treatment-related adverse event was hyperglycemia, which was observed in 21.7% (15) of the 69 study patients during the study treatment period and 6.1% (4) during the observation period. Secondary infections occurred in 2.9% of the patients during the study treatment period (1 fungal infection and 1 bacterial pneumonia) and 6.1% (3 cases of ventilator-associated pneumonia and 1 pleural infection) during the observation period. Hyperuricemia, a known adverse effect of favipiravir, 27 was observed as follows: grade 1 in 36.2% (25) of the patients and grade 3 in 1.4% (1) during the study treatment period and 6.1% (4) during the observation period. Severe adverse events (SAEs) were observed in 34.8% (24) of the patients. The most common SAE was respiratory failure or ARDS due to progression of COVID-19 pneumonia, where 24.6% (17) patients presented grade 4 and 4.3% (3) died. Pleural infection, fungal infection, decreased platelet count, and a thromboembolic event occurred in one patient each (1.5%).

- The MVCTI-14 proportion was 29.2% (90% CI 20.1-39.9, p = 0.200) in the full analysis set (n = 65). In the per protocol set (n = 63), excluding 2 patients from the full analysis set who met the exclusion criteria after the study treatment initiation, the MVCTI-14 proportion was 28.6% (90% CI 19.4-39.4, p = 0.175). - Regarding the secondary endpoints, the proportions of patients who required MV or died within 14 and 30 days of the study treatment initiation were 23.1% and 26.2%, respectively. The 30-day and in-hospital mortality proportions were 4.9% and 4.4%, respectively. - Among the 19 patients who met the primary endpoint (patients with treatment failure), 16 (84.2%) met the endpoint during the first 5 days of the study treatment (during administration of methylprednisolone 1 mg/IBW/day). - Regarding the time course of the PaO2/FiO2 ratio between the patients who did not meet the primary endpoint (non-treatment failure group) and those who did (treatment failure group), the decrease in the mean PaO2/FiO2 ratio from baseline to day 1 was greater in the treatment failure group than in the non-treatment failure group (37 [285 +/- 104 at baseline to 248 +/- 62 at day 1] vs. 22 [309 +/- 91 to 287 +/- 66]). - To assess the factors associated with treatment failure (meeting the primary endpoint), we performed a univariable logistic analysis. Smoking history was significantly associated with treatment failure (OR 4.1, 95% CI 1.2-14.2, p = 0.027). The following factors also tended to increase the risk of treatment failure: absolute lymphocyte count <800/uL (OR 2.9, 95% CI 0.9-9.5, p = 0.076); age >=65 years (OR 2.8, 95% CI 0.9-9.1, p = 0.085); chronic lung diseases (OR 3.8, 95% CI 0.8-19.1, p = 0.102); and diabetes (OR 2.6, 95% CI 0.7-9.1, p = 0.141).

Sixty-nine patients were enrolled and received study treatment. The proportion of patients who needed mechanical ven was 29.2% (90% confidence interval (CI): 20.1-39.9, p=0.200). The proportion of patients who needed MV or death within 30 days was 26.2%. Thirty-day mortality was 4.9%. The significant risk factor for MVCTI-14 was smoking history (odds ratio: 4.1, 95% CI: 1.2-14.2). The most common grade 3-4 treatment-related adverse event was hyperglycemia that was observed in 21.7%.

Aug. 08, 2021

Aug. 08, 2021

https://link.springer.com/article/10.1007/s40121-021-00512-9

No

https://jrct.niph.go.jp/latest-detail/jRCTs041200025

Yuichiro Shindo

NAGOYA UNIVERSITY HOSPITAL

65, Tsurumai-cho, Showa-ku, Nagoya, Aichi

yshindo@med.nagoya-u.ac.jp

Yuichiro Shindo

NAGOYA UNIVERSITY HOSPITAL

65, Tsurumai-cho, Showa-ku, Nagoya, Aichi

+81-52-741-2111

yshindo@med.nagoya-u.ac.jp

Complete

July. 01, 2020

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Patients who developed pneumonia* and need inpatient treatment (*pneumonia is defined as the presence of a new infiltrate on a chest radiograph or a computed tomography scan in addition to at least one of the following: new or increased cough or sputum production, new pleuritic chest pain, new or increased dyspnea, fever (temperature >= 37.5 degrees) or hypothermia (temperature <35.0 degrees), leukocytosis [white blood cell count (WBC) >=10,000/mm3] or leukopenia (WBC <4,000/mm3), elevated level of CRP value (exceed the upper threshold of each study institution), or new hypoxemia or deterioration of hypoxemia)
2. Positive PCR or antigen testing of SARS-CoV-2
3. Within 12 days of onset of symptoms
4. Patients with hypoxemia who need oxygen therapy (who meet one of the following: SpO2 =< 93% on room air; arterial oxygen partial pressure (PaO2) =< 60 mmHg or PaO2/ fraction of inspired oxygen (FiO2) < 300; or AaDO2 >= 40)
5. Age >= 20 years old
6. Informed consent must be obtained prior to participation in this study
7. Patients who were registered in observational registry studies organized by National Center for Global Health and Medicine or Fujita Health University (This criterion will not be applicable after the approval of favipiravir)

1. Patients who meet the criteria of tracheal intubation (at least one of the following: 5 L/min or more of oxygen flux; unstable circulatory dynamics; or consciousness disturbance)
2. Intubated or tracheostomy was performed at time of initiation of treatment
3. Patients who need vasopressor(s) at time of initiation of treatment
4. Patients who are receiving systemic corticosteroids or immunosuppressive agents including biological ones at time of initiation of treatment
5. Patients with HIV or immunodeficiency disorders
6. Respiratory failure due to cardiac pulmonary edema
7. Apparent asthma attack
8. Apparent pulmonary embolism
9. Chronic pulmonary diseases (e.g., interstitial pneumonia and severe COPD) which potentially affect assessment of the efficacy of study treatment
10. Long term oxygen therapy
11. Malignant diseases which potentially affect assessment of the efficacy of study treatment
12. Complicating pneumonia due to apparent bacterial infection or aspiration
13. Patients who are receiving anti-SARS-CoV-2 agents (e.g., favipiravir, lopinavir/ritonavir, remdesivir, ciclesonide, etc.)
14. Patients who need to receive medications that affect the effect of corticosteroids (e.g., rifampicin, phenobarbital, phenytoin, and ephedrine)
15. Contraindication for use of favipiravir or corticosteroids (e.g., allergy to them)
16. Pregnant women and women suspected of being pregnant
17. Women who are not able to give informed consent regarding protected sexual intercourse from the initiation of favipiravir to 90 days after the end of its administration
18. Men or their partners who are not able to give informed consent regarding protected sexual intercourse from the initiation of favipiravir to 90 days after the end of its administration
19. Patients who may have difficulty receiving efficacy assessment due to dementia or mental disorders
20. Patients who are participating in other clinical studies which do not allow use of corticosteroids or those who are expected to participate in them
21. Patients in whom physicians in charge judged inappropriate for registration

Both

Coronavirus disease 2019 (COVID-19)

Combination therapy with favipiravir and methylprednisolone

COVID-19, pneumonia

Drug Therapy, Combination; Favipiravir; Methylprednisolone

C000657245

D004359; C462182; D000998

Proportion of patients who need mechanical ventilation or those who meet the criteria of tracheal intubation* within 14 days of initiation of treatment (*at least one of the following: 5 L/min or more of oxygen flux; unstable circulatory dynamics; or consciousness disturbance)

- Proportion of patients who need tracheal intubation or death within 14 and 30 days of initiation of treatment
- Time to performing mechanical ventilation (including noninvasive positive pressure ventilation [NPPV]) or meeting the criteria of tracheal intubation
- Time to tracheal intubation or death
- 30-day mortality
- In-hospital mortality
- Time course of oxygenation (PaO2/FiO2)
- Viral load of SARS-CoV-2
- Time to becoming negative for PCR testing of SARS-CoV-2
- Proportion of positivity of antibody testing for SARS-CoV-2
- Adverse events

(Exploratory)
- Length of hospital stay
- Tracheal intubation
- Death
- Clinical recovery at 7 and 14 days after initiation of treatment

+81-52-951-1111

June. 08, 2020

none