Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome (CIRCA-19)

Cellular Immuno-Therapy for COVID-19 ARDS (CIRCA-19)

The clinical picture of the novel corona virus 2 (SARS-CoV-2) disease (COVID-19) is rapidly evolving. Although infections may be mild, up to 25% of all patients admitted to hospital require admission to the intensive care unit, and as many as 40% will progress to develop severe problems breathing due to the acute respiratory distress syndrome (ARDS). ARDS often requires mechanical ventilation, with a 50% risk of mortality. Researchers at the Ottawa Hospital Research Institute (OHRI) have been studying the potential therapeutic role of mesenchymal stromal/stem cells, or MSCs, for the treatment of ARDS for over a decade. This has led to the world's first clinical trial using MSC therapy for patients with severe infections (sepsis) which is often associated with ARDS (NCT02421484). This trial demonstrated tolerability, and potential signs of efficacy. In addition, the investigators have established expertise in producing clinical-grade MSCs and have received approval from Health Canada for the use of MSCs in three different clinical studies.

This protocol consists of 2 sequential trials using the same trial infrastructure, noted as the Phase 1 trial 'CIRCA-1901' and the Phase 2a trial 'CIRCA-1902'. CIRCA-1901 is an open-label, dose-escalating and safety trial using a 3+3+3 design to determine the safety, and maximum feasible tolerated dose of repeated delivery of Umbilical Cord Mesenchymal Stromal Cells (UC-MSC) intravenously. The investigators will enroll up to 9 patients; each receiving repeated unit doses of UC-MSCs delivered by IV infusion on each of 3 consecutive days (24±4 hours apart) according to the following dose-escalation schedule (3 patients per dose panel): (i) Panel 1: 25 million cells/unit dose (cumulative dose: 75 million MSCs), (ii) Panel 2: 50 million cells/unit dose (cumulative dose: 150 million MSCs), (iii) Panel 3: up to 90 million cells/unit dose (cumulative dose: up to 270 million MSCs). If no safety issues are identified, we will continue to the Phase 2a trial.

CIRCA-1902 is a single-arm, open-label extension of the CIRCA-1901 trial to assess early signs of efficacy (major morbidity and mortality). The Phase 2a trial (CIRCA-1902) will enroll 12 patients to assess early signals of benefit on mortality and major morbidity in a high risk, high mortality population.

Study Overview

• Status: Completed
• Conditions: Covid19; Acute Respiratory Distress Syndrome
• Intervention / Treatment: Biological: Mesenchymal Stromal Cells

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital

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:

• Age of ≥18 years
• Laboratory-confirmed SARS-CoV-2 infection during the current admission
• On invasive, non-invasive mechanical ventilation (NIV) (PEEP≥5 cmH20) or high-flow nasal canula (HFNC) oxygen therapy (minimum total flow rate of 40 lpm)
• ARDS (onset <96h) as per the international consensus definition (P/F) ratio < 300 on fraction of inspired oxygen (FiO2)≥0.5, with PEEP ≥5cm H2O or on HFNC), not due to cardiac causes.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this trial:

• No consent/inability to obtain consent
• Moribund patient not expected to survive 24 hours
• Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50%
• Currently receiving extracorporeal life support
• Pregnant or lactating
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Moderate to severe chronic liver disease (Childs-Pugh Score > 12)
• Severe chronic respiratory disease with a baseline PaCO2 > 50 mm Hg or the use of home oxygen
• Lung transplant patient
• Documented deep venous thrombosis or pulmonary embolism within the past 3 months
• Inability/contra-indications to receiving local standard of care thromboprophylaxis
• Chronic immunosuppression (any chronic immunotherapy including daily oral steroid use >6months)
• Known HIV, Hep B/C positive, or active Tuberculosis
• Multisystem shock (SOFA score of >2 in >2 systems)
• Patient, surrogate, or physician not committed to full support including intubation (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Panel 1; 25 million cells/unit dose (cumulative dose: 75 million MSCs)	Biological: Mesenchymal Stromal Cells; The Mesenchymal Stromal Cells will be administered intravenously
EXPERIMENTAL: Panel 2; 50 million cells/unit dose (cumulative dose: 150 million MSCs)	Biological: Mesenchymal Stromal Cells; The Mesenchymal Stromal Cells will be administered intravenously
EXPERIMENTAL: Panel 3; up to 90 million cells/unit dose (cumulative dose: up to 270 million MSCs)	Biological: Mesenchymal Stromal Cells; The Mesenchymal Stromal Cells will be administered intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0	Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 to determine the maximum feasible tolerated dose (MFTD) of UC-MSCs given to patients with COVID-19	At time of infusion until one year post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants alive by Day 28	Number of Participants alive by Day 28	Day 28
Number of Participants with ventilator-free Days by Day 28	Number of Participants with ventilator-free Days by Day 28	Day 28

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Stem Cell Network; Ontario Research Fund
• Investigators: Principal Investigator: Duncan J Stewart, MD, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 15, 2020
• Primary Completion (ACTUAL): April 22, 2021
• Study Completion (ACTUAL): April 22, 2021

Study Registration Dates

• First Submitted: April 27, 2020
• First Submitted That Met QC Criteria: May 20, 2020
• First Posted (ACTUAL): May 22, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 26, 2021
• Last Update Submitted That Met QC Criteria: April 23, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; ARDS; Mesenchymal Stromal Cells
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: 20200243-01H

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