A Study of Auxora in Patients With Severe COVID-19 Pneumonia

A Randomized Double Blind, Placebo-Controlled Study of Auxora for the Treatment of Severe COVID-19 Pneumonia (CARDEA)

Part 1 of this trial enrolled 30 patients to receive Auxora (formerly CM4620) in a 2:1 randomized, open label trial of patients with severe and critical COVID-19 pneumonia. Part 2 will consist of a randomized, double blind, placebo-controlled (RCT) study that will evaluate efficacy, safety, and the pharmacokinetic profile of Auxora in patients with severe COVID-19 pneumonia. The number of patients with an imputed PaO2/FiO2 >200 randomized into the study will be capped at 26. 320 patients with a PaO2/FiO2 ≤200 will be enrolled. Patients with an estimated PaO2/FiO2 of 75-200 will be stratified to ensure balanced randomization between the Auxora and placebo arms. Subgroup analyses will be performed to explore how time to recovery is influenced by baseline variables and to evaluate the treatment effect at different levels of each of these variables. The dose of Auxora will be 2.0 mg/kg (1.25 mL/kg) administered at 0 hour, and then 1.6 mg/kg (1 mL/kg) at 24 hours and 1.6 mg/kg (1 mL/kg) at 48 hours from the SFISD. The dose of placebo will be 1.25 mL/kg administered at 0 hour and then 1 mL/kg at 24 hours and 1 mL/kg at 48 hours from the SFISD. Remdesivir, corticosteroids and convalescent plasma will be allowed. The infusion of Auxora will start within 12 hours from the time the patient or LAR provides informed consent. Efficacy analyses will be presented by treatment group (Auxora vs Placebo) based on the Efficacy Analysis Set of the imputed PaO2/FiO2 ≤200 subgroup, except where it is specified otherwise. The statistical analysis approach will be designed to assess the significance of the primary and first secondary endpoint using the Benjamini and Hochberg method to control the overall trial level alpha level.

Study Overview

• Status: Completed
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Auxora; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 284
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial
    • Los Angeles, California, United States, 90033
      • University of Southern California / LA County
    • San Diego, California, United States, 92123
      • Sharp Memorial San Diego
  • Colorado
    • Denver, Colorado, United States, 80220
      • National Jewish Health / St. Joseph's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Baton Rouge General
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai Grace
  • Minnesota
    • Saint Louis Park, Minnesota, United States, 55426
      • Methodist Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
  • Texas
    • El Paso, Texas, United States, 79905
      • Texas Tech University Medical Center
    • Fort Worth, Texas, United States, 76104
      • John Peter Smith Hospital
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54311
      • Aurora Baycare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (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;
   • PCR positive in sample collected ≥ 72 hours prior to randomization, with inability to obtain a repeat sample (e.g. due to lack of testing supplies, or limited testing capacity, or results taking >24 hours, etc.) or progressive disease suggestive of ongoing SARS-CoV-2 infection;
2. At least 1 of the following symptoms: Fever, cough, sore throat, malaise, headache, muscle pain, dyspnea at rest or with exertion, confusion, or respiratory distress;

3. At least 1 of the following signs at Screening or noted in the 24 hours before Screening:

   • PaO2/FiO2 ≤200 when receiving supplemental oxygen. The PaO2/FiO2 may be estimated from pulse oximetry (Appendix 1) or determined by arterial blood gas;
   • If SpO2 ≥97%, must be receiving 10L or more of supplemental oxygen;
4. The presence of a respiratory infiltrate or abnormality consistent with pneumonia that is documented by either a chest X-ray or computerized tomography scan of the lungs;
5. The patient is ≥ 18 years of age;
6. A female patient of childbearing potential must not attempt to become pregnant for 39 months, and if sexually active with a male partner, is willing to practice acceptable methods of birth control for 39 months after the last dose of CM4620-IE;
7. A male patient who is sexually active with a female partner of childbearing potential is willing to practice acceptable methods of birth control for 39 months after the last dose of CM4620-IE. A male patient must not donate sperm for 39 months;
8. The patient is willing and able to, or has a legal authorized representative (LAR) who is willing and able to, provide informed consent to participate, and to cooperate with all aspects of the protocol.

Exclusion Criteria:

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 ≤75 at the time of Screening. The PaO2/FiO2 may be estimated from pulse oximetry (Appendix 1) or determined by arterial blood gas;
5. Noninvasive positive pressure ventilation;
6. Invasive mechanical ventilation via endotracheal intubation or tracheostomy;
7. Extracorporeal membrane oxygenation (ECMO);
8. Shock defined by the use of vasopressors;
9. Multiple organ dysfunction or failure;
10. Positive Influenza A or B testing if tested as local standard of care;

11. The patient has a history of:

    1. Organ or hematologic transplant;
    2. HIV;
    3. Active hepatitis B, or hepatitis C infection;

12. Current treatment with:

    1. Chemotherapy;
    2. Immunosuppressive medications or immunotherapy (Section 5.3 for list of prohibited immunosuppressive medications and immunotherapy) at the time of consent;
    3. Hemodialysis or Peritoneal Dialysis;
13. 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;
14. The patient is known to be pregnant or is nursing;
15. Currently participating in another study of an investigational drug or therapeutic medical device at the time of consent;
16. Allergy to eggs or any of the excipients in study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Auxora; Patients will be randomized 1:1 to receive either Auxora or placebo	Drug: Auxora; Auxora will be given at 2.0 mg/kg (1.25 mL/kg) on Day 1 and then 1.6 mg/kg (1.0 mL/kg) on Days 2 and 3. All doses of Auxora will be administered intravenously (IV) over 4 hours.; Other Names: CM4620-Injectable Emulsion (IE)
Placebo Comparator: Placebo; Patients will be randomized 1:1 to receive either Auxora or placebo	Drug: Placebo; Placebo will be given at 1.25 mL/kg on Day 1 and then 1.0 mL/kg on Days 2 and 3. All doses of placebo will be administered intravenously over 4 hours.; Other Names: Placebo-Injectable Emulsion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days from the Start of the First Infusion of Study Drug (SFISD) to recovery	Defined as the number of days hospitalized but not requiring supplemental oxygen or ongoing medical care, or; discharged and requiring supplemental oxygen, or; discharged, not requiring supplemental oxygen.	From start of first infusion of study drug to day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who have died at day 60 (mortality)		Day 60
Proportion of patients who have died at day 30 (mortality)		Day 30
Proportion of patients requiring invasive mechanical ventilation or dying		from start of start of first infusion of study drug and up to day 60
Proportion of patients requiring invasive mechanical ventilation		from start of start of first infusion of study drug and up to day 60
Differences in outcomes as measured by an 8-point ordinal scale	The ordinal scale is an assessment of the clinical status in a given day. The scale is as follows: 1. Death 2. Hospitalized, requiring invasive mechanical ventilation or ECMO 3. Hospitalized, requiring non-invasive ventilation or high flow supplemental oxygen 4. Hospitalized, requiring low flow supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care 6. Hospitalized, not requiring supplemental oxygen or ongoing medical care 7. discharged, requiring supplemental oxygen 8. Discharged, not requiring supplemental oxygen	from randomization through Days 12 and 30
Number of days in the hospital		from admission into the hospital until discharge from the hospital
Number of days in the Intensive Care Unit (ICU)		from admission into ICU until discharge from ICU
Incidence, intensity and relationship of treatment emergent adverse events (TEAE) and serious adverse events (SAE)		from randomization and through day 60
CM4620-IE serum concentration	Concentration measured using a validated assay	enrollment through 72 hours

Collaborators and Investigators

• Sponsor: CalciMedica, Inc.

Publications and helpful links

General Publications

• Bruen C, Al-Saadi M, Michelson EA, Tanios M, Mendoza-Ayala R, Miller J, Zhang J, Stauderman K, Hebbar S, Hou PC. Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial. Crit Care. 2022 Apr 8;26(1):101. doi: 10.1186/s13054-022-03964-8.
• Miller J, Bruen C, Schnaus M, Zhang J, Ali S, Lind A, Stoecker Z, Stauderman K, Hebbar S. Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. Crit Care. 2020 Aug 14;24(1):502. doi: 10.1186/s13054-020-03220-x.

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2020
• Primary Completion (Actual): June 28, 2021
• Study Completion (Actual): July 30, 2021

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 13, 2020
• First Posted (Actual): April 14, 2020

Study Record Updates

• Last Update Posted (Actual): August 3, 2021
• Last Update Submitted That Met QC Criteria: July 30, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Pneumonia; Coronavirus; COVID-19; CM4620; Calcium release-activated calcium channel (CRAC) inhibitors; Auxora
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia
• Other Study ID Numbers: CM4620-204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No