Covid-19 living Data

Auxora vs Standard care/Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2022-05-16

Studies description

Trial NCT04345614
Publication CARDEA - Bruen C, Crit Care (2022) (published paper)
Dates: 2020-09-08 to 2021-05-24
Funding: Private (CalciMedica, Inc. (La Jolla, CA, USA))
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 60
Inclusion criteria	Adults with a laboratory-confirmed diagnosis of COVID-19 determined by polymerase chain reaction or other assay and pneumonia as documented by chest imaging ≥1 symptom consistent with COVID-19 and respiratory failure, defined as baseline imputed PaO2/FiO2 ≤300, requiring oxygen therapy using either a high flow (HFNC) or low flow nasal cannula
Exclusion criteria	Baseline imputed PaO2/FiO2 ≤75 receiving either non-invasive mechanical ventilation or invasive mechanical ventilation Current treatment with immunosuppressive medications or immunotherapy
Interventions
	Treatment Auxora Initial dose: 2.0 mg/kg IV on day 1 - Maintenance dose: 1.6 mg/kg IV on days 2 and 3
	Control Placebo
Participants
	Randomized participants : Placebo=141 Auxora=143
	Characteristics of participants N= 284 Mean age : NR 190 males Severity : Mild: n=0 / Moderate: n=98 / Severe: n=164 Critical: n=0
Primary outcome
	In the register Number of days from the Start of the First Infusion of Study Drug (SFISD) to recovery [ Time Frame: From start of first infusion of study drug to day 60 ]
	In the report Time to recovery through Day 60, defined as meeting the criteria for category 6 (Hospitalized, not requiring supplemental oxygen or ongoing medical care), category 7 (Discharged, requiring supplemental oxygen), or category 8 (Discharged, not requiring supplemental oxygen) using an 8-point ordinal scale.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, pre-print article, the protocol, the SAP, the supplementary material, the study registry and data from contact with authors were used in data extraction and risk of bias assessment. The study terminated early due to declining rates of US COVID-19 hospitalizations in the spring of 2021, and the adoption of tocilizumab as standard of care in patients at many study sites. Consequently. The trial (n = 284) did not achieve its target sample size (n = 400). There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. The study was first posted to SSRN but was later removed. The study was updated on February 2nd, 2022 with data from the Research Square report. The study was updated on April 28th, 2022 with data acquired after contact with authors. The study was updated on May 11th, 2022 with data from the published report.

Trial NCT04345614
Publication Miller J, Crit Care (2020) (published paper)
Dates: 2020-04-08 to 2020-05-13
Funding: Private (CalciMedica, Inc. )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA Follow-up duration (days): 30
Inclusion criteria	Adults with a diagnosis of COVID-19 determined by reverse transcription polymerase chain reaction and pneumonia documented by chest imaging. In addition, patients were required to have ? 1 symptom consistent with COVID-19, such as fever, cough, sore throat, malaise, headache, muscle pain, dyspnea, confusion, or respiratory distress, and ? 1 clinical sign suggesting respiratory compromise, such as respiratory rate ? 30 breaths per minute, heart rate ? 125 bpm, SpO2 < 93% on room air or requiring > 2 L oxygen by nasal cannula to maintain SpO2 ? 93%, or PaO2/FiO2 < 300, imputed from pulse oximetry or determined by arterial blood gas
Exclusion criteria	From the registry 1. Expected survival or time to withdrawal of life-sustaining treatments expected to be <7 days. 2. Do Not Intubate order 3. Home mechanical ventilation (noninvasive ventilation or via tracheotomy) except for continuous positive airway pressure or bi-level positive airway pressure (CPAP/BIPAP) used solely for sleep-disordered breathing 4. PaO2/FiO2 ? 100 at Screening or noted in the 24 hours before Screening. The PaO2/FiO2 may be estimated from pulse oximetry (Appendix 1) or determined by arterial blood gas 5. High flow supplemental oxygen using a high flow nasal cannula 6. Noninvasive positive pressure ventilation 7. Invasive mechanical ventilation via endotracheal intubation or tracheostomy 8. Extracorporeal membrane oxygenation (ECMO) 9. Shock defined by the use of vasopressors 10. Multiple organ dysfunction or failure 11. Positive Influenza A or B testing if tested as local standard of care 12. Pathogens detected by a respiratory panel if tested as local standard of care 13. The patient has a history of: a. Organ or hematologic transplant b. HIV c.Active hepatitis B, or hepatitis C infection 14. Current treatment with: a. Chemotherapy b. Immunosuppressive medications or immunotherapy (Section 5.3 for list of prohibited immunosuppressive medications and immunotherapy) at the time of consent c. Hemodialysis or Peritoneal Dialysis 15. Have a history of venous thromboembolism (VTE) (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 12 weeks prior to screening or have a history of recurrent (> 1) VTE 16. The patient is known to be pregnant or is nursing 17. Currently participating in another study of an investigational drug or therapeutic medical device at the time of consent 18. Allergy to eggs or any of the excipients in study drug.
Interventions
	Treatment Auxora Initial dose: 2.0 mg/kg IV infusion, maximum 250 mg followed by 1.6 mg/kg IV infusion, maximum 200 mg the next 2 days
	Control Standard care
Participants
	Randomized participants : Standard care=9 Auxora=17
	Characteristics of participants N= 26 Mean age : NR 12 males Severity : Mild: n=0 / Moderate: n=26 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Number of days from the Start of the First Infusion of Study Drug (SFISD) to recovery [ Time Frame: From start of first infusion of study drug to day 30 ]
	In the report recovery rate defined as the first day the patient satisfied criterion 6, 7, or 8 of the 8-point ordinal scale
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published article, the study registry and supplementary appendix were used in data extraction and risk of bias assessment. The study was terminated early by the US Food and Drug Administration. As a result, the target sample size specified in the registry was not achieved. Quote "The FDA provided guidance on May 12, 2020, to limit further enrolment in the open-label study and transition to a randomized, blinded, placebo-controlled study, and as such, both arms A and B ceased further enrolment". The study reported the results in two arms based on severity of the disease. Data on the arm with patients requiring high flow oxygenation (Arm B) was not used in this review as the sample size (n=4) was too small. In the trial registration, the control treatment was intended to be Placebo but was Standard care in the published report. There was no change from the trial registration in the intervention and control treatments in the primary outcome. Some secondary outcomes (number of days in the ICU and CM4620-IE serum concentration) were reported in the registry and not in the published article.