Phase II Investigator-Initiated Clinical Trial to Investigate the Efficacy and Safety of T-705 Injection (Favipiravir) in Combination with Oseltamivir for Influenza
Phase II Investigator-Initiated Clinical Trial to Investigate the Efficacy and Safety of T-705 Injection (Favipiravir) in Combination with Oseltamivir for Influenza
Ohmagari Norio
National Center for Global Health and Medicine, Japan Institute for Health Security
1-21-1 Toyama Shinjuku Tokyo
+81-3-3202-7181
ohmagari.n@jihs.go.jp
Sho Saito
National Center for Global Health and Medicine, Japan Institute for Health Security
1-21-1 Toyama Shinjuku Tokyo
+81-3-3202-7181
saito.s@jihs.go.jp
Recruiting
Jan. 17, 2025
Jan. 22, 2025
80
Interventional
randomized controlled trial
double blind
no treatment control/standard of care control
parallel assignment
treatment purpose
(1) Patients whose nasopharyngeal swab specimen tested positive for influenza virus by nucleic acid amplification test (NAAT) or antigen test.
(2) Patients with influenza symptoms who can initiate protocol treatment within 2 days after symptom onset
(e.g., if symptoms begin on June 1, treatment may be initiated up to June 3).
(3) Patients aged 65 years or older (at the time of consent).
(4) Patients with influenza symptoms* requiring hospitalization.
(5) Patients who can understand the details of this clinical trial and are able to provide written informed consent themselves or through a legally authorized representative.
*Symptoms include: Fever, feeling of warmth, chills, cough, sore throat, nasal discharge, nasal congestion, myalgia, generalized pain, headache, fatigue, vomiting, diarrhea, dyspnea, shortness of breath, chest pain, abdominal pain, dizziness, altered consciousness, convulsions, decreased urine output, muscle weakness.
(1) Patients with coexisting respiratory viral infections other than influenza.
(2) Patients expected to die within 48 hours.
(3) Patients unable to take oral capsule formulations.
(4) Patients who have been administered anti-influenza drugs within 30 days prior to enrollment.
(5) Patients receiving treatment for severe liver dysfunction equivalent to Grade C in the Child-Pugh classification.
(6) Patients requiring regular hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)
(7) Patients whose creatinine clearance is 10 mL per minute or less.
(8) Patients with a history of gout attacks or with uric acid levels exceeding the reference range.
(9) Patients with hereditary xanthinuria.
(10) Patients diagnosed with hypouricemia (less than 1 mg/dL) or a history of xanthine urolithiasis.
(11) Patients with a history of alcohol dependence or drug abuse.
(12) Patients with hypersensitivity to concomitant medication (oseltamivir phosphate).
(13) Patients with hypersensitivity to favipiravir.
(14) Pregnant or lactating patients or patients who may be pregnant.
(15) Premenopausal female patients who are unable to use contraceptive methods such as oral contraceptives, intrauterine devices, or barrier methods (e.g., diaphragm, condom) or combine these methods from the start of the investigational drug administration until 10 days after the end of the administration.
(16) Patients who have received any investigational drug within the past 90 days.
(17) Patients deemed by the principal investigator or sub-investigator to be unsuitable for appropriate efficacy evaluation or adverse event assessment due to underlying diseases (e.g., advanced dementia) or complications.
65age old over
No limit
Influenza
The protocol treatment will commence on the registration date. The treatment period (administration period) will be 5 days.
Experimental Group:
In addition to the concomitant medication (oseltamivir phosphate) administered orally as 75 mg of oseltamivir twice daily for 5 days, the investigational drug (T-705IV) will be administered as follows:
On Day 1: 1600 mg once daily.
On Days 2-5: 600 mg once daily.
The investigational drug will be dissolved in normal saline to prepare an infusion solution. The solution will be administered intravenously twice daily, over approximately 60 minutes. The infusion volume will be 200 mL per dose. There must be at least 4 hours between the start times of the two daily doses.
Control Group:
In addition to the concomitant medication (oseltamivir phosphate) administered orally as 75 mg of oseltamivir twice daily for 5 days, normal saline will be administered as a placebo in the same manner as the investigational drug.
Normal saline will be infused intravenously over approximately 60 minutes twice daily for 5 days. The infusion volume will be 200 mL per dose. The interval between the two daily doses will follow the same schedule as the investigational drug, with at least 4 hours between the start times of the two doses.
Influenza
Time to Recovery from Enrollment/Randomization
[Evaluation Method]
The principal investigator or sub-investigator will use a 7-point ordinal scale for clinical evaluation. The patient's condition will be assessed daily from enrollment/randomization through Day 29 of hospitalization. The highest score representing the patient's condition on each day will be recorded as that day's value. Recovery will be defined as the point at which the patient remains in a discharge-eligible state (score 1 or 2) for three consecutive days or is discharged. The time to recovery will be calculated up to the first day on which recovery is confirmed.
Clinical Endpoints
(1) Percentage of Patients Over 29 Days Based on a 7-Point Scale
[Evaluation Method]
The principal investigator or sub-investigator will use a 7-point scale for clinical evaluation. From enrollment/randomization through Day 29 of hospitalization, the highest score for each day will be recorded. The percentage of patients according to the 7-point scale will be calculated daily until Day 29.
(2) Worsening Rate Over 15 Days and 29 Days Based on a 7-Point Scale
[Evaluation Method]
The investigator will use a 7-point scale. From enrollment/randomization through Day 29 of hospitalization, the highest score for each day will be recorded. Worsening is defined as a decline of at least one level from baseline. The percentage of patients who experienced worsening by Day 15 and Day 29 will be calculated.
(3) Time to Defervescence
[Evaluation Method]
The investigator will assess the patient's highest body temperature daily from enrollment/randomization through Day 15. Defervescence is defined as a temperature below 37.5 C for two consecutive days, regardless of antipyretic use. The time to first defervescence will be calculated. Evaluation after defervescence is not required.
(4) 29-Day Mortality Rate
[Evaluation Method]
The percentage of patients who died within 29 days, regardless of cause, will be calculated.
(5) 29-Day ICU Admission Rate
[Evaluation Method]
The percentage of patients admitted to intensive care units within 29 days will be calculated.
(6) 15-Day Incidence of Pneumonia Complications
[Evaluation Method]
After enrollment and randomization, the incidence of pneumonia requiring initiation of new antibiotic treatment during hospitalization through Day 15 will be calculated.
Virological Endpoints
(1) Influenza Virus Titer (Day 1, 2, 3, 7)
[Evaluation Method]
Using the provided viral transport medium container and swab, nasopharyngeal samples will be collected on Day 1 (before the first dose), Day 2 (before the third dose), Day 3 (before the fifth dose), and Day 7 (after the final dose). The influenza virus titers in the samples [unit: TCID50/mL (TCID50: the median Tissue Culture Infectious Dose showing cytopathic effect in 50% of inoculated cells)] will be measured by a central laboratory. The virus titers will be log10-transformed and plotted over time, and the AUC over the first 3 days will be compared between the investigational and control groups.
TCID50 will be determined by serially diluting the nasopharyngeal samples in culture medium and inoculating the dilutions onto cultured cells. Infection will be assessed based on cytopathic effects (CPE), and the TCID50 value will be calculated using the Karber method. In addition, changes in virus titers from Day 1 (log10[TCID50/mL]) and the proportion of patients with titers below the lower limit of quantification will be evaluated.
(2) Influenza Virus RNA Levels (Day 1, 2, 3, 7)
[Evaluation Method]
Using the provided viral transport medium container and swab, nasopharyngeal samples will be collected on Day 1 (before the first dose), Day 2 (before the third dose), Day 3 (before the fifth dose), and Day 7 (after the final dose). The influenza virus RNA levels in the samples (copy/mL) will be measured by a central laboratory. The RNA levels will be log10-transformed and plotted over time, and the AUC over the first 3 days will be compared between the investigational and control groups. In addition, changes in RNA levels (log10[copy/mL]) and the proportion of patients with RNA levels below the lower limit of quantification will be evaluated.
Note: "Third dose" and "fifth dose" refer to the number of infusions administered according to the scheduled dosing regimen in the investigational or control group.
AMED (Japan Agency for Medical Research and Development)
Not applicable
Institutional Review Board, National Center for Global Health and Medicine, Japan Institute for Health Security
