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: jRCT2031200035

Registered date:20/05/2020

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Novel Coronavirus Infectious Disease (COVID-19)
• Date of first enrollment: 22/06/2020
• Target sample size: 35
• Countries of recruitment: United States,Japan,Denmark,Japan,Korea,Japan,Mexico,Japan,Singapore,Japan,Spain,Japan,United Kingdom,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 as under the EUA or similar mechanism, then start at 100 mg/day. Any doses of remdesivir under an EUA (or similar mechanism) prior to enrollment will be counted, so the total duration of remdesivir (i.e. EUA + on this trial) is 10 days (i.e., a maximum of 10 total infusions). If one or two doses of remdesivir were administered (under EUA or similar mechanism) prior to study enrollment, this should be documented in eClinical as a concomitant medication given prior to Day 1.
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 crushed 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 crushed for NG tube, daily for the duration of the hospitalization up to a 14-day total course.

Outcome(s)

Primary Outcome

-The overall objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutics relative to the control arm among hospitalized adults who have COVID-19.
-To evaluate the clinical efficacy, as assessed by time to recovery, of different investigational therapeutics as compared to the control arm.
-To evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 15

Secondary Outcome

1.To evaluate the clinical efficacy of different investigational therapeutics as compared to the control arm as assessed by
(1) Clinical Severity
1) Ordinal scale
-Time to an improvement of one category and two categories from Day1(baseline) using an ordinal scale.
-Subject clinical status using ordinal scale at Days 3, 5, 8, 11, 15, 22, and 29.
-Mean change in the ordinal scale from Day 1 to Days 3, 5, 8, 11, 15, 22, and 29.
2)National Early Warning Score (NEWS)
-Time to discharge or to a NEWS of <= 2 and maintained for 24 hours, whichever occurs first.
-Change from Day 1 to Days 3, 5, 8, 11, 15, and 29 in NEWS.
3)Oxygenation
-Oxygenation use up to Day 29.
-Incidence and duration of new oxygen use during the study.
4)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.
5)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.(2) Hospitalization
1)Duration of hospitalization(days)
(3) Mortality
1)14-day mortality
2)28-day mortality

2. To evaluate the safety of different investigational therapeutics as compared to the control arm as assessed by
(1) Cumulative incidence of SAEs through Day 29.
(2) Cumulative incidence of Grade 3 and 4 clinical and/or laboratory AEs through Day 29.
(3) Discontinuation or temporary suspension of study product administrations (for any reason)
(4) Changes in white blood cell (WBC) count with differential, hemoglobin, platelets, creatinine, glucose, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin time (PT) over time (analysis of lab values in addition to AEs noted above).

Key inclusion & exclusion criteria

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

Include criteria

1.Admitted to a hospital with symptoms suggestive of COVID-19 infection.
2.Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
3.Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
4.Male or non-pregnant female adult =>18 years of age at time of enrollment.
5.Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen, as documented by either of the following
-PCR positive in sample collected < 72 hours prior to randomization OR
-PCR positive in sample collected => 72 hours prior to randomization, documented inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited testing capacity, results taking > 24 hours, etc.). AND progressive disease suggestive of ongoing SARS-CoV-2 infection.
6.Illness of any duration, and at least one of the following
-Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
-SpO2 <= 94% on room air, OR
-Requiring supplemental oxygen, OR
-Requiring mechanical ventilation.
7.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.
8.Agrees to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 through Day 29.

Exclude criteria

1. ALT or AST > 5 times the upper limit of normal.
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving hemodialysis or hemofiltration at time of screening.
3. Neutropenia (absolute neutrophil count <1000 cells/microL) (<1.0 x 103/microL or <1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count <200 cells/microL) (<0.20 x 103/microL or <0.20 GI/L)
5. Pregnancy or breast feeding.
6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
7. Allergy to any study medication.
8. Received three or more doses of remdesivir, including the loading dose, outside of the study under the EUA (or similar mechanism) for COVID-19.
9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, the current illness for which they are being enrolled.
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), in the 1 week prior to screening
11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.
13. Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with baricitinib is larger than the risk of COVID-19.
14. Received =>20 mg/day of prednisone or equivalent for =>14 consecutive days in the 4 weeks prior to screening.
15. Use of probenecid that cannot be discontinued at study enrollment.
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
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.
19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE).
20. Immunocompromised patients, patients with a chronic medical condition, or those taking a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at increased risk for serious infections or other safety concerns given the study products.

Related Information

• Primary Sponsor: Ohmagari Norio
• Source(s) of Monetary Support: Ministry of Health, Labour and Welfare
• Secondary ID(s): NCT04401579