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

Study Overview
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Brief Summary
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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.

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

Conditions
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Pneumonia

Intervention / Treatment
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* Drug: Auxora
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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; 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; 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; 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; The patient is ≥ 18 years of age; 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; 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; 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: Expected survival or time to withdrawal of life-sustaining treatments expected to be <7 days. Do Not Intubate order; 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; 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; Noninvasive positive pressure ventilation; Invasive mechanical ventilation via endotracheal intubation or tracheostomy; Extracorporeal membrane oxygenation (ECMO); Shock defined by the use of vasopressors; Multiple organ dysfunction or failure; Positive Influenza A or B testing if tested as local standard of care; The patient has a history of: Organ or hematologic transplant; HIV; Active hepatitis B, or hepatitis C infection; Current treatment with: Chemotherapy; Immunosuppressive medications or immunotherapy (Section 5.3 for list of prohibited immunosuppressive medications and immunotherapy) at the time of consent; Hemodialysis or Peritoneal Dialysis; 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; The patient is known to be pregnant or is nursing; Currently participating in another study of an investigational drug or therapeutic medical device at the time of consent; Allergy to eggs or any of the excipients in study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Auxora<br>Patients will be randomized 1:1 to receive either Auxora or placebo | Drug: Auxora<br>* 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.<br>* Other names: CM4620-Injectable Emulsion (IE);|
| Placebo Comparator: Placebo<br>Patients will be randomized 1:1 to receive either Auxora or placebo | Drug: Placebo<br>* 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.<br>* Other names: Placebo-Injectable Emulsion;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CM4620, COVID-19, Coronavirus, Pneumonia, Calcium release-activated calcium channel (CRAC) inhibitors, Auxora