RBR-85vh8fx Evaluation with favipiravir in patients with COVID-19.

Date of registration: 09/29/2021 ^(mm/dd/yyyy)
Last approval date : 02/21/2022 ^(mm/dd/yyyy)

Study type:

Interventional

Scientific title:

Trial identification

• UTN code: U1111-1274-5868

• Public title:

  en

  Evaluation with favipiravir in patients with COVID-19.

  pt-br

  Avaliação com favipiravir em pacientes com COVID-19.

• Scientific acronym:

  en

  SARS-CoV-2

  pt-br

  SRAS-CoV-2

• Public acronym:

  en

  Sakura SARS-CoV-2

  pt-br

  Sakura SRAS-CoV-2

• Secondaries identifiers:
  • Número do CAAE: 46417321.6.1001.5248
    Issuing authority: Órgão emissor: Plataforma Brasil
  • Número do Parecer do CEP: 4.834.307
    Issuing authority: Órgão emissor: Comissão Nacional de Ética em Pesquisa

Sponsors

• Primary sponsor: Fundação Oswaldo Cruz
• Secondary sponsor:
  • Institution: Vice-Presidência de Pesquisa e Coleções Biológicas - VPPCB
• Supporting source:
  • Institution: Vice-Presidência de Produção e Inovação em Saúde - VPPIS

Health conditions

• Health conditions:

  en

  Corona virus infection

  pt-br

  Infecção por corona vírus

• General descriptors for health conditions:

  en

  B97.2 Coronavirus, as a cause of diseases classified under other chapters

  pt-br

  B97.2 Coronavírus, como causa de doenças classificadas em outros capítulos

• Specific descriptors:

  en

  C01.925.782.600.550.200 corona virus infectious

  pt-br

  C01.925.782.600.550.200 infecção por corona vírus

Interventions

• Interventions:

  en

  Participants will be randomised to favipiravir arm 200mg coated tablets or placebo, Participants up to 75 kg: on day 1 (D1), 1600 mg (8 tablets) twice daily (total tablets/day: 16 tablets). From D2 to D10, 600 mg (3 tablets) twice daily (total tablets/day: 6 tablets), Number of participants= 201 Participants from 75 to 90 kg: on day 1 (D1), 2000 mg (10 tablets) twice daily (total tablets/day: 20 tablets), From D2 to D10, 800 mg (4 tablets) twice daily (total tablets/day: 8 tablets), Participants over 90 kg: on day 1 (D1), 2400 mg (12 tablets) twice daily (total tablets/day: 24 tablets), From D2 to D10, 1000 mg (5 tablets) twice daily (total tablets/day: 10 tablets) Number of participants= 207

  pt-br

  Participantes serão randomizados para receber favipiravir comprimidos revestidos de 200mg ou placebo, Participantes até 75 kg: no primeiro dia (D1), 1600 mg (8 comprimidos) duas vezes ao dia (total de comprimidos/dia: 16 comprimidos) Do D2 até D10, 600 mg (3 comprimidos) duas vezes ao dia (total de comprimidos/dia: 6 comprimidos) Numero de participantes 201 Participantes de 75 até 90 kg: no primeiro dia (D1), 2000 mg (10 comprimidos) duas vezes ao dia (total de comprimidos/dia: 20 comprimidos), Do D2 até D10, 800 mg (4 comprimidos) duas vezes ao dia (total de comprimidos/dia: 8 comprimidos), Participantes com mais de 90 kg: no primeiro dia (D1), 2400 mg (12 comprimidos) duas vezes ao dia (total de comprimidos/dia: 24 comprimidos), Do D2 até D10, 1000 mg (5 comprimidos) duas vezes ao dia (total de comprimidos/dia: 10 comprimidos) Numero de participantes 207

• Descriptors:

  en

  D27.505.954.122.388 antiviral

  pt-br

  D27.505.954.122.388 Antivirais

Recruitment

• Study status: Not yet recruiting
• Countries
  • Brazil
• Date first enrollment: 02/25/2021 ^(mm/dd/yyyy)

• Target sample size:	Gender:	Minimum age:	Maximum age:
  402	-	18 Y	0

• Inclusion criteria:

  en

  Participants with a diagnosis of COVID-19 confirmed by PCR-RT or positive rapid antigen test; Participants aged 18 years or older; Participants with a score between 1 and 3 on the WHO Clinical Progression Scale; Participants with a score greater than or equal to 10 on the CALL Score; Consent from men to use barrier contraception during the study and one (1) week after the end of the use of study medication if the partner is of the opposite sex • Informed consent form signed by the participant. • Able to receive oral medication and attend protocol visits.

  pt-br

  Participantes com diagnóstico de COVID-19 confirmado por PCR-RT ou teste rápido de antígeno positivo; Participantes com idade igual ou maior que 18 anos; Participantes com score entre 1 e 3 na WHO Clinical Progression Scale; Participantes com score maior ou igual a 10 no CALL Score; Consentimento dos homens para usar contraceptivo de barreira durante o estudo e 1 (uma) semana após o fim uso do medicamento do estudo caso o parceiro seja do sexo oposto; Termo de Consentimento Livre e Esclarecido assinado pelo participante; Capaz de receber medicação oral e atender as visitas previstas em protocolo

• Exclusion criteria:

  en

  Non-hysterectomised women of childbearing age; Symptomatic patients for more than 72 hours; Participants with severe liver failure equivalent to Child-Pugh grade C and advanced renal disease requiring haemodialysis or grade 3 or 4 according to the classification of the severity grade of adverse events of the Common Terminology Criteria for Adverse Events (CTCAE, version 5), or still, at the physician's discretion; Participants taking antiretroviral drugs or pyrazinamide, repaglinide, theophylline, famciclovir and sulindac; Disease progression greater than 5 (WHO Score) with need for intensive care; Participants who have received COVID-19 vaccine

  pt-br

  Mulheres em idade fértil não histerectomizadas; Pacientes sintomáticos há mais de 72h; Participantes com insuficiência hepática grave equivalente ao grau C na classificação de Child-Pugh e doença renal avançada que requer hemodiálise ou grau 3 ou 4 de acordo com a classificação do grau de severidade dos eventos adversos do Common Terminology Criteria for Adverse Events CTCAE, versão 5, ou ainda, a critério médico; Participantes em uso dos antirretrovirais ou pirazinamida, repaglinide, teofilina, famciclovir e sulindac; Progressão para maior de 5 Score WHO com necessidade de terapia intensiva; Participantes que tenham recebido vacina contra COVID- 19.

Study type

• Study design:

• Expanded access program	Purpose	Intervention assignment	Number of arms	Masking type	Allocation	Study phase
  1	Treatment	Parallel	2	Double-blind	Randomized-controlled	2-3

Outcomes

• Primary outcomes:

  en

  Evaluate the proportion of participants maintaining the same mild to moderate clinical profile of the disease at study entry and at 10 days after end of treatment according to WHO Clinical Progression Scale (score between 1 to 3) in high risk population according to CDC list.

  pt-br

  Avaliar a proporção de participantes mantendo o mesmo perfil clínico leve a moderado da doença na entrada do estudo e aos 10 dias após o término do tratamento de acordo com a pontuação da Escala de Progressão Clínica da OMS (pontuação entre 1 a 3) em populações com risco aumentado de acordo com lista do CDC.

• Secondary outcomes:

  en

  Virus clearance rate on days 5, 10, 15, 20, 30 measured by PCR; Time to viral elimination; Time to normalisation of clinical symptoms (respiratory rate, fever, SpO2); Frequency of adverse events.

  pt-br

  Taxa de eliminação de vírus no dia 5, 10, 15, 20, 30 aferida por PCR; Tempo para eliminação viral; Tempo para normalização dos sintomas clínicos (frequência respiratória, febre, SpO2); Frequência de eventos adversos.

Summary Results

• Baseline char:

  en

  This is a multicentre, double-blind, adaptive, randomised, placebo-controlled clinical trial to compare the efficacy and safety of Favipiravir in reducing the progression of SARS CoV-2 infection to severe cases in a population at increased risk.

• Participants flow:

  en

  Participants seen with suspected SARs CoV-2 infection and who declare availability for daily treatment and care (telemedicine, home or outpatient visit) for the duration of COVID-19 treatment, at the physician's discretion, will be evaluated for clinical and laboratory examination, including antigen testing and PCR-RT with nasopharyngeal swab for COVID-19, CBC, lymphocyte count, liver enzymes, renal function and serology (IgA/IgM and IgG). >> Inclusion and Randomization: Eligible participants will be randomized in alternating block sizes between the placebo and treatment arms of the study in a 1:1 ratio. All study participants will receive symptomatic treatment at the physician's discretion. >> During the 10-day treatment period with the study drug (favipiravir/placebo), the participant will have to be accompanied during the visits foreseen in the protocol, which may take place by telemedicine, home visit or in person at the research centre. There is also the possibility of the participant staying part of the treatment period in the hospital (hospitalized) and/or part at home, depending on the medical decision of how many days the participant will need to remain hospitalized. During the period of treatment with study medication (favipiravir/placebo), the participant will receive clinical follow-up to check his or her health and whether the medication is being taken correctly (supervised treatment): if the doctor decides to admit the participant, this follow-up will be done at the back hospital of the research centre; but if the participant is not admitted, this follow-up will be by outpatient care, by video call or by home visit. However, on day 5 and day 10, the participant will be required to come to the hospital for clinical evaluation and follow-up laboratory tests. After the 10-day treatment period, the participant will receive daily clinical follow-up for 5 consecutive days (from day 11 to day 15) and then on day 20 and day 30. The clinical follow-up will be from day 11 to day 14 at home by video call daily by a member of the study team. However, on the 15th, 20th and 30th the participant will have to go to the hospital for clinical evaluation and laboratorial examinations. Participants requiring advanced life support (for example: intubation) will be considered as a negative outcome, i.e. treatment failure and will be removed from the study and followed up according to the treatment routine of each centre.
  

• Adverse events:

  en

  Adverse events will be classified using the Common Terminology Criteria for Adverse Events (CTCAE, version 5) scale and recorded using Medical Dictionary for Regulatory Activities (MedDRA, version 2020AB), at all visits and at any time the participant seeks assistance with the study team.

• Outcome measure:

  en

  Primary Outcome:
  Proportion of participants with mild to moderate disease, i.e. maintaining the same clinical profile as at study entry 10 days after end of
  treatment.
  Secondary Outcome:
  1) Virus clearance rate on day 5, 10, 15, 20, 30 as measured by RT-PCR 2) Time to viral clearance 3) Time to normalisation of clinical symptoms (respiratory rate, fever, SpO2) 4) Frequency of adverse events.

• Results summary:

  en

  Data Analyses: Exploratory analyses that consider the impact on the primary outcome of the different scores at the
  inclusion, as well as other demographic characteristics should be performed. Similarly, the primary outcome (no progression to scores higher than 5 on the WHO progression scale), should be treated as binary outcomes, but analyses that consider the score at inclusion will be conducted. Secondary endpoints, time to viral clearance and time to resolution of clinical symptoms will be analysed in survival models. Cox regressions should include the evaluation of different conditions at the time of inclusion. Adverse events will be grouped according to MedDRa's SOC (System-Organ Class) (version 2020AB) and classified by intensity, severity, causality relationship with treatment and study arm. A sample size of 167 participants per arm will allow the detection of a 30% reduction on disease progression, considering the expected progression with worsening of medical conditions from mild-moderate to severe-terminal grade to be at least 50%, with 80% power and 5% alpha using two-tailed proportions tests in the comparison between study arms. Considering an interim analysis with only the upper bound comparison to stop the study for early efficacy, a small adjustment for 169 per group will be necessary. Considering losses during the participant recruitment process in the margin of 20%, 201 volunteers are expected to be included in each of the two study arms with a total sample size of 402 participants. > Interim Data Analysis: A Safety Data Monitoring Committee (SDMC) will conduct an interim analysis to detect early efficacy when 85 participants in each arm of the trial have finished follow-up. An alpha spending functions approach will be used for sequential comparison analyses. In addition, as data are collected, the WSSC will monitor disease progression in the control arm of the study and may recommend inclusion of patients with an increased likelihood of progression and/or recalculate the sample if progression proves to be significantly different from the initially projected 50% in the control group. As it does not involve comparison of groups, this procedure will not impact on the type 1 error. >> Primary outcome measure: Proportion of participants with mild to moderate disease 10 days after end of treatment and no progression to scores > 5 on the WHO Progression Scale; Secondary outcome measures: Virus clearance rate on days 5, 10, 15, 20, 30 measured by PCR; Time to viral clearance; Time to normalization of clinical symptoms (respiratory rate, fever, SpO2); Frequency of adverse events.
  
  

Data Sharing Plan

• Data Sharing Plan:

  en

  Yes

• Data Sharing Description:

  en

  Data will be made available at ARCAdados FIOCRUZ at the end of the study

Contacts

• Public contact
  • Full name: André B Daher
  • • Address: Av. Comandante Guaranys, 447 Jacarepaguá,
    • City: Rio de Janeiro / Brazil
    • Zip code: 22775-903
  • Phone: +55 21 3348-5050
  • Email: andredaher@gmail.com
  • Affiliation: Fundação Oswaldo Cruz
   
• Scientific contact
  • Full name: André B Daher
  • • Address: Av. Comandante Guaranys, 447 Jacarepaguá,
    • City: Rio de Janeiro / Brazil
    • Zip code: 22775-903
  • Phone: +55 21 3348-5050
  • Email: andredaher@gmail.com
  • Affiliation: Fundação Oswaldo Cruz
   
• Site contact
  • Full name: Jayme Tadeu Fernandes
  • • Address: Av. Brasil, 4036 - Maré, Rio de Janeiro - RJ
    • City: Rio de Janeiro / Brazil
    • Zip code: 21040-361
  • Phone: +5521982986166
  • Email: jayme.fernandes@fiocruz.br
  • Affiliation: Fundação Oswaldo Cruz
   

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