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: jRCT2031200092

Registered date:21/08/2020

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Novel Coronavirus Infectious Disease (COVID-19)
• Date of first enrollment: 20/08/2020
• 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 subjectswill receive remdesivir as a 200 mg intravenous (IV) loading dose on Day1, followed by a 100mg once-daily IV maintenance dose up to a 10-day total coursewhile hospitalized.Enrollment may proceed for subjects who received one or two doses of remdesivir under EUA or similar mechanism prior to randomization. If subjectsalready received the loading dose, then start at100 mg/dayon Day1.Any doses of remdesivir under an EUA (or similar mechanism) within 1week of enrollment will be counted, so the maximum number of remdesivir doses given to a subject is 10(i.e. EUAdoses+ doses on this trial). 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 Day1.

For the subcutaneous interferon beta-1a/ placebocomponent, subjects will receive either active product or placebo as follows:
_Interferon beta-1a will be administered every other day as a 44-microgram subcutaneous dose for a total of 4 doses while hospitalized
_A saline placebo will be administered every other day as a subcutaneous injection for a total of 4 doses while hospitalized

Outcome(s)

Primary Outcome

_To evaluate the clinical efficacy of RDV+interferonbeta-1a compared to RDV + placebo, as assessed by time to recovery.
_To evaluate the clinical efficacy of RDV+interferonbeta-1a compared to RDV + placebo, as assessed by clinical status (8-point ordinal scale) at Day 15
_To evaluate the clinical efficacy of RDV+interferonbeta-1a compared to RDV + placebo in those not on mechanical ventilation (baseline ordinal score of 4, 5, or 6) as assessed by time to recovery.

Secondary Outcome

1.To evaluate the clinical efficacy of RDV+interferonbeta-1a compared to RDV + placebo as assessed by:
(1) Clinical Severity
1) Ordinal scale:
_Time to an improvement of one category and two categories from Day 1 (baseline) using an ordinal scale.
_Subjectclinical 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
(4)Laboratory efficacy:
1) d-dimer, and C-reactive protein (CRP)over time

2.To evaluate the safety of RDV+interferonbeta-1a compared to RDV + placebo as assessed by:
1) Cumulative incidence of SAEsthrough 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, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and INRover time (analysis of lab values in addition to AEs noted above).

3.Exploratory_To evaluate the virologic efficacy of RDV+interferonbeta-1a compared to RDV + placebo as compared to the control arm as assessed by:
1) Percent of subjectswith SARS-CoV-2 detectable in OP sample at Days 3, 5, 8, 11, 15, and 29.
2) Quantitative SARS-CoV-2 virus in OP sample at Days 3, 5, 8, 11, 15, and 29.
3) Development of resistance of SARS-CoV-2in OP sample at Days 3, 5, 8, 11, 15, and 29.
4) Quantitative SARS-CoV-2 virus in blood at Days 3, 5, 8, and 11.

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.
2.Subject(or legally authorizedrepresentative) 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 adults => 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(e.g., NAAT and antigen tests)in any respiratoryspecimen, as documented by either of the following:
_PCR or other assay positive in sample collected < 72 hours prior to randomization; OR
_PCR or other assay positive in sample collected =>72 hours but < 7 daysprior to randomizationAND progressive disease suggestive of ongoing SARS-CoV-2 infection.
Note: if written documentation of the positive test result is not available at the time of enrollment(e.g., report came from other institution), the subjectmay be enrolled but the PCR should be repeatedat the time of enrollment.
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 (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day29.

Exclude criteria

1.Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
2.Subject is on or being prepared to go on ECMO at the time of screening.
3.Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the potential risk of study participation.
4.ALT or AST > 5 timesthe upper limitsof normal.
5.Total white cell blood cell count (WBC) <1500 cells/microL.
6.Plateletcount<50,000/microL.
7.History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of bleeding esophageal or gastric varices). No laboratory testing is needed.
8.Pregnancy or breast feeding (lactating women who agree to discard breast milkfrom Day 1 to two weeks after the last study product is givenare not excluded).
9.Allergy to any study medication including history of hypersensitivity to natural or recombinant interferon beta or human albumin.
10.Patient has a chronic or acute medical condition or is taking a medication that cannot be discontinued at enrollment, that in the judgement of the PI, places them at unacceptable risk for a poor clinical outcome if they were to participate in the study.
11.Received three or more doses of remdesivir,including the loading dose, outside of the study for COVID-19.
12.Received convalescent plasma or intravenous immunoglobulin [IVIg] for the treatment of COVID-19.
13.Received any interferon product within two weeks of screening,either for the treatment of COVID-19 or for a chronic medicalcondition (e.g., multiple sclerosis, HCV infection).
14.Received any of the following in the two weeks prior to screeningas 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.
15. Suject with severe depression or suicidal ideation, or a history of severe depression or suicidal ideation
16. Subject with autoimmune hepatitis
17. Subject with epilepsy who are not adequately managed by treatment
18. Subject who is receiving the treatment of Shosaikoto

Related Information

• Primary Sponsor: Ohmagari Norio
• Source(s) of Monetary Support: Ministry of Health, Labour and Welfare
• Secondary ID(s): NCT04492475