NCT04843761.

Study name	'ACTIV‐3b: therapeutics for severely ill inpatients with COVID‐19 (TESICO)'
Methods	Trial design: RCT Allocation: randomised Intervention model: parallel assignment Masking: triple (participant, care provider, investigator) Primary purpose: treatment Sample size: NR Estimated enrolment: 640 participants Setting: inpatient Language: English Number of centres: 51 Type of intervention: drug
Participants	Inclusion criteria: Signed informed consent Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes) Current respiratory failure (i.e. receipt of high‐flow nasal cannula, non‐invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxaemic respiratory failure) SARS‐CoV‐2 (COVID‐19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomisation Respiratory failure is believed to be due to SARS‐CoV‐2 pneumonia Exclusion criteria: Known allergy to investigational agent or vehicle More than 4 days since initiation of support for respiratory failure Chronic/home mechanical ventilation (invasive or non‐invasive) for chronic lung or neuromuscular disease (non‐invasive ventilation used solely for sleep‐disordered breathing is not an exclusion) Moribund patient (i.e. not expected to survive 24 hours) Active use of "comfort care" or other hospice‐equivalent standard of care Expected inability to participate in study procedures In the opinion of the investigator, any condition for which participation would not be in the best interest of the participant or that could limit protocol‐specified assessments Previous enrolment in TESICO Agent‐specific exclusion criteria Prior receipt of any dose of remdesivir during present illness (remdesivir agent) GFR (glomerular filtration rate) < 30 mL/min and not receiving dialysis (remdesivir agent) ALT (alanine aminotransferase) or AST (aspartate aminotransferase) > 10 times upper limit of normal (remdesivir agent) Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs placebo (remdesivir agent) Refractory hypotension (aviptadil agent) Severe diarrhoea (aviptadil agent) Current C. difficile infection (aviptadil agent) Pregnancy or current breast‐feeding (aviptadil agent) End‐stage liver disease (aviptadil agent)
Interventions	Details of intervention: Drug: aviptadil placebo + remdesivir + SOC Dose: RDV 200 mg loading dose (day 1), 100 mg (once daily, 9 days) maintenance doses Dose: aviptadil placebo: 0.9% sodium chloride solution over 12 hours per day for 3 days Route of administration: both intravenous Treatment details of control group: Drug: remdesivir placebo Dose: RDV placebo 200 mg loading dose (day 1), 100 mg (once daily, 9 days) maintenance dose Route of administration: intravenous Concomitant therapy: corticosteroid (in line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC)
Outcomes	Primary outcome: Recovery, assessed at 90 days Recovery categorised as 1 (Best): At home and not receiving new supplemental oxygen for ≥ 77 consecutive days; 2: At home and not receiving new supplemental oxygen for 49 to 76 consecutive days; 3: At home and not receiving new supplemental oxygen for 1 to 48 consecutive days; 4: Discharged from hospital but either not yet home or home but receiving new supplemental oxygen; 5: Still hospitalised or receiving hospice care; 6 (Worst): Dead Secondary outcomes: All‐cause mortality (time frame: through day 90) Time to death (time frame: through day 90) Composite of time to recovery, days at home off new supplemental oxygen and time to death (time frame: through day 90) Composite of alive, at home, and off new supplemental oxygen (time frame: through day 90) Composite of recovered, alive and not recovered, and dead (time frame: through day 90) Recovery defined as alive, at home, and off new supplemental oxygen Time from randomisation to recovery (time frame: through day 90) Recovery defined as alive, at home, and off oxygen (treating death as competing risk) Days alive outside short‐term acute care hospital (time frame: up to day 90) Incidence of clinical organ failure or serious infections (time frame: through day 28) Defined as any one or more of: worsening respiratory dysfunction; cardiac and vascular dysfunction; renal dysfunction; hepatic dysfunction; neurological dysfunction, haematological dysfunction; serious infection Composite of death, clinical organ failure or serious infections (time frame: through day 90) Composite of cardiovascular events and thromboembolic events (time frame: through day 28) Composite of cardiovascular events and thromboembolic events (time frame: through day 90) Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death (time frame: through days 5 and 28) Incidence of infusion reactions (time frame: through day 180) Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason (time frame: through day 90) Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event (time frame: through day 90) Composite of hospital readmissions or death (time frame: through day 180) Incidence of no home use of supplemental oxygen above pre‐morbid oxygen use (time frame: 14 days) Measured as: alive at home for an uninterrupted 14‐day period and no use of continuous supplemental oxygen at end of 14‐day time period. Time to hospital discharge from initial hospitalisation (time frame: through day 180) Composite of death or serious clinical COVID‐19 related events (time frame: through day 90) Pulmonary ordinal outcome (time frame: days 1 to 7, 14, and 28) Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used. Composite of SAEs or death (time frame: through day 180) Incidence of home use of supplemental oxygen above pre‐morbid oxygen use (time frame: through day 180) Measured as: alive at home and no use of continuous supplemental oxygen for an uninterrupted 14‐day period In category 4, 5 or 6 at day 90 vs in categories 1 to 3 at day 90 (time frame: day 90) In category 5 or 6 at day 90 vs in categories 1 to 4 at day 90 (time frame: day 90) Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49 to 76 consecutive days; 3: At home and off oxygen for 1 to 48 consecutive days; 4: Not hospitalised and either at home on oxygen or not at home; 5: Hospitalised for medical care or in hospice care; 6 (Worst): Dead
Starting date	20 April 2021
Contact information	Samuel Brown, MD Intermountain Medical Center/University of Utah
Notes	Recruitment status: active, not recruiting Prospective completion date: April 2023 Date last update was posted: 3 June 2022 Sponsor/funding: National Institute of Allergy and Infectious Diseases (NIAID)