Crizanlizumab for Treating COVID-19 Vasculopathy (CRITICAL)

The purpose of this trial is to test the efficacy and safety of crizanlizumab in patients hospitalized with COVID-19.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Crizanlizumab; Other: 0.9% saline

Detailed Description

Infection with severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) causes coronavirus disease 2019 (COVID-19). The clinical course of COVID-19 is variable, and some patients develop severe pneumonia, multi-organ failure, and shock.

Severe COVID-19 is characterized by a hyper-inflammatory and hyper-thrombotic state. We propose that this state is caused by viral injury of the vascular endothelium, leading to endothelial release of von Willebrand Factor (VWF) and P-selectin, which in turn drive thrombosis and vascular inflammation.

Crizanlizumab is a monoclonal antibody that targets P-selectin. Crizanlizumab can decrease inflammation by binding to P-selectin, blocking leucocyte and platelet adherence to the vessel wall.

We now plan to test the safety and efficacy of crizanlizumab in decreasing biomarkers of inflammation and thrombosis in a placebo-controlled, double-blind randomized clinical trial

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Willing to provide written informed consent
2. Willing to comply with all study procedures and be available for the duration of the study
3. Male or female ≥ 18 years of age
4. SARS-CoV-2 infection (COVID-19) within the past 10 d documented by laboratory test (nucleic acid test (NAT) or reverse transcriptase-polymerase chain reaction (RT-PCR))
5. Currently hospitalized
6. Symptoms of acute respiratory infection (at least one of the following: cough, fever > 37.5°C, dyspnea, sore throat, anosmia),
7. Radiographic evidence of pulmonary infiltrates
8. Requiring supplemental oxygen or the peripheral capillary oxygenation saturation (SpO2) < 94% on room air at screening
9. Elevated D-Dimer > 0.49 mg/L
10. Negative pregnancy test for females of childbearing potential

Exclusion Criteria:

1. Use of home oxygen at baseline
2. Current use of mechanical ventilation
3. Inability to provide consent
4. Do not intubate status
5. Prisoner or incarcerated
6. Pregnancy or Breast Feeding
7. Participation in other interventional therapy trials for COVID-19.
8. International normalized ratio (INR) > 3 or activated partial thromboplastin time (aPTT) > 60

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: Crizanlizumab; Crizanlizumab is a monoclonal antibody targeting P-selectin. Crizanlizumab 5.0 mg/kg in 100 ml IV once.	Drug: Crizanlizumab; Crizanlizumab 5.0 mg/kg in 100 ml IV once.
Active Comparator: Placebo Saline; 0.9% saline 100 ml IV once.	Other: 0.9% saline; 0.9% saline 100 ml IV once.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Soluble P-selectin Level	Level of soluble P-selectin in ng/mL.	Day 3 after randomization or day of hospital discharge, whichever is earlier

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Soluble P-selectin Level	Level of soluble P-selectin in ng/mL.	Day 7 after randomization
Soluble P-selectin Level	Level of soluble P-selectin in ng/mL.	Day 14 after randomization
D-dimer Level	Level of D-dimer in mg/L.	Day 3 after randomization
D-dimer Level	Level of D-dimer in mg/L.	Day 7 after randomization
D-dimer Level	Level of D-dimer in mg/L.	Day 14 after randomization
VWF Level	Level of von Willebrand Factor (VWF) antigen in IU/mL.	Day 3 after randomization
VWF Level	Level of VWF antigen in IU/mL.	Day 7 after randomization
VWF Level	Level of VWF antigen in IU/mL.	Day 14 after randomization
CRP Level	Level of C-reactive protein (CRP) in mg/dL.	Day 3 after randomization
CRP Level	Level of C-reactive protein (CRP) in mg/dL.	Day 7 after randomization
CRP Level	Level of C-reactive protein (CRP) in mg/dL.	Day 14 after randomization
Change in Clinical Status as Assessed by the World Health Organization (WHO) Ordinal Scale for Coronavirus Disease 2019 (COVID-19) Trials	Change in the clinical status over 14 days as measured by an ordinal scale that is the first assessment of the clinical status on a given study day. The scale is as follows: 0 = Uninfected; no viral RNA detected; = Ambulatory; asymptomatic; viral RNA detected; = Ambulatory; symptomatic; independent; = Ambulatory; symptomatic; assistance needed; = Hospitalized; no oxygen therapy; = Hospitalized; oxygen by mask or nasal prongs; = Hospitalized; oxygen by non-invasive ventilation (NIV) or high flow; = Hospitalized; intubation and mechanical ventilation, partial pressure of oxygen / fraction of inspired oxygen (pO2/FIO2) ≥ 150 or oxygen saturation / FIO2 (SpO2/FIO2) ≥ 200; = Hospitalized; intubation and mechanical ventilation, pO2/FIO2 < 150 or SpO2/FIO2 < 200 or vasopressors; = Hospitalized; intubation and mechanical ventilation, pO2/FIO2 < 150 or SpO2/FIO2 < 200 and vasopressors, dialysis, or extracorporeal membrane oxygenation (ECMO); = Dead	Days 3, 7 and 14 after randomization
Time to Hospital Discharge	Time (days) to hospital discharge	Up to 30 days after randomization
Safety of Crizanlizumab as Assessed by Adverse Events	Safety of crizanlizumab will by assessed by adverse events, serious adverse events, and suspected unexpected serious adverse reactions.	Up to day 14 after randomization

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Novartis; Brigham and Women's Hospital; Socar Research SA
• Investigators: Principal Investigator: Charles J Lowenstein, MD, Johns Hopkins University

Publications and helpful links

General Publications

• Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2;376(5):429-439. doi: 10.1056/NEJMoa1611770. Epub 2016 Dec 3.
• Leucker TM, Osburn WO, Reventun P, Smith K, Claggett B, Kirwan BA, de Brouwer S, Williams MS, Gerstenblith G, Hager DN, Streiff MB, Solomon SD, Lowenstein CJ. Effect of Crizanlizumab, a P-Selectin Inhibitor, in COVID-19: A Placebo-Controlled, Randomized Trial. JACC Basic Transl Sci. 2021 Dec;6(12):935-945. doi: 10.1016/j.jacbts.2021.09.013. Epub 2021 Dec 8.
• Metkus TS, Sokoll LJ, Barth AS, Czarny MJ, Hays AG, Lowenstein CJ, Michos ED, Nolley EP, Post WS, Resar JR, Thiemann DR, Trost JC, Hasan RK. Myocardial Injury in Severe COVID-19 Compared With Non-COVID-19 Acute Respiratory Distress Syndrome. Circulation. 2021 Feb 9;143(6):553-565. doi: 10.1161/CIRCULATIONAHA.120.050543. Epub 2020 Nov 13.

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2020
• Primary Completion (Actual): November 28, 2020
• Study Completion (Actual): January 4, 2021

Study Registration Dates

• First Submitted: June 16, 2020
• First Submitted That Met QC Criteria: June 16, 2020
• First Posted (Actual): June 17, 2020

Study Record Updates

• Last Update Posted (Actual): November 9, 2021
• Last Update Submitted That Met QC Criteria: November 3, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: coronavirus
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: IRB00249874

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