A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults

JRCT ID: jRCT2031200252

Registered date:18/12/2020

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Novel Coronavirus Infectious Disease (COVID-19)
• Date of first enrollment: 14/01/2021
• Target sample size: 20
• Countries of recruitment: United States,Japan,Korea,Japan,Mexico,Japan,Singapore,Japan
• Study type: Interventional

Intervention(s)

<Dosing and Administration>
All subjects will receive remdesivir as a 200 mg intravenous (IV) loading dose on Day 1, followed by a 100 mg once-daily IV maintenance dose for the duration of the hospitalization up to a 10-day total course. If subjects already received the loading dose prior to study enrollment, then start at 100 mg/day on Day 1. Any doses of remdesivir given prior to enrollment will be counted, so the total duration of remdesivir (i.e. pre-enrollment + on this trial) is 10 days (i.e. a maximum of 10 total infusions). Any doses of remdesivir were administered prior to study enrollment should be documented in Advantage eClinical as a concomitant medication given prior to Day 1. The duration of dosing may be adjusted by the site similar to what is described in the package insert and based on a subject's clinical course and ultimate disease severity.
For the baricitinib component, subjects will receive either active product or placebo as follows:
- Baricitinib will be administered as a 4 mg orally (po)(two, 2mg tablets) or dissolved for NG tube, daily for the duration of the hospitalization up to a 14-day total course.
- A placebo will be given as two tablets po or dissolved for NG tube, daily for the duration of the hospitalization up to a 14-day total course.

Outcome(s)

Primary Outcome

- To evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29.
- To evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir according to clinical status (8-point ordinal scale) at Day 15.

Secondary Outcome

- Time to recovery by Day 29
- Time to an improvement of one category and two categories from Day 1 (baseline) using ordinal scale.
- Subject clinical status using ordinal scale at Days 3, 5, 8, 11, 15, 22 and 29.
- Desirability of Outcome Ranking (DOOR) at Day 15 and Day 29
- Oxygenation
_Oxygenation use up to Day 29.
_Incidence and duration of new oxygen use during the study.
- Non-invasive ventilation/high flow oxygen
_Non-invasive ventilation/high flow oxygen use up to Day 29.
_Incidence and duration of new non-invasive ventilation or high flow oxygen use during the study.
- Invasive Mechanical Ventilation / extracorporeal membrane oxygenation (ECMO)
_Ventilator / ECMO use up to Day 29.
_Incidence and duration of new mechanical ventilation or ECMO use during the study.
- Hospitalization
_Duration of hospitalization (days).
- Mortality
_14-day mortality
_28-day mortality
- Laboratory efficacy
_d-dimer, and C-reactive protein (CRP) over time
- To evaluate the safety of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by:
_Cumulative incidence of SAEs through Day 29.
_Cumulative incidence of Grade 3 and 4 clinical and/or laboratory AEs through Day 29.
_Discontinuation or temporary suspension of study product administrations (for any reason).
_Changes in white blood cell (WBC) count with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time (PT reported as INR).
- Virology: To evaluate the virologic efficacy of Arm 1 as compared to Arm 2 as assessed by:
_Percent of subjects with SARS-CoV-2 detectable in OP sample at Days 3, 5, 8, 11, 15 and 29.
_Quantitative SARS-CoV-2 virus in OP sample at Days 3, 5, 8, 11, 15 and 29.
_Quantitative SARS-CoV-2 virus in blood at Days 3, 5, 8 and 11.
- Serology: To evaluate the influence of baricitinib and dexamethasone on SARS-CoV-2 antibody response.
- Immunophenotype: To define immunophenotype of subjects by analyzing markers of inflammation and transcriptomics.
- Chronic Clinical Sequelae: To describe clinical status of subjects 2 months after treatment, overall and by treatment arm.

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Hospitalized with symptoms suggestive of COVID-19.
2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures and understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adults => 20 years of age at time of enrollment.
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other commercial or public health assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva <= 14 days prior to randomization.
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or increased oxygen requirement if on chronic oxygen) and requires at the time of randomization low or high flow oxygen devices or use of non-invasive mechanical ventilation (ordinal scale category 5 or 6).
6. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29 or at least until the 1-month menstrual cycle after taking the study drug.
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.

Exclude criteria

1. Prior enrollment in ACTT-3 or ACTT-4.
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).
3. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of randomization.
4. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
5. Subjects with a low glomerular filtration rate (eGFR), specifically:
a. Subjects with an eGFR 20-30 mL/min are excluded unless in the opinion of the PI, the potential benefit of participation outweighs the potential risk of study participation.
b. All subjects with an eGFR <20 mL/min (including hemodialysis and hemofiltration) are excluded.
6. Neutropenia (absolute neutrophil count <700 cells/microL, 0.7 x 10^3/microL).
7. Lymphopenia (absolute lymphocyte count <200 cells/microL, 0.20 x 10^3/microL).
8. Received five or more doses of remdesivir including the loading dose, outside of the study as treatment for COVID-19.
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until two weeks after the last study product is given are not excluded).
10. Allergy to any study medication.
11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the current illness for which they are being enrolled.
12. Received any of the following in the two weeks prior to screening as treatment of COVID-19:
- small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib, acalabrutinib, etc.);
- monoclonal antibodies targeting cytokines (e.g. TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);
- monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19.
13. Use of probenecid that cannot be discontinued at study enrollment.
14. Received more than one dose of dexamethasone 6 mg or larger (or equivalent for other glucocorticoids) in the 7 days prior to time of randomization. Note: total daily dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 160 mg hydrocortisone.
15. Received =>20 mg/day of prednisone (or equivalent for other glucocorticoids) for =>14 consecutive days in the 4 weeks prior to screening.
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 weeks with appropriate therapy (by history only, no screening required).
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive medications that in the opinion of the investigator could constitute a risk when taking baricitinib or dexamethasone.
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects.

Related Information

• Primary Sponsor: Ohmagari Norio
• Source(s) of Monetary Support: Ministry of Health, Labour and Welfare
• Secondary ID(s): NCT04640168