Preliminary Report of the Favipiravir Observational Study in Japan

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Salient features:

This article focuses on:

  • Introduction
  • Method
  • Results
  • Demographics
  • Administration of favipiravir
  • Severity of illness
  • Clinical status and outcome stratified by severity of illness
  • Clinical status and outcome stratified by age groups
  • Adverse events
  • Discussion

Detailed summary:

Introduction:

  • Favipiravir was approved in 2014 in Japan for the treatment of new or re-emergent influenza against which conventional anti-influenza agents are ineffective.
  • Its use has been strictly controlled by the government due to potential risk for teratogenicity.
  • Favipiravir is an RNA-dependent RNA polymerase inhibitor which in its ribosyl triphosphate form inhibits replication of a broad range of RNA viruses.
  • Favipiravir is active against SARS-CoV-2 in vitro.
  • Clinically, a nonrandomized study conducted in China reported faster achievement of SARS-CoV-2 PCR negativity and improvement of chest CT findings at 14 days when COVID-19 patients were given favipiravir in combination with interferon-alpha compared with lopinavir-ritonavir in combination with interferon alpha, both for 14 days.
  • A randomized clinical study of COVID-19 patients, also conducted in China, compared clinical efficacy of favipiravir and umifenovir, an anti-influenza agent, both given for 10 days. While the primary endpoint of better clinical improvement at 7 days was not met, durations of fever and cough were significantly shorter among those who received favipiravir.

Methods:

  • Favipiravir is provided to hospitals admitting confirmed COVID-19 patients from FUJIFILM Toyama Chemical Co., Ltd.
  • The hospitals are asked at the time to join the Favipiravir Observational Study and provide information regarding the patient demographics, comorbidities, severity of illness, dose and duration of favipiravir, use of other medications targeting SARS-CoV-2, adverse events likely related to favipiravir use, clinical status 7 and 14 days from the start of the use of favipiravir and clinical outcome approximately one month after admission to the hospital.
  • The data were collected using the survey function of REDCap.
  • The study was approved by the institutional review board of Fujita Health University.

 

Results:

  • A total of 2,158 cases were registered from 407 hospitals as of 6 pm on May 15, 2020.
  • Among them, patient demographics, clinical status at day 7, clinical status at day 14, clinical outcome at one month were available for 2,127, 1,713, 1,282 and 1,918 cases, respectively.
  • This study utilizes a survey function in an effort to prioritize timeliness of the data and ease of data entry at each hospital, and only limited data cleaning has been performed.

Demographics

  • In terms of demographics, 52.3% were age 60 years or older, and 67.1% were male.
  • One of the four comorbidities surveyed was present in 49.2%.
  • Ciclesonide, an inhaled steroid agent which is shown to possess activity against SARS-CoV-2 5), was coadministered in 41.6% of the patients.

Administration of favipiravir

  • In 92.8% of the patients, favipiravir was dosed at 2 doses of 1,800 mg orally on the first day followed by 800 mg orally twice a day on subsequent days.
  • The median duration was 11 days.
  • The median days from the positive PCR test and hospital admission to the initiation of favipiravir therapy were 2 and 1 days, respectively.

Severity of illness

  • 976 patients had mild disease, 947 patients had moderate disease and 239 patients had severe disease.

Clinical status and outcome stratified by severity of illness

  • Clinical status at 7 and 14 days from the start of favipiravir therapy was recorded as improved, worsened, unchanged compared with when therapy was started, based on the providers’ clinical assessment.
  • Rates of clinical improvement at 7 days were 73.8%, 66.6% and 40.1% for mild, moderate and severe disease, respectively.
  • Rates of clinical improvement at 14 days were 87.8%, 84.5% and 60.3%, respectively.
  • Rates of clinical worsening at 7 days were 13.1%, 21.3% and 28.3% for mild, moderate and severe disease, respectively.
  • Rates of clinical worsening at 14 days were 5.9%, 8.8% and 25.2%, respectively.
  • Clinical outcome was surveyed at approximately one month into hospitalization as discharged alive, died in hospital, transferred for de-escalation of care, transferred for escalation of care, and still in hospital.
  • The mortality rates at the time of survey were 5.1%, 12.7% and 31.7% for mild, moderate and severe disease, respectively.

Clinical status and outcome stratified by age groups

  • Clinical improvement rates were 79.0% at 7 days and 92.4% at 14 days for those 59 years old or younger, whereas they were 55.0% at 7 days and 73.8% at 14 days for those 60 years old or older.
  • The mortality rates at the time of survey were 1.8% for those 59 years old or younger and 20.8% for those 60 years old or older.

Adverse events

  • Presence or absence of adverse events possibly or likely related to favipiravir use was recorded for 2,158 patients.
  • A total of 626 events were reported for 532 patients.
  • The most common adverse events were hyperuricemia followed by liver injury or liver function test abnormalities

Discussion

  • Favipiravir Observational Study is being conducted in Japan to collect real-time data on the safety and efficacy of favipiravir that is being administered to COVID-19 patients as off-label, compassionate use.
  • The data reported suggested that the vast majority of patients with mild and moderate disease have recovered from the illness, whereas poor prognosis is not uncommon among those with severe disease.
  • Mortality rates are disproportionately higher among older patients.
  • This study only captures patients who received favipiravir, which precludes direct comparison of the clinical course with those who did not receive the agent.
  • Hyperuricemia and liver function abnormalities were the most commonly observed adverse events associated with favipiravir use.
  • Nonetheless, the dose and duration of therapy are higher and longer, respectively, when used for COVID-19 compared with those approved for influenza (i.e. 2 doses of 1,600 mg orally on the first day followed by 600 mg orally twice a day on subsequent days for a total of 5 days), and close monitoring of these adverse events are recommended.
  • Pregnancy must be excluded due to its teratogenicity before dosing of favipiravir in premenopausal women, and all patients and their sexual partners should practice effective contraception during and 10 days after the end of favipiravir therapy.

Reference Link: https://www.news-medical.net/news/20200602/Preliminary-report-of-Favipiravir-Observational-Study-in-Japan-released.aspx

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