Ensitrelvir vs Placebo (RCT)

Mild outpatients

FOREST PLOTS -2022-11-22

Studies description

Trial jRCT2031210350
Publication Mukae H, medRxiv (2022) (preprint)
Dates: 2022-01-02 to 2022-02-09
Funding: Mixed (Shionogi & Co., Ltd. ; Organization of the Ministry of Health, Labour and Welfare. Employees of Shionogi & Co., Ltd., participated in and approved the design and conduct of the study; wrote the protocol; and were involved in the collection, management, analysis, and interpretation of data. Institutional authors reviewed and approved the protocol and collected and interpreted the data.)
Conflict of interest: Yes

Methods
RCT
Blinding: triple blinding
Location : Multicenter / Japan, South Korea
Follow-up duration (days): 28
Inclusion criteria
  • Patients aged 12 to 69 years
  • tested positive for SARS-CoV-2 (assessed by SARS-CoV-2 antigen or nucleic acid detection testing) within 120 hours prior to randomization
  • patients aged <20 years should have recorded a body weight of ≥40 kg at enrollment
  • at least one moderate or severe symptom or worsening of an existing symptom among the 12 COVID-19 symptoms (stuffy or runny nose, sore throat, shortness of breath, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, or diarrhea) and a symptom duration of ≤120 hours
  • patients were eligible for enrollment irrespective of treatment settings (inpatient, outpatient, recuperation at home, or recuperation at designated hotels) because some of them required hospitalization or recuperation for the purpose of isolation or clinical trial participation, regardless of disease severity, at the time of this research.
Exclusion criteria
  • Awake oxygen saturation of ≤93% (room air)
  • oxygen administration
  • likely worsening of COVID-19 within 48 hours from randomization in the opinion of the investigator
  • suspected active and systemic infections requiring treatment (except for COVID-19)
  • current or chronic history of moderate or severe liver disease, known hepatic or biliary abnormalities (except for Gilbert’s syndrome or asymptomatic gallstones), or moderate-to-severe kidney disease
  • pregnant, possibly pregnant, or breastfeeding women
  • and blood donation (≥400 mL within 12 weeks or ≥200 mL within 4 weeks prior to enrollment)
  • used drugs for SARS-CoV-2 infection within 7 days prior to randomization or a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or inducer or St. John’s wort products within 14 days prior to randomization.
Interventions
Treatment
Ensitrelvir
Initial dose: 375 mg orally once daily on day 1 - Maintenance dose: 125 mg orally once daily on days 2-5

Ensitrelvir 250
Initial dose: 750 mg orally once daily on day 1 - Maintenance dose: 250 mg orally once daily on days 2-5

Ensitrelvir 125
Initial dose: 375 mg orally once daily on day 1 - Maintenance dose: 125 mg orally once daily on days 2-5
Control
Placebo

Participants
Randomized
participants :
Ensitrelvir=285
Placebo=143
Ensitrelvir 250=143
Ensitrelvir 125=142
Characteristics of participants
N= 713
Mean age : NR
260 males
Severity : Mild: n= 570/ Asymptomatic: n=0
Primary outcome
In the register
Change in total score of 12 symptoms of COVID-19 from Day 1 to Day 6 per unit time ; Day 4 Change in virus titer of SARS-CoV-2 from baseline.
In the report
Change from baseline (day 1, before drug administration) in the SARS-CoV-2 viral titer on day 4 of treatment ; change from baseline up to 120 hours in the total score of COVID-19 symptoms.
Documents
avalaible

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the pre-print article, the prospective trial registry and supplementary appendices were used in data extraction and assessment of risk of bias. There is no change from the trial registration in the intervention and control treatments. The primary outcomes in the article reflect those in the registry. The trial (n = 428) did not achieve its target sample size (n = 435). This paper reports on a part b of a 2 part phase 2 trial.
The study was updated on November 18th, 2022 with data extracted after contact with authors.

Trial jRCT2031210350
Publication Mukae H, Antimicrob Agents Chemother (2022) (published paper)
Dates: 2021-09-28 to 2022-01-30
Funding: Mixed (Shionogi & Co., Ltd ; Japan Agency for Medical Research and Development. Employees of Shionogi & Co., Ltd. participated in and approved the design and conduct of the study, wrote the protocol, and were involved in the collection, management, analysis, and interpretation of data. Institutional authors reviewed and approved the protocol and collected and interpreted the data.)
Conflict of interest: Yes

Methods
RCT
Blinding: triple blinding
Location : Multicenter / Japan
Follow-up duration (days): 28
Inclusion criteria
  • Patients (aged 12 to <70 years
  • body weight ≥40 kg for those aged <20 years to avoid increased drug exposure)
  • tested positive for SARS-CoV-2 within 120 hours prior to randomization (SARS-CoV-2 antigen tests or nucleic acid detection testing, including RT-PCR)
  • with mild-to-moderate COVID-19 - at least 1 moderate or severe symptom among the 12 COVID-19 symptoms (stuffy or runny nose, sore throat, shortness of breath, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, or diarrhea), or worsening of at least 1 moderate or severe COVID-19 symptom
  • Patients without the 12 COVID-19 symptoms listed, anosmia, or dysgeusia within 2 weeks prior to randomization were classified as those with asymptomatic SARS-CoV-2 infection
Exclusion criteria
  • Awake oxygen saturation of ≤93% (room air)
  • need for oxygen administration
  • worsening of COVID-19 within 48 hours from randomization strongly suspected by the investigator
  • suspected active and systemic infections requiring treatment (except for COVID-19)
  • current or chronic history of moderate or severe liver disease, known hepatic or biliary abnormalities (except for Gilbert syndrome or asymptomatic gallstones), or kidney disease
  • recent blood donation (≥400 mL within 12 weeks or ≥200 mL within 4 weeks prior to enrollment)
  • use of drugs for COVID-19 within 7 days
  • and use of strong CYP3A inhibitors or inducers or St John’s wort products within 14 days prior to randomization
  • pregnant, possibly pregnant, or breastfeeding.
Interventions
Treatment
Ensitrelvir
Initial dose: 375 mg orally on day 1 - Maintenance dose: 125 mg orally on days 2-5.

Ensitrelvir 250
Initial dose: 750 mg orally on day 1 - Maintenance dose: 250 mg orally on days 2-5.

Ensitrelvir 125
Initial dose: 375 mg orally on day 1 - Maintenance dose: 125 mg orally on days 2-5.
Control
Placebo

Participants
Randomized
participants :
Ensitrelvir=45
Ensitrelvir 250=23
Placebo=24
Ensitrelvir 125=22
Characteristics of participants
N= 114
Mean age : NR
37 males
Severity : Mild: n= 54/ Asymptomatic: n=9
Primary outcome
In the register
Change in virus titer of SARS-CoV-2 from baseline at each time point
In the report
Change from baseline (day 1, before drug administration) in SARS-CoV-2 viral titer on days 2, 4, 6, 9, 14, and 21 (or study discontinuation).
Documents
avalaible

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the pre-print article, the trial registry and supplementary appendices were used in data extraction and assessment of risk of bias. There is no change from the trial registration in the intervention and control treatments. The primary outcome in the article reflect those in the registry. The trial (n = 69) its target sample size (n = 69). This paper reports on a part a of a 2 part phase 2 trial.
This study was updated on November 18th, 2022 with data extracted from the published report and after contact with authors.