Conditions: COVID-19
Keywords: coronavirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

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

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

Arms:
arm 1: Crizanlizumab is a monoclonal antibody targeting P-selectin. Crizanlizumab 5.0 mg/kg in 100 ml IV once. arm 2: 0.9% saline 100 ml IV once.

Interventions: intervention 1: Crizanlizumab intervention 2: 0.9% saline
Intervention descriptions: intervention 1: Crizanlizumab 5.0 mg/kg in 100 ml IV once. intervention 2: 0.9% saline 100 ml IV once.

Protocol document:
Prot_SAP_000.pdf: 
 
 
  
  
  
  
      
 
 
 
 
 
 
CRITICAL:   
CRI zanlizumab for  T reat I ng  C OVID19 v A scu L opathy  
  
Clinical Trial Protocol  
 
  
Principal Investigator:  Charles Lowenstein, MD  
  
Version Number:  30  
  
Date:  14-December-2020  
 
  
  
  
  
  
       
 
 
 
This document is confidential.  
No part of it may be transmitted, reproduced, published, or used by other persons without prior written  
authorization from the Principal Investigator.  
 
  


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SIGNATURE PAGE  
  
I have read the foregoing protocol and agree that it contains all necessary details for carrying out this study. I 
will conduct the study in accordance with the design and specific provisions outlined herein; deviations from the 
protocol are acceptable only with a mutually agreed upon protocol amendment.  
  
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who assist 
in the conduct of this study. I will discuss this material with them to ensure they are fully informed regarding the 
study drug and the conduct of the study.   
  
I will use the informed consent form approved by the principal investigator and will fulfill all responsibilities for 
submitting pertinent information to the Institutional Review Board or Ethics Committee responsible for this 
study.  
  
I also agree to report all information or data in accordance with the protocol and, in particular, I agree to report 
any serious adverse experiences as defined in Section 8 of this protocol.  
  
I also agree to handle all clinical supplies (including study drug) provided by the principal investigator and collect 
and handle all clinical specimens in accordance with the protocol.  
  
The below signed confirm herewith to have read and understood this trial protocol and/or amendment and 
appendices; furthermore, to accomplish this study in accordance to the protocol and Good Clinical Practice 
guidelines, as well as local regulations; and to accept respective revisions conducted by authorized personnel by 
regulatory authorities.  
  
  
 PRINTED OR TYPED NAME(S)  
  SIGNATURE  
  DATE  
  
  
  
  
  
 
 Principal Investigator(s)   
    
    
 
 Principal Investigator(s)  
    
    
  
  
  
 Steering Committee  
  
 Charles J. Lowenstein, MD  
Scott D. Solomon, MD  
Michael B. Streiff, MD  
 Professor of Medicine  
Professor, Harvard Medical School  Professor of Medicine  
Chief of Cardiology  
Brigham and Women’s Hospital  
Johns Hopkins Medicine  
Johns Hopkins Medicine  
75 Francis Street  
Baltimore, MD Baltimore, MD  
Boston, MA 
02115  mstreif@jhmi.edu  
clowens1@jhmi.edu  
ssolomon@rics.bwh.harvard.edu  
4105028642  
410-955-3097  
857-307-1960  
  
 Clinical Coordinating Center  
  


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Shannon Kelley  
Gary G. Gerstenblith, MD JD  
 Research Program Coordinator  
Professor of Medicine  
Johns Hopkins Medicine  
Johns Hopkins Medicine  
  
  
Thorsten Leucker, MD PhD  
David N. Hager, MD, PhD  
Assistant Professor of Medicine Assistant Professor of Medicine Johns Hopkins Medicine  Johns Hopkins 
Medicine   
  
 Data Coordinating Center  
  
 Scott D. Solomon, MD  
Brian Claggett, PhD  
 Professor, Harvard Medical School   
Chief Statistician, Cardiac Imaging Core Laboratory and  
 Brigham and Women’s Hospital  
Clinical Trials Endpoints Center  
75 Francis Street  
Brigham and Women’s Hospital Boston, MA 02115  
Assistant Professor of 
Medicine  
 ssolomon@rics.bwh.harvard.edu  
Harvard Medical School  
857-307-1960  
75 Francis St  
 
  
Boston, MA 02115  
 
  
Tel. 617.525.9541  
 
  Email: bclaggett@partners.org  
 Contact: Bridget-Anne Kirwan, PhD  
  
 Email: Bridget.Kirwan@socar.ch  
  
Contact: Sophie de Brouwer, PhD  
Email: sophie.debrouwer@socar.ch  
SOCAR Research SA  
Ch. de Chantermerle 18  
1260 Nyon  
Switzerland  
  
 Laboratories  
  
Cardiovascular Research Laboratory   
Laboratory Services  
Charles J. Lowenstein, MD  
Department of Pathology  
Johns Hopkins Medicine  
Johns Hopkins Medicine   
600 N. Wolfe St., Ross 844  
Baltimore, MD 21287  
Baltimore, MD 21287  
 Drug Distribution   
  
  
Laura Wachter, BS, MA, BS Pharm, Pharm D  
Research Pharmacist  
Investigational Drug Services  
The Johns Hopkins Hospital 600 
N Wolfe St. – Osler 100  
Baltimore, MD 21287  
T: 410-955-6337.   F: 410-614-8074  
  
TABLE OF CONTENTS  
  


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1.0  
PROTOCOL SUMMARY .......................................................................................................................... 7  
2.0 KEY ROLES ............................................................................................................................................. 9  
Steering 
Committee.................................................................................................................................... 
9  
Clinical Coordinating Center ..................................................................................................................... 10  Data 
Coordinating Center (DCC) .............................................................................................................. 10  Study 
Sites ............................................................................................................................................... 10  
 
  
Funding Source 
........................................................................................................................................ 11  
3.0  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................ 11  
 
  
Disease Background and Study Rationale 
................................................................................................ 11  
 
  
Investigational Product Background .......................................................................................................... 12  
4.0 OBJECTIVES/ENDPOINTS ................................................................................................................... 14  
Primary 
Endpoint...................................................................................................................................... 
14  
Secondary 
Endpoints 
............................................................................................................................... 
14  
Exploratory Endpoints .............................................................................................................................. 15  
 
  
Safety Assessments 
................................................................................................................................. 15  
 
  
Correlative Objective 
................................................................................................................................ 15  
5.0  
STUDY DESIGN ..................................................................................................................................... 15  
6.0 STUDY POPULATION ........................................................................................................................... 16  
Eligibility 
Criteria....................................................................................................................................... 
17  
Accrual Goal ............................................................................................................................................ 17  
 
  
Subject Identification and Recruitment 
...................................................................................................... 17  
7.0  
STUDY DRUGS ..................................................................................................................................... 18  
Crizanlizumab .......................................................................................................................................... 18  
 Placebo 
.................................................................................................................................................... 
18 
Packaging ................................................................................................................................................ 18 
Acquisition and Shipping .......................................................................................................................... 18 
Storage .................................................................................................................................................... 18 
Accountability Procedures ........................................................................................................................ 19 
Randomization, Dosage and Administration ............................................................................................. 19 
Duration of Treatment and Follow-up ........................................................................................................ 19  
Dose Modifications ................................................................................................................................... 19  
Assessment of Subject Compliance .......................................................................................................... 20  
Concomitant Medications ......................................................................................................................... 20  
Precautions .............................................................................................................................................. 20  
 
  
Criteria for Study Treatment Discontinuation 
............................................................................................. 20  
8.0  
VISIT SCHEDULE AND STUDY PROCEDURES................................................................................... 20  
 Visit 1 (Screening/Baseline)...................................................................................................................... 20  Visit 
2 (Randomization and Treatment) ..................................................................................................... 21  Visit 3 
(Day 3 post randomization) ............................................................................................................ 21  
 Visit 4 (Day 7 post randomization) ............................................................................................................ 21  Visit 
5 (Day 14 post randomization) .......................................................................................................... 21  Visit 6 
Phone Call Follow-up (Day 30 post randomization) ........................................................................ 21  Early 
Withdrawal Visit ............................................................................................................................... 21  Schedule 
of Time and Events Table ......................................................................................................... 22  
 
  
Study Procedures 
..................................................................................................................................... 22  
  
  
  
  
  
  
  
  


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9.0  
ASSESSMENT OF EFFICACY .............................................................................................................. 22  
 
  
Specification of the Efficacy Parameters for 
Biomarkers ........................................................................... 22  
 
  
Specification of the Efficacy Parameters for Biomarkers ........................................................................... 23  
10.0 ASSESSMENT OF SAFETY .................................................................................................................. 23  
 
  
Specification of Safety Parameters 
........................................................................................................... 23  
 
  
Classification of an Adverse 
Event............................................................................................................ 23  
 
  
Time Period and Frequency for Event Assessment and Follow-Up ........................................................... 24  
REPORTING PROCEDURES ......................................................................................................................... 24  
 Follow-up of Subjects after Adverse Events .............................................................................................. 25  
Unblinding Procedure ............................................................................................................................... 25  
 
  
Safety 
Oversight....................................................................................................................................... 25  
11.0 CORRELATIVE STUDIES ...................................................................................................................... 25  
 Correlative Studies ................................................................................................................................... 26  
Sample Collection Guidelines ................................................................................................................... 26  
 
  
Specimen Banking 
................................................................................................................................... 26  
12.0 STATISTICAL CONSIDERATIONS ....................................................................................................... 26  
Statistical Analysis Plan............................................................................................................................ 26  
 Analysis Population .................................................................................................................................. 26 
Analysis of Baseline Characteristics ......................................................................................................... 27 
Analysis of Primary Endpoint .................................................................................................................... 27 
Analysis of Secondary Endpoints ............................................................................................................. 27  
Analysis of Exploratory Endpoints ............................................................................................................ 27  
  Missing data ............................................................................................................................................. 28 
Interim Analysis ........................................................................................................................................ 28  
Level of Significance and Sample Size ..................................................................................................... 28  
Stopping Rules for Termination of the Trial ............................................................................................... 28  
Spurious Data Procedures ....................................................................................................................... 28  
Deviation Reporting Procedures ............................................................................................................... 29  
Subjects to be Included in Analyses ......................................................................................................... 29  
Measures to Minimize and Avoid Bias ...................................................................................................... 29  
 Data and Safety Monitoring Board (DSMB) ............................................................................................... 29  
13.0 ETHICS AND PROTECTION OF HUMAN SUBJECTS .......................................................................... 30  
 Ethical Standard ....................................................................................................................................... 30  
Institutional Review Board (IRB) ............................................................................................................... 30  
 
  
Informed Consent Process 
....................................................................................................................... 30  
 
  
Exclusion of Women, Minorities and Children (Special Populations) ......................................................... 30  
14.0 TRIAL MANAGMENT AND COMMUNICATION PLAN .......................................................................... 31  
 Monitoring IRB Approvals ......................................................................................................................... 31  
Monitoring of Modifications ....................................................................................................................... 31  
Problem Management .............................................................................................................................. 31  
 
  
Communication 
........................................................................................................................................ 31  
  
  
  
  
  
  
  


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15.0 DATA COLLECTION AND QUALITY ASSURANCE ............................................................................. 31  
  Data Management Responsibilities........................................................................................................... 31  
 
Clinical Trial Data Management System ................................................................................................... 32  
 
Data Management Procedures ................................................................................................................. 32  
 
Direct Access to Source Data ................................................................................................................... 32  
 
Specimen Collection Management ........................................................................................................... 33  
 
Confidentiality of Data .............................................................................................................................. 33  
 
Confidentiality of Subject Records ............................................................................................................ 33  
 
  
Protocol Deviations 
.................................................................................................................................. 34  
16.0 PUBLICATION POLICY ......................................................................................................................... 34 
17.0 REFERENCES ....................................................................................................................................... 34  
LIST OF ABBREVIATIONS  
  
Abbreviation  
Abbreviation Term  
AE  
Adverse Event/Adverse Experience  
BID  
Twice daily  
BP  
Blood Pressure  
BWH  
Brigham and Women’s Hospital  
BUN  
Blood Urea Nitrogen   
CC  
Coordinating Center  
CFR  
Code of Federal Regulations  
CIOMS  
Council for International Organizations of Medical Sciences  
CRF  
Case Report Form  
CTDMS  
Clinical Trials Data Management System   
CV  
Cardiovascular  
CVD  
Cardiovascular Disease   
DCC  
Data Coordinating Center  
DSMB  
Data and Safety Monitoring Board  
DSUR  
Development Safety Update Report  
eCRF  
Electronic Case Report Form  
EF  
Ejection Fraction  
eGFR  
Estimated Glomerular Filtration Rate  
EMR  
Electronic Medical Record  
eSOCDAT  
Electronic Source Consultation Data Acquisition Tool  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
HIPAA  
Health Insurance Portability and Accountability Act  
IB  
Investigator’s Brochure  
ICF  
Informed Consent Form  
ICH   
International Conference on Harmonisation  
ICMJE  
International Committee of Medical Journal Editors  
IDS  
Investigational Drug Service  
IN  
Investigator Notification  
IND   
Investigational New Drug Application  


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IRB  
Institutional Review Board  
ITT  
Intention-to-Treat  
JH  
Johns Hopkins  
JHH  
Johns Hopkins Hospital  
JHM  
Johns Hopkins Medicine  
JHU  
Johns Hopkins University  
MOP  
Manual of Procedures  
N  
Number (typically refers to subjects)  
NIH  
National Institutes of Health  
OHRP  
Office for Human Research Protections  
PHI  
Protected Health Information  
PI  
Principal Investigator  
PO  
“per os” (by mouth, orally)  
QA  
Quality Assurance  
QC  
Quality Control  
SAE   
Serious Adverse Event/Serious Adverse Experience  
SES  
Subject Enrollment System  
SOCAR  
SOcieté CArdiaque Recherche  
SOP  
Standard Operating Procedure  
UP  
Unanticipated Problem  
UPIRTSO  
Unanticipated Problem Involving Risks to Subjects or Others  
US  
United States  
VWF  
Von Willebrand Factor  
  
 


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1.0  
PROTOCOL SUMMARY  
Title  
CRITICAL:  CRIzanlizumab for TreatIng COVID19 vAscuLopathy  
Brief title  
  
Crizanlizumab for Moderate COVID-19  
Sponsor and Clinical 
Phase  
Johns Hopkins Medicine    
Investigation type  
Drug  
Study type  
Interventional  
Purpose   
The overall objective of this trial is to determine the therapeutic effect and 
tolerance of crizanlizumab in patients with coronavirus disease 2019 
(COVID-19).    
Primary Objective   
The primary objective of this study is to compare crizanlizumab to placebo 
in reducing soluble P-selectin in patients with moderate COVID-19 at day 3 
post randomization or hospital discharge day whichever is earlier.  
Secondary Objectives  
  
• 
To compare crizanlizumab to placebo in reducing markers of vascular 
inflammation and thrombosis including VWF, D-dimer, and CRP at 
days 3, 7 and 14 after randomization, and soluble P-selectin at day 7 
and 14 after randomization.  
• 
To compare crizanlizumab to placebo in improving an ordinal severity 
of illness scale (incorporating O2 requirement, mechanical ventilation, 
death) measured daily.    
• 
To compare crizanlizumab to placebo in time to hospital discharge.  
• 
To assess the safety of crizanlizumab compared to placebo in patients 
with moderate COVID-19.  
Exploratory Objectives  
  
• 
To compare crizanlizumab to placebo in reducing markers of vascular 
inflammation and thrombosis including fibrinogen, IL-6, PCSK9 at days 
3, 7 and 14 after randomization.  
• 
To compare crizanlizumab to placebo for time to resolution of fever.  
• 
To compare crizanlizumab to placebo for time to liberation from 
supplemental oxygen.   
• 
To compare crizanlizumab to placebo in need for and duration of high 
flow nasal cannula at FiO2>0.3 and/or flow >30 L/min,   
• 
Time to death or mechanical ventilation  
• 
To compare crizanlizumab to placebo in need for and duration of 
mechanical ventilation   
• 
To compare crizanlizumab to placebo in time to arterial or venous 
vascular event,  ischemic stroke, or myocardial infarction  
Study design  
This pilot study is a single-center, randomized, double-blind, parallel 
group, placebo-controlled, trial.  
Population  
Approximately 40 male and female patients ≥ 18 years of age who are 
currently hospitalized with COVID-19 and elevated D-Dimer.  


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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 (NAT or 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) within past 10 
days  
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  
Key Exclusion criteria  
1. Use of home oxygen at baseline  
2. Current use of mechanical ventilation  
3. Inability to provide informed consent  
4. Do Not Intubate status  
5. Prisoner or incarcerated status  
6. Pregnant or nursing (lactating) women.  
7. Participation in other interventional drug trials for COVID-19 
(emergency use or unblinded use of convalescent plasma is 
permitted).  
8. INR > 3 or aPTT > 60  
Investigational and 
reference therapy  
Crizanlizumab 5.0 mg/kg vs. Matching Placebo  
  


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Efficacy assessments  
• 
Soluble P-selectin at 7 and 14 days after randomization  
• 
D-dimer at 3, 7 and 14 days after randomization  
• 
VWF at 3, 7 and 14 days after randomization  
• 
CRP at 3, 7 and 14 days after randomization  
• 
Fibrinogen at 3, 7 and 14 days after randomization  
• 
IL-6 at 3, 7 and 14 days after randomization  
• 
PCSK9 at 3, 7 and 14 days after randomization  
• 
Liberation from supplemental oxygen at day 3, 7 and day 14,   
• 
Need for and duration of high flow nasal cannula at FiO2>0.3 and/or 
flow >30 L/min,   
• 
Need for and duration of mechanical ventilation,   
• 
Time to death or mechanical ventilation  
• 
Time to hospital discharge  
• 
Time to arterial or venous vascular event  
• 
Time to ischemic stroke  
• 
Time to myocardial infarction  
• 
World Health Organization (WHO) Ordinal Scale for COVID-19 Trials 
measured daily up to 14 days after crizanlizumab.1 The ordinal scale is 
an assessment of the clinical status at the first assessment of a given 
study day. The scale is as follows: (0) Uninfected; no viral RNA 
detected.  (1) Ambulatory; asymptomatic; viral RNA detected.  (2) 
Ambulatory; symptomatic; independent.  (3) Ambulatory; symptomatic; 
assistance needed.  (4) Hospitalized: no oxygen therapy.  (5) 
Hospitalized; oxygen by mask or nasal prongs.  (6). Hospitalized; 
oxygen by NIV or high flow.  (7) Hospitalized; intubation and 
mechanical ventilation, pO2/FIO2 ≥ 150 or SpO2/FIO2 ≥ 200. (8). 
Hospitalized; intubation and mechanical ventilation pO2/FIO2 < 150 or 
SpO2/FIO2 < 200 or vasopressors.  (9) Hospitalized; intubation and 
mechanical ventilation pO2/FIO2 < 150 or SpO2/FIO2 < 200 and 
vasopressors, dialysis, or ECMO.  (10) Dead.  
Safety assessments  
• 
Suspected Unexpected Serious Adverse Reactions  
• 
Deaths, requirement for mechanical ventilation, thrombotic events will 
be assessed as efficacy endpoints  
• 
Time to major bleeding event.  
• 
Presence of arthralgia, diarrhea, pruritis, vomiting, chest pain  
Data analysis  
The primary efficacy variable will be assessed as analysis of covariance of 
a log-transformed P-selectin levels with baseline value and treatment  
 
allocation as covariates. Secondary biomarker efficacy assessments will be 
similarly analyzed.   
  
Schematic of Trial Design 
Crizanlizumab 


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 Labs 
  
  
  
  
2.0  
KEY ROLES   
  
 
  
Steering Committee  
The Steering Committee is responsible for oversight and management of the conduct of the study 
at the single study site.  Specifics duties include:  
• 
Protocol development  
• 
Ensuring all study staff are trained on the conduct of the protocol and study procedures  
• 
Ensuring adequate resources are available  
• 
Ensuring that the investigation is conducted according to the investigational plan, protocol and 
applicable regulations  
• 
Ensuring proper monitoring of the investigation  
• 
Ensuring that the reviewing Institutional Review Board(s) (IRB) and regulatory authorities are 
promptly informed of significant new information or significant new adverse effects/risks  
• 
Public registration of study with ClinicalTrials.gov.  
Screening 
Baseline 
Randomization 
5.0 mg/kg IV  
N = 20 
Placebo 
N = 20 
Day 1 
Day 7 
Day 14 
Day 3 


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Clinical Coordinating Center   
The Johns Hopkins Medicine Division of Cardiology  will serve as the clinical coordinating center 
(CCC), providing technical and administrative leadership under the authority and direction of the 
lead Principal Investigator (PI).  Responsibilities include working with the lead PI to complete the 
following:   
• 
Developing and maintaining the protocol and Manual of Procedures (MOP)  
• 
Assisting with the development and design of data collection methods (e.g., case report forms) 
•  Assisting with budgets   
• 
Collecting and maintaining critical documents from affiliated investigators (e.g., resume/CV, 
medical license, certification of completion of training, laboratory certifications and laboratory 
norms)  
• 
Conducting regular study meetings   
• 
Ensuring the study site has the most current version of the protocol, investigational product 
information, consent form(s) and other study documents  
• 
Tracking, reporting and maintaining documentation of all serious adverse events and 
unanticipated problems and disseminating the information to the Sponsor  
• 
Providing periodic updates to affiliated investigators on subject enrollment, general study 
progress, and relevant scientific advances   
  
 
  
Data Coordinating Center (DCC)  
Brigham and Women’s Hospital and SOCAR research will serve as the Data Coordinating Center 
(DCC). The DCC will be responsible for providing expertise and support for data management, 
quality control and quality assurance, information technology for communication and trial conduct 
monitoring, and statistical methods for design including randomization, interim monitoring, final 
analysis and final interpretation of findings from analysis, preparation of results in tabular and 
graphical formats for presentation and publication of findings from the trial.   
  
 
  
Study Sites  
Subjects will be recruited from sites within Johns Hopkins Medicine (Table 1).  Roles and 
responsibilities of the local investigators and study team include: •  Compliance with 
protocol, MOP, IRB, federal and state regulations  
• 
Participation in site initiation visit and study meetings  
• 
Recruitment, screening and enrollment of subjects  
• 
Protection of subjects' rights  
• 
Data collection and subject follow-up through study completion  
• 
Transfer of data to the DCC and resolution of all queries   
• 
Compliance with and accountability of administration of study intervention  
• 
Retention of specific records, (e.g., drug distribution records)  
• 
Communication of questions, concerns, and/or observations to the CCC  
• 
Notifying the CCC of changes in study staff  
• 
Adhering to the CCC’s policies and procedures   
  
  
Table 1:  Cli nical Study Sites  
Study Site  
Local PI  
IRB of Record  
Johns Hopkins Hospital 600 
N. Wolfe St.  
Baltimore, MD 21287  
Charles J. Lowenstein, MD 
clowens1@jhmi.edu 410-955-
3097  
JHM IRB  
00249874  
  


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Johns Hopkins Bayview Medical Center  
4940 Eastern Ave  
Baltimore, MD 21224  
Charles J. Lowenstein, MD 
clowens1@jhmi.edu 410-955-3097  
JHM IRB  
00249874  
 
Howard County General Hospital  
5755 Cedar Ln  
Columbia, MD 21044  
 
Charles J. Lowenstein, MD 
clowens1@jhmi.edu 410-955-3097  
JHM IRB  
00249874  
 
  
 
  
Funding Source   
Novartis Pharmaceuticals Corporation is providing financial support and study drug for this 
investigator-initiated clinical trial. Specific responsibilities include:    
• 
Approving protocol changes in writing   
• 
Providing appropriate quantities of investigational product  
• 
Preparing and issuing investigator notifications (INs) for the study drug within 15 calendar days 
of first notification of the suspected unexpected SAE or subsequent follow-up information   
• 
Incorporating a summary of the institution-generated DSUR for the study into the Novartis 
DSUR for the product  
  
3.0  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE   
  
 
  
Disease Background and Study Rationale   
Epidemiology: Infection with severe acute respiratory syndrome coronavirus 2 
(SARSCoV-2) causes coronavirus disease 2019 (COVID-19).2,3  The COVID-19 pandemic has 
affected over 4,000,000 individuals around the world, and cases continue to accumulate.    
Clinical course: The clinical course of COVID-19 is variable.  The incubation period of about 
5 d is followed by clinical disease that can progress from mild to moderate to severe disease.4,5  A 
classification of COVID-19 has been proposed:6  
I. 
Stage I: Mild COVID-19  About 80% of infected patients develop mild disease and then 
recover.  This stage involves viral replication with non-specific symptoms. Symptoms include 
fever, malaise and cough; laboratory tests include viral PCR.   
II. 
Stage II: Moderate COVID-19 About 15% of patients progress to moderate disease.  This 
stage is characterized by pneumonia.  Symptoms can include fever, cough, and dyspnea; 
laboratory tests show lymphopenia and transaminitis, and imaging tests show bilateral 
infiltrates in the lung. Hypoxia can occur at this stage.     
III. 
Stage III: Severe COVID-19 develops in about 5% of patients; this stage is characterized by 
systemic hyperinflammation.  Severe COVID-19 includes acute respiratory distress syndrome 
(ARDS), shock, or multiorgan dysfunction leading to death in about 1% of all cases. Abnormal 
laboratory features include lymphopenia, elevated lactate dehydrogenase, and elevated 
inflammatory markers. Imaging findings include chest CT with ground-glass opacities in a 
peripheral distribution. It is likely that the vascular injury is not confined to the pulmonary 
circulation, but extends to other organs such as the brain, heart, and kidneys. Inflammation in 
the coronary circulation, as well as the myocardium itself, predispose to cardiac arrhythmias, 
including atrial fibrillation and malignant ventricular arrhythmias which are often the terminal 
event in these patients.    
Unique characteristics of COVID-19 suggest microvascular inflammation and thrombosis:   
We propose that microvascular inflammation and thrombosis plays a central role in the 
pathophysiology of COVID-19 and its clinical sequela.  Our conclusion is based on a combination 
of clinical and lab findings in patients with moderate and severe stage COVID-19 – including 
elevated inflammatory biomarkers, elevated thrombotic biomarkers, increased thrombosis, 


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sequestration of leukocytes, and autopsies of patients dying from COVID-19 – which taken 
together suggest vascular inflammation and thrombosis.  
1. COVID-19 is associated with high levels of biomarkers of systemic inflammation such as IL-6, 
TNF-a, IL-1ß.   
2. COVID-19 is associated with high levels of markers of endothelial activation, such as VWF.7   
3. COVID-19 is characterized by high levels of biomarkers of thrombosis such as D-Dimer and 
fibrinogen.8  
4. The incidence of thrombosis in patients with COVID-19 is unusually high: as many as 25% - 
30% of patients with COVID-19 hospitalized in an ICU have venous thromboembolism (VTE) 
such as deep vein thrombosis (DVT) and pulmonary embolism (PE).9-11  Physicians at Hopkins 
and elsewhere have also noted thrombi in the lungs, hearts, liver and kidneys of some patients 
with COVID-19.   
5. The profound lymphopenia seen in COVID-19 suggests that an inflamed vasculature is 
sequestering lymphocytes in the lung and possibly other organs as well.    
6. ARDS associated with COVID-19 is very different from typical ARDS: COVID-19 associated 
ARDS includes compliant lungs (less stiff than classic ARDS), and a unique pattern of lung 
injury seen on chest CT with interstitial inflammation and ground-glass opacifications often in 
the lung periphery (different in appearance and location from typical of classic ARDS). This 
unique form of COVID-19 associated ARDS could suggest a vascular inflammatory process.   
7. Finally, a recent report documents extensive vascular injury and endothelial inflammation in 
several patients who died from severe COVID-19.12  
  
New COVID-19 Paradigm: Vascular Inflammation and Thrombosis:  Taken together, these 
findings suggest a new paradigm for inflammation in COVID-19.  The SARS- 
CoV-2 virus activates endothelial cells in the 
pulmonary vasculature, and then lung 
endothelial cells release both pro- 
COVID-19 causes microvascular 
obstruction and organ damage. 
thrombotic and pro-inflammatory mediators together, such as VWF and Pselectin.  P-
selectin activates two parallel pathways: P-selectin mediates leukocyte rolling along the 
vessel wall, and Pselectin anchors VWF to the vessel wall where VWF interacts with 
platelets.  
 
Leukocytes and platelets adhere to the  
Lungs & 
These vascular events cause a unique form of pulmonary inflammation with ARDS and can lead to 
systemic inflammation.    
Auto-Amplifying Inflammatory Loop: 
This 
vascular pathway creates an auto-amplifying 
inflammatory loop: pulmonary vascular 
inflammation and thrombosis leads to 
pulmonary injury, which causes more 
pulmonary vascular inflammation and 
thrombosis.  This process starts in the lung, 
and then 
may expand to an auto-amplifying loop in 
the 
entire body: systemic vascular inflammation leads to injury in multiple organs which causes further 
systemic vascular inflammation.    
Need for Interventions: New therapies for COVID-19 are urgently needed.  Over 1000 trials 
registered on clinicaltrials.gov study various classes of therapy for COVID-19 including: 
antiinflammatory drugs (glucocorticoids, NSAIDs, IL-6 pathway inhibitors), anti-viral drugs 
(remdesivir, hydroxychloroquine), and convalescent plasma. No current or proposed therapy 
directly targets vascular inflammation in COVID-19.  The unique aspect of our proposal is a drug 
endothelial cells and obstruct the lung 
microvasculature, leading to a prothrombotic 
and pro-inflammatory state.  
Other Organs 
Coronavirus injures small blood vessels, vessels release mediators, platelets 
and leukocytes obstruct small blood vessels, causing thrombosis and 
inflammation of lungs and other organs. 
Coronavirus 
Vessels 
P-selectin 
VWF 
D-dimer 
CRP 
IL-6 
TF 
Platelets & 
Leukocytes 
Thrombosis & 
Inflammation 


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that targets the vasculature, interrupting the auto-amplifying loop by breaking the link between 
vascular inflammation and tissue injury.  
  
 
  
Investigational Product Background  
Summary:  Crizanlizumab is an IgG2 kappa humanized monoclonal antibody that binds to 
P-selectin with high affinity, blocking the interaction between P-selectin and its ligand.   
Mechanism of Action:  The interaction between P-selectin and its ligand is the first step in 
vascular inflammation and thrombosis.  Resting endothelial cells and resting platelets do not 
express P-selectin.  Immediately following injury or activation, endothelial cells and platelets 
display P-selectin on the outer surface of the cell.  P-selectin on endothelial cells interacts with 
leukocytes and begins the process of vascular inflammation.  P-selectin on the surface of platelets 
begins the process of platelet adherence and thrombosis.  Crizanlizumab blocks the interaction 
between P-selectin and its ligand, interfering with leukocyte and platelet adherence to the vessel 
wall.  
Indication:   Crizanlizumab is indicated to reduce the frequency of vasoocclusive crisis in 
patients 16 and older with sickle cell disease (SCD).  The SUSTAIN clinical trial showed that 
crizanlizumab prevents vaso-occlusive events in patients with SCD, a process that involves 
endothelial release of P-selectin and vaso-occclusion.13  This trial led to FDA approval of 
crizanlizumab to reduce the frequency of vaso-occlusive sickle cell crises in 2019.  
Pharmacology:  Crizanlizumab is administered 5.0 mg/kg intravenously over 30 min in 
patients with SCD.  Crizanlizumab is 100% bioavailable.  The median time to reach maximum 
concentration is 1.6 h.  The volume of distribution is 4.3 L after a single dose in healthy volunteers.   
The half-life is 10.6 d. The route of elimination is not through the liver or kidneys.  
Safety:  Crizanlizumab has a favorable safety profile.  In a randomized double-
blindplacebo controlled trial (SUSTAIN) of 198 patients, serious adverse events were reported in 
55 patients, including 17 patients in the placebo group, 21 in the low dose crizanlizumab group, 
and  
17 in the high dose crizanlizumab group.13  There were no significant adverse events in the 
SUSTAIN trial.  “The serious adverse events that occurred in at least 2 patients in either active 
treatment group and at a higher frequency than in the placebo group were pyrexia and influenza. A 
total of 5 patients died during the trial, including 2 patients in the high-dose crizanlizumab group (1 
patient from the acute chest syndrome, and 1 from endocarditis and sepsis), 1 in the low- dose 
crizanlizumab group (from the acute chest syndrome, aspiration, respiratory failure, and 
progressive vascular congestion), and 2 in the placebo group (1 from right ventricular failure, and 1 
from vaso-occlusive crisis, ischemic stroke, coma, sepsis, and venous thrombosis of the right 
lower limb). Three additional single-occurrence adverse events that were considered to be both 
serious and life-threatening but that did not result in death included sepsis (in the placebo group), 
anemia (in the low-dose crizanlizumab group), and intracranial hemorrhage (in the low-dose 
crizanlizumab group). The patient with intracranial hemorrhage was being treated with ketorolac, 
which is associated with an increased risk of hemorrhagic stroke, at the time of the event. No other 
clinically significant bleeding events were observed in the trial. Adverse events that occurred in 
10% or more of the patients in either active-treatment group were headache, back pain, nausea, 
arthralgia, pain in upper and lower limbs, urinary tract infection, upper respiratory tract infection, 
pyrexia, diarrhea, musculoskeletal pain, pruritus, vomiting, and chest pain.”13  “Adverse events that 
occurred in 10% or more of the patients in either active treatment group and at a frequency that 
was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, 
and chest pain.”13  
Infusion related reactions:  Administration of monoclonal antibodies can be associated with 
infusion related reactions (IRR) In the SUSTAIN trial of crizanlizumab for the prevention of 
vasoocclusive events in patients with sickle cell disease, , IRRs were more frequent in the 5 mg/kg 
arm (23 patients, 34.8%) than placebo arm (13 patients, 21.0%). However, only 1 event, nausea, 
was reported in at least 10% of patients: 10.6% vs. 1.6% patients in 5 mg/kg vs. placebo arm, 
respectively. Except for nausea, none of the events were reported with an absolute differences of 


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more than 5% in the crizanlizumab 5 mg/kg arm vs. placebo. A review of potential IRR events 
revealed few cases supportive of typical IRRs. None of these AEs were suggestive of severe 
allergic or anaphylactic reactions. Most patients continued their treatments without need for 
premedication.13  
Subjects in the current trial protocol will be randomly assigned to crizanlizumab 5.0 mg/kg  
IV or a matching placebo once. All study drug will be provided free of charge by Novartis during  
the treatment phase. Additional open label anti-inflammatory and antithrombotic medications and 
other medications will be permitted for subjects.   
  
3.2.1 Summary of Findings from Relevant Clinical Trials  
The SUSTAIN trial (Study to Assess Safety and Efficacy of Crizanlizumab (SelG1) with or 
without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell–Related Pain 
Crises) was a multicenter, randomized, double-blind, placebo-controlled trial in 198 
subjects with sickle cell disease and a history of vaso-occlusive crises.13 Subjects were 
randomized to receive crizanlizumab or placebo every 2 weeks and followed for 52 weeks.  
The primary endpoint was the annual rate of vaso-occlusive pain crises.  Secondary 
endpoints included annual rate hospitalized days, annual rate of uncomplicated crises, 
annual rate of acute chest syndrome, pain score by questionnaire, time to first and second 
vaso-occlusive crisis.  Crizanlizumab therapy decreased the rate of vaso-occlusive crises 
(45% lower rate, P = 0.001).  “Adverse events that occurred in 10% or more of the patients 
in either active treatment group and at a frequency that was at least twice as high as that in 
the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.”13  
  
3.2.2 Summary of the Known and Potential Risks and Benefits to Human Subjects Risks 
associated with crizanlizumab have been reported in the SUSTAIN trial.13   Adverse 
events that occurred in at least 10% of patients receiving crizanlizumab and that occurred 
more than twice the rate of patient receiving placebo included arthralgia, diarrhea, pruritus, 
vomiting, and chest pain.  Serious adverse reactions to crizanlizumab include pyrexia 2%. 
A summary of all adverse reactions to crizanlizumab include: nausea 14%, abdominal pain 
8%, diarrhea 8%, vomiting 5%, pyrexia 2%.  
  
  
4.0  
OBJECTIVES/ENDPOINTS  
  
 
  
Primary Endpoint  
The primary endpoint is the difference in level of soluble P-selectin between the group receiving 
crizanlizumab and the group receiving placebo at day 3 after randomization or hospital discharge 
day, whichever is earlier.    
  
 
  
Secondary Endpoints  
The secondary objectives are as follows:  
• 
level of soluble P-selectin at day 7 and 14 (+/- 1 d)  
• 
level of D-dimer at day 3, day 7 and 14,   
• 
level of VWF at day 3, day 7 and 14,   
• 
level of CRP at day 3, day 7 and 14;     
• 
World Health Organization (WHO) Ordinal Scale for COVID-19 Trials measured daily up to 
14 days after crizanlizumab.  The ordinal scale is an assessment of the clinical status at the 
first assessment of a given study day. The scale is as follows:   
0. Uninfected; no viral RNA detected  
1. Ambulatory; asymptomatic; viral RNA detected  
2. Ambulatory; symptomatic; independent  
3. Ambulatory; symptomatic; assistance needed  


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4. Hospitalized; no oxygen therapy   
5. Hospitalized; oxygen by mask or nasal prongs  
6. Hospitalized; oxygen by NIV or high flow   
7. Hospitalized; intubation and mechanical ventilation, pO2/FIO2 ≥ 150 or SpO2/FIO2 ≥ 
200  
8. Hospitalized; intubation and mechanical ventilation, pO2/FIO2 < 150 or SpO2/FIO2 < 
200 or vasopressors  
9. Hospitalized; intubation and mechanical ventilation, pO2/FIO2 < 150 or  
SpO2/FIO2 < 200 and vasopressors, dialysis, or ECMO   
10. Dead  
• 
time to hospital discharge  
• 
safety of crizanlizumab  
  
Note: units for labs include: soluble P-selectin ng/ml, VWF antigen %, CRP mg/dL, D-dimer mg/L 
FEU, IL-6 pg/mL.  
  
 
  
Exploratory Endpoints  
The exploratory endpoints are as follows:  
• 
levels of fibrinogen at day 3, day 7 and day 14,   
• 
levels of IL-6 at day 3, day 7 and day 14,   
• 
level of TNF-alpha at day 3, day 7 and day 14  
• 
level of factor 8 at day 3, day 7 and day 14  
• 
levels of soluble ICAM-1 at day 3, day 7 and day 14  
• 
levels of soluble VCAM-1 at day 3, day 7 and day 14  
• 
levels of CCL2 at day 3, day 7 and day 14   
• 
level of troponin isoform T or I at day 3, day 7 and day 14  
• 
level of NT-pro-BNP at day 3, day 7 and day 14  
• 
levels of PCSK9 at day 3, day 7 and day 14,   
• 
time to resolution of fever,  
• 
time to liberation from supplemental oxygen,   
• 
time to mechanical ventilation,   
• 
time to hospital death,  
• 
time to arterial or venous vascular event  
• 
time to ischemic stroke,  
• 
time to myocardial infarction  
• 
time to hospital discharge.     
  
  
 
  
Safety Assessments   
Standard laboratories will be collected at days 3, 7, and 14 including: basic metabolic panel (Na, K, 
HCO2, Cl, BUN, Cr) and complete blood count (WBC, Hct, Hgb, Plt) with differential.   
  
 
  
Correlative Objective  
None.  
  
  
5.0  
STUDY DESIGN  
  
CRIzanlizumab for TreatIng COVID19 vAscuLopathy (CRITICAL) is a prospective, single center, 
doubleblind, placebo-controlled, randomized, phase II trial to compare the effects of crizanlizumab to 
placebo in patients with moderate severity COVID-19.  A total of 40 subjects will be enrolled at a single 


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center. Subject accrual will occur over 6 months with the total duration of the trial expected to be 8 
months.     
  
Following the completion of screening and baseline procedures, eligible subjects will be randomized to a 
single dose of crizanlizumab 5.0 mg/kg IV or  placebo. Subjects will be followed as inpatients for 14 d or 
until discharge.  Subjects discharged before 14 d will be called at home.  Clinical labs will be assessed at 
baseline (visit 1) and 7 and 14 d  post randomization and hospital discharge day.  
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Figure 2: Study Flow Diagram  
  
Study Flow Diagram 


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Inpatient with documented diagnosis of COVID-19 
Screening 
Baseline 
Randomization 
14 days 
treatmentN = 
20 
N = 20 
 
 Clinical Assessments 
 
Labs at day 3, 7, 14 
Follow-up Phone Call at day 30 
Follow-up 
STOP 
  
  
  
6.0  
STUDY POPULATION  
  
 
  
Eligibility Criteria   
Eligibility will be determined by the below inclusion and exclusion criteria and confirmed by medical 
record review as necessary.    
  
Inclusion Criteria   
1. Willing to provide written informed consent   
 
4. SARS-CoV-2 infection (COVID-19) within the past 10 d documented by laboratory test 
(NAT or 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   
Active Group 
Crizanlizumab 
Informed Consent 
Subject meets eligibility criteria 
Randomization 1:1 
Placebo Group 
Placebo 
Indicate reason on  
Screening log 
STOP 


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8. Requiring supplemental oxygen or the peripheral capillary oxygenation saturation (SpO2) < 
94% on room air at screening  
9. Elevated D-Dimer > 0.49 mg/dL  
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 drug trials for COVID-19 (emergency use or unblinded 
use of convalescent plasma is permitted).  
8. INR > 3 or aPTT > 60  
  
 
  
Accrual Goal  
A total of 40 subjects will be enrolled from clinical sites within Johns Hopkins Medicine.  
  
 
  
Subject Identification and Recruitment  
Several recruitment strategies will be employed.  Specific recruitment strategies are as follows 
(non-comprehensive list):  
  
6.3.1 Inpatient Visits  
Potential subjects may be identified by visits to the hospital inpatient floors in the 
recruiting site, review of Emergency Department admission logs, or notification by 
treating physicians.  A member of the clinical team will inform patients of the 
research opportunity and ask if they would like more information.  If the patient is 
agreeable, the research team will initiate contact or the potential subject may also 
directly contact the study team.  Potential subjects will be pre-screened through 
medical record review and conversation with the subject using an IRB-approved 
script with appropriate protection for study personnel.  Information collected from 
patients who fail pre-screening will be destroyed. Patients who meet all prescreening 
criteria will be invited to participate as an inpatient in a formal screening/baseline 
visit.     
  
6.3.2 Electronic Medical Record (EMR) Query   
Potential subjects may also be identified via EMR query using diagnostic codes for 
COVID-19 or viral infection or coronavirus and other eligibility criteria.  The research team 
will conduct further prescreening of individual records to further refine the list of potential 
subjects.  The treating physician of potentially eligible subjects will be notified prior to 
approaching their patient about the research study.  If the treating physician does not 
object, the study team will contact the patient in the hospital and offered the chance to 
opt out.  Patients who do not opt-out will be contacted by a member of the study team to 
discuss the project using an IRB-approved script.  Information collected from patients 
who fail pre-screening will be destroyed. Patients who meet all pre-screening criteria will 
be invited to participate as an inpatient in a formal screening/baseline visit.     
  
  
7.0  
STUDY DRUGS  
  


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Crizanlizumab  
Crizanlizumab is a monoclonal IgG2 kappa humanized antibody to P-selectin. The FDA approved 
the use of crizanlizumab 5.0 mg/kg every two weeks to prevent vaso-occlusive disease in patients 
with sickle cell anemia.  
  
Pharmacology:  Crizanlizumab is administered intravenously (IV), and is 100% bioavailable. The 
median time to reach maximum serum concentration (Tmax) was 1.6 hours at steady state 
following an IV administration of 5 mg/kg over a period of 30 minutes in SCD patients. Distribution 
is typical of endogenous human antibodies within the vascular and extracellular spaces. The 
volume of distribution at steady state (Vz) was 4.3 L after a single 5 mg/kg IV infusion in healthy 
volunteers. Antibodies are predominately eliminated via proteolysis by lysosomal enzymes into 
small peptides and amino acids. In healthy volunteers, the mean terminal elimination half-life 
(T1/2) was 10.6 days, and the mean clearance was 11.7 mL/hr at a dose level 5 mg/kg. In patients 
with SCD, the mean apparent T1/2 during dosing interval was 7.6 days, and the estimated 
clearance was 17.2 mL/hr. There was no indication of accelerated clearance or time-dependent 
change in the PK properties of crizanlizumab following repeated administration. No dedicated 
studies have been conducted to evaluate specific pathways of crizanlizumab excretion, or to 
investigate the pharmacokinetics PK of crizanlizumab in patients with renal or hepatic impairment, 
since antibodies are not metabolized by cytochrome P450 enzymes, and the kidneys/liver are not 
a major organ for antibody metabolism or excretion.  
  
 
  
Placebo  
A matched placebo to crizanlizumab will be prepared by the Investigational Drug Service of The 
Johns Hopkins Hospital.  The placebo will be commercially available sterile normal saline 0.9% 
100 mL bags.  
  
 
  
Packaging  
Crizanlizumab will be supplied in single use vials containing 10 mL at a concentration of 10 mg/mL 
for administration by IV infusion.   
  
 
  
Acquisition and Shipping   
All study drug will be provided free of charge by Novartis during the treatment phase.  The placebo 
of saline will be supplied by the Johns Hopkins Investigational Drug Service.  The Johns Hopkins 
Investigational Drug Service will be responsible for blinding and labeling the study drug vials and 
distributing study drug to the inpatient floors.  The randomization and the randomization codes will 
be supplied by SOCAR.  
  
 
  
Storage  
Investigational product must be stored at a temperature between 2°C to 8°C (36°F to 46°F) in the 
original carton.  Investigational product must be stored separately from normal hospital stocks and 
must be stored in a securely locked area accessible only to authorized trial personnel until 
dispensed. The temperature must be monitored and documented on the appropriate form for the 
entire time that the investigational product is at the trial site. If the storage temperature deviates 
from the permitted range, the investigational product must not be administered, and the Site 
Investigator or responsible person should contact the DCC for further instructions.  
  
 
  
Accountability Procedures  
The person in charge of product management at Johns Hopkins Investigational Drug Service will 
maintain records of product delivery to the trial site, product inventory at the site, the dose given to 
each subject, and the disposal of or return of unused doses to Johns Hopkins Investigational Drug 
Service. The DCC will verify the trial site’s product accountability records against the record of 


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administered doses in the eCRFs, the source documents, and the communication from the online 
randomization program.  
  
In case of any expected or potential shortage of product during the trial, the Investigator or an 
authorized designee should alert the DCC as soon as possible, so that a shipment can be 
arranged. In the event of a quality issue, the site should quarantine the investigational product and 
contact Biologics for further instructions.  
  
 
  
Randomization, Dosage and Administration  
Subjects will be randomized (1:1) to receive either crizanlizumab or placebo using a secure web 
based randomization system – cf. section Error! Reference source not found.. When a patient is 
randomized, the Unblinded Pharmacist will receive an automated e-mail message indicating the 
study treatment number assigned to each subject. The email notification will also detail the 
patient’s body weight.  
  
Subjects will be randomized to one of the below treatment arms:  
• 
Active Group:  crizanlizumab 5.0 mg/kg IV  
• 
Placebo Group: placebo IV  
  
7.7.1 Crizanlizumab  
For subjects randomized to the crizanlizumab group, using the body weight shown on the email 
notification received (cf. section Error! Reference source not found.), the pharmacist or 
designated personnel will prepare individual doses of crizanlizumab for subjects on a milligram per 
kilogram basis in a 100 mL infusion bag in accordance with the Pharmacy Manual. Crizanlizumab 
will be administered over 30 minutes by IV infusion. To maintain blinding, the 100 ml saline pouch 
will be placed inside an amber colored outer bag.   
7.7.2 Placebo  
For subjects randomized to the placebo group, the pharmacist or designated personnel will 
prepare the individual 100 ml infusion bag in accordance with the Pharmacy Manual. The placebo 
infusion will be administered over 30 minutes by IV infusion. To maintain blinding, the 100 ml 
saline pouch will be placed inside an amber colored outer bag.   
  
Once prepared by the pharmacist, the 100 ml saline pouches containing the study treatment 
infusion will be labelled and placed in an amber colored outer bag.   
  
  
  
 
  
Duration of Treatment and Follow-up  
Subjects will be administered a single dose of study treatment on day 1.  The subject will be 
monitored for one (1) hour after infusion.  
  
 
  
Dose Modifications  
Not applicable.   
  
 
  Assessment of Subject Compliance  
Not applicable.   
  
 
  Concomitant Medications  
Use of all concomitant medications are permitted during the study.  
  


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Interactions between crizanlizumab and other medicinal products have not been investigated in 
dedicated studies.  Monoclonal antibodies are not metabolized by cytochrome P450 (CYP450) 
enzymes. Therefore, medicinal products that are inhibitors or inducers of CYP450 are not 
expected to affect PK of crizanlizumab. Concomitant medications including HU/HC had no effect 
on crizanlizumab PK in patients with SCD in clinical studies.  
  
Based on the data generated to date, crizanlizumab does not have a clinically relevant effect on 
the QT interval.  The relationship between crizanlizumab exposure and changes in QTc from 
baseline (ΔQTc) was assessed using a linear mixed effect model in pooled data from 66 healthy 
subjects for whom at least 1 valid time-matched PK-ECG measurement was available.  The model 
estimated mean ΔQTc at steady state Cmax observed in SCD patients was 0.23 ms (90% CI: 
0.72, 1.20 ms). This effect is not clinically relevant since the upper 90% CI is well below the 
regulatory threshold of change in QTc interval of 10 ms.  
  
 
  Precautions   
None.  Crizanlizumab can cause lab testing artifacts in automated platelet counts.  Platelet counts 
in blood drawn from patients can show false low platelet levels due to platelet clumping in the test 
tube.  There is no evidence that crizanlizumab causes a reduction in circulating platelets or has a 
pro-aggregant effect in vivo.   
  
False low readings of platelet counts are observed in blood collected in lavender top test tubes 
containing EDTA.  False low readings of platelet counts can be avoided by collecting blood in  blue 
top test tubes with sodium citrate.  When needed, manual platelet estimation via blood smear to 
assess adequacy of the platelet count may be considered.  
  
  
 
  Criteria for Study Treatment Discontinuation   
Subjects may discontinue protocol therapy at any time at their own request or at the discretion of 
the investigator.  The reasons(s) for discontinuation will be documented and may include:  
• 
Subjects withdraws from treatment (follow-up permitted)  
• 
Subject withdraws consent (termination of treatment and follow-up)  
• 
Subject is unable to comply with protocol requirements  
  
  
8.0  
VISIT SCHEDULE AND STUDY PROCEDURES  
  
 
  
Visit 1 (Screening/Baseline)  
• 
Obtain written informed consent  
• 
Obtain contact information, demographic information  
• 
Review and document required past medical history, medication history  
• 
Assess inclusion and exclusion criteria  
• 
Pregnancy testing (urine or blood) in women of childbearing age  
• 
Assess vital signs (BP, HR, RR, Temp), record SpO2%, record weight, assess further inclusion 
and exclusion criteria  
• 
Draw blood for laboratory tests including: soluble P-selectin, VWF, D-dimer, CRP, fibrinogen, 
IL-6, TNF-alpha, Factor 8, sICAM-1, sVCAM-1, CCL2, troponin, NT-pro-BNP, PCSK9.  
• 
Contact Johns Hopkins Investigational Drug Service  
• 
Schedule Day 3, 7, and Day 14 Study Visit  
 
  
Visit 2 (Randomization and Treatment)  
• 
Randomization  
• 
Treatment with crizanlizumab or placebo  
  


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Visit 3 (Day 3 post randomization)  
• 
Assess the occurrence of (S)AEs of interest  
• 
Document concomitant medicines of interest (anticoagulants, anti-platelets, 
immunosuppressants, antivirals)  
• 
Obtain vitals (BP, HR, RR, Temp) and SpO2%  
• 
Complete hospital log   
• 
Draw blood for laboratory tests including: soluble P-selectin, VWF, D-dimer, CRP, fibrinogen, 
IL-6, TNF-alpha, Factor 8, sICAM-1, sVCAM-1, CCL2, troponin, NT-pro-BNP, PCSK9.  
• 
Schedule Day 7 Study Visit  
  
 
  
Visit 4 (Day 7 post randomization)  
• 
Assess the occurrence of (S)AEs of interest  
• 
Document concomitant medicines of interest (anticoagulants, anti-platelets, 
immunosuppressants, antivirals)  
• 
Obtain vitals (BP, HR, RR, Temp) and SpO2%  
• 
Complete hospital log (if still hospitalized)  
• 
Draw blood for laboratory tests including: soluble P-selectin, VWF, D-dimer, CRP, fibrinogen, 
IL-6, TNF-alpha, Factor 8, sICAM-1, sVCAM-1, CCL2, troponin, NT-pro-BNP, PCSK9. • 
 
Schedule Day 14 Study Visit   
  
 
  
Visit 5 (Day 14 post randomization)   
• 
Assess the occurrence of (S)AEs of interest  
• 
Document concomitant medicines of interest (anticoagulants, anti-platelets, 
immunosuppressants, antivirals)  
• 
Obtain vitals (BP, HR, RR, Temp) and SpO2%  
• 
Complete hospital log (if still hospitalized)  
• 
Draw blood for laboratory tests including: soluble P-selectin, VWF, D-dimer, CRP, fibrinogen, 
IL-6, TNF-alpha, Factor 8, sICAM-1, sVCAM-1, CCL2, troponin, NT-pro-BNP, PCSK9.  
  
 
  
Participant Discharge  
In the event that a participant discharges before day 14, the study team will draw blood for 
inflammatory and safety markers on the day of discharge along with obtaining vitals and 
completing the hospital log.  
  
  
 
  
Visit 6 Phone Call Follow-up (Day 30 post randomization)  
• 
Assess AEs by querying subjects about new signs and symptoms of acute respiratory infection 
(cough, fever > 37.5°C, dyspnea, sore throat, anosmia).  
• 
Collect information regarding possible signs or symptoms of venous thromboembolism (new 
shortness of breath, new swollen leg, new painful leg) and bleeding  
• 
Document subject study completion  
  
 
  
Early Withdrawal Visit  
• 
Collect study medications  
• 
Assess AEs  
• 
Document early withdrawal  
• 
Patients will be encouraged to not withdraw informed consent if they simply do not wish to 
continue with study procedures. All attempts will be made to follow patients for vital status.  
  
  


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Schedule of Time and Events Table   
  
Study Procedure  
Visit 1 
Day 0  
Visit 2* 
Day 1  
Daily Day 
1-14  
Visit 3 
Day 3  
Visit 
4 
Day 7  
Visit 5  
Day 14  
Visit 6  
Day 30  
Unscheduled  
Visit  
Inclusion/Exclusion Criteria  
x  
   
  
   
   
   
   
   
Vital Signs: BP, HR, RR, 
Temp, SpO2%  
x  
   
  
  
x  
x  
   
x  
Pregnancy Test  
x  
   
  
   
   
   
   
   
WHO Clinical Scale,  and 
Fever   
x  
x  
x  
x  
x  
x  
  
  
Clinical Labs  
x  
   
  
x  
x  
x  
  
x  
Randomization  
  
     x   
  
   
   
   
   
   
Administer study 
medication  
   
     x  
  
   
   
   
   
   
Adverse Event Monitoring  
   
     x  
x  
x  
x  
x  
   
x  
Phone Call  
   
   
  
   
   
   
x  
   
* Visit 2 might be on physical day 3 depending on availability of screening labs  
  
  
 
  Study Procedures  
  
8.10.1 Clinical Labs  
Approximately 15 ml (about 3 teaspoons) of blood will be collected at four time points 
(Visits 1, 3, 4, and 5) to assess soluble P-selectin, VWF, D-dimer, CRP, and exploratory 
endpoint labs (including fibrinogen, IL-6, TNF-alpha, Factor 8, sICAM-1, sVCAM-1, CCL2, 
troponin, NT-pro-BNP, PCSK9).  Samples will be processed by Johns Hopkins Pathology 
Labs or by the investigator using commercially available ELISA kits.  In addition, blood will 
be drawn by the medical team for standard laboratories for clinical care.    
  
If the study team is unable to obtain a blood sample on a patient who agreed to participant 
have his or her blood drawn for research purposes (difficult stick, early discharge, 
hemolyzed sample) we will obtain a remnant blood sample from the waste repository to 
measure the biomarkers listed above.  
   
8.10.2 Pregnancy Test  
Females of childbearing potential must have a negative pregnancy test (urine or blood) 
prior to randomization. Samples should be processed by the site’s clinical laboratory.  
  
  
9.0  
ASSESSMENT OF EFFICACY   
  
 
  
Specification of the Efficacy Parameters for Biomarkers  
Standard biomarkers will be measured by the Johns Hopkins Pathology Laboratory.  Non-standard 
biomarkers will be measured in the Principal Investigator’s laboratory.  The primary efficacy variable 
will be assessed as analysis of covariance of a log-transformed P-selectin levels with baseline value 


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and treatment allocation as covariates.  The secondary efficacy biomarker variables will be assessed 
similarly.    
  
  
 
  
Specification of the Efficacy Parameters for Biomarkers  
The secondary efficacy variables that involve clinical variables will be abstracted from the EMR and 
recorded in eSOCDAT by the investigational team.  The WHO composite scale will be calculated by 
the investigational team based on the EMR.     
  
  
10.0  ASSESSMENT OF SAFETY  
  
 
  Specification of Safety Parameters  
  
10.1.1 Definition of Adverse Events (AE)  
An AE is any untoward or unfavorable medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, 
or disease, temporally associated with the subject’s participation in the research, whether 
or not considered related to the subject’s participation in the research.  
  
10.1.2 Definition of Serious Adverse Events (SAE)  
A SAE is one that meets one or more of the following criteria:  
• 
Results in death  
• 
Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred)  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in a persistent or significant disability or incapacity  
• 
Results in a congenital anomaly or birth defect    
• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
  
10.1.3 Suspected Unexpected Serious Adverse Reaction (SUSAR)   
An AE is considered unexpected, when either the type of event or the severity of the event 
is not listed in the protocol or package insert/product monograph.   
  
 
  Classification of an Adverse Event  
  
10.2.1 Severity of Event  
• 
Mild: no intervention required; no impact on activities of daily living (ADL)  
• 
Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on 
ADL  
• 
Severe: significant symptoms requiring invasive intervention; subject seeks medical 
attention, needs major assistance with ADL  
  
10.2.2 Relationship to Study Agent  
• 
Definitely Related:  There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals.   
  


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• 
Probably Related:  There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the drug, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals.  
  
• 
Possibly Related:  There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later 
be upgraded to “probably related” or “definitely related,” as appropriate.  
  
• 
Unlikely to be Related: A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration 
of the trial medication) and in which other drugs or chemicals or underlying disease 
provides plausible explanations (e.g., the subject’s clinical condition, other concomitant 
treatments).  
  
• 
Not Related:  The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.  
  
10.2.3 Follow-up of Subjects After a Reportable SAE    
SAEs with a causal relationship to trial participation must be followed until the event or its 
sequelae resolve or stabilize to a level acceptable to the local investigator.    
  
10.2.4 Expectedness   
Expected events are those that have been previously identified as resulting from 
administration of the investigational product.  An AE is considered unexpected, when either 
the type of event or the severity of the event is not listed in the protocol or package insert.   
  
 
  Time Period and Frequency for Event Assessment and Follow-Up  
All adverse events of interest occurring following administration of the study drug  will be 
collected until 30 d post randomization.  
  
Safety parameters will be assessed at study visits. Safety data will be collected including: 
vitals (including blood pressure), chemistries and hematology labs. Events of interest include:   
arthralgia, diarrhea, pruritis, vomiting, chest pain.    
  
All serious adverse events that are possible trial endpoints (including death, 
rehospitalization, or venous or arterial  thromboembolism)  within 30 days post randomization, 
will be collected on the appropriate adverse event collection forms. Serious adverse events that 
are trial endpoints do not also need to be reported as separate SAEs. All serious adverse 
events thought to be possibly, probably, or definitely related to study drug or not covered by 
endpoint collection forms will be collected on appropriate SAE CRFs. CRFs will be completed 
at the time the event becomes known to study investigators, either by notification by the 
subject, or during influenza season surveillance, at which time investigators will inquire about 
the occurrence of events since the last time of contact.   
All suspected unexpected serious adverse reactions (SUSARs) will be collected on 
appropriate CRFs during the course of the trial. All SUSARs will be collected at the time they are 


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known to study investigators and may be subject to specific reporting requirements by health 
authorities or local IRBs.  
Non-serious adverse events not temporally related to study drug  administration and not 
suspected to be related to study drug administration will not be collected unless required by 
local GCP guidelines  
  
REPORTING PROCEDURES  
 Adverse Event Reporting:  All adverse events will be reported in the appropriate section of the 
eCRF.  
.  
  
Serious Adverse Event Reporting:  All reportable serious adverse events  must be reported 
within 24 h of the investigators’ awareness of the event.    
  
Reportable serious adverse events and trial endpoints (death or hospitalization) will be collected 
until 30 days post administration of study drug.  Serious, unexpected adverse drug reactions will 
be reported to FDA and sponsor in an expedited manner as required.  SUSAR and SAE not 
collected as study endpoints will be reported to local IRBs per local IRB requirements.    
  
  
Unanticipated Problem Reporting:  All suspected unexpected serious adverse reactions 
(SUSARs) will be collected at the time they are known to study investigators.  All non-fatal or 
non-life threatening SUSARs must be filed as soon as possible but no later than 15 calendar 
days after the event becomes known to study investigators. All SUSARs will be reported to 
Novartis and to local IRBs as per local IRB requirements.  
  
 
  Follow-up of Subjects after Adverse Events  
SAEs will be followed until 30 d after administration of study drug or until it is judged to be 
permanent, and an assessment will be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the drug of interest, the interventions 
required to treat it, and the outcome.  
  
The Steering Committee shall support the site in the following-up of all SAEs so that complete 
information is available to maintain patient safety and also as part of any commitments by Novartis 
to any Health authority OR specific Health authority follow-up requests for the product under 
investigation.  
  
  
  
 
  Unblinding Procedure  
In an emergency situation where knowledge of a subject’s study treatment allocation must be 
known in order to determine the further medical management of the subject concerned, or if 
knowledge of a subject’s treatment allocation is required for regulatory reporting purposes, the 
PI will be able to access to the study treatment code for the subject concerned via the secure, 
web-based trial-specific treatment allocation system within eSOCDAT. Instructions for access 
(which is password protected) and use may be found in the respective Manual of Operations. All 
information (i.e., the name of the person who has accessed the treatment code, the reason, 
date and time and subject for whom the code was accessed) concerning study treatment code 
access will be tracked and stored in the web-based system. Further medical management is at 
the discretion of the Investigator. However, clinical status permitting, all remaining planned 
outpatient clinic visits and telephone calls must be completed in accordance with the protocol 
schedule unless the subject refuses further follow-up.  
  


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  Safety Oversight  
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including cardiovascular disease, pulmonary disease, infectious disease, 
statistics, and ethics. The DSMB will meet frequently to assess ongoing safety of participants, 
validity of data, and the integrity of the study. The DSMB will operate under the charter of this 
trial. The DSMB will provide its input to the study executive committee.  
  
  
11.0  
CORRELATIVE STUDIES  
  


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  Correlative Studies   
  
Additional pathways may be involved in the pathogenesis of COVID-19.  Potential thrombotic 
and inflammatory and immune responses may exacerbate COVID19, and potential fibrinolytic or 
anti-inflammatory pathways may speed recovery form COVID-19.  
  
 
  Sample Collection Guidelines  
Subjects electing to participate in the optional correlatives studies will contribute one blood 
sample (10 ml).    
  
  
 
  Specimen Banking  
Subject samples collected for this study will be retained at the Johns Hopkins Hospital. 
Specimens will be coded and stored until the trial is completed, after which samples will be 
anonymized and stored until they are used up. If use is denied or withdrawn by the subject 
during the course of the trial, best efforts will be made to stop any additional studies and to 
destroy the specimens.   
  
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that there is 
the potential for financial gain by the Johns Hopkins University, the investigator or a 
collaborating researcher or entity.   
  
  
After the study is completed, the Ancillary Studies Committee will be responsible for reviewing 
and approving requests for de-identified clinical specimens from potential research collaborators 
outside of the Executive Committee investigators. Collaborators will be required to complete an 
agreement (a Material Transfer Agreement or recharge agreement) that states specimens will 
only be released for use in disclosed research, as well as provide documentation of IRB 
approval or exemption from their institution for receiving the specimens.   
  
   
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:   
• 
Underlying medical conditions (past medical history)  
• 
Collection time in relation to study treatment  
• 
Results from biomarker studies  
• 
Demographic data  
  
  
12.0  STATISTICAL CONSIDERATIONS  
  
 
  Statistical Analysis Plan  
All statistical data analyses will be performed using Stata, SAS and R.   
  
 
  Analysis Population  
All randomized subjects regardless of their compliance with the protocol treatment and follow-up 
will be included in the primary analysis following the intention-to-treat (ITT) principle for the 
analysis of randomized controlled trials including for the assessment of the balance of baseline 


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subject characteristics.  Reporting of adverse events will be according to the treatment actually 
received.   
  
 
  Analysis of Baseline Characteristics  
Baseline characteristics between treatment groups will be compared using t-tests for normally 
distributed continuous variables or Wilcoxon rank-sum tests for non-normally distributed 
continuous variables, and Chi-Square or Fisher’s exact tests, as appropriate, for categorical 
variables.  These comparisons are to evaluate the adequacy of randomization and to identify 
baseline characteristics that may need to be considered for adjustment in the analysis of the 
outcome measures.  
   
 
  Analysis of Primary Endpoint  
The primary endpoint of soluble P-selectin at 3 days or hospital discharge day (whichever is 
earlier) will be summarized for each treatment group with descriptive statistics, including mean, 
standard deviation, median, and interquartile range.  For the assessment of the primary endpoint, 
change in soluble P-selectin will be assessed in an analysis of covariance, which will be 
implemented using linear regression with day 3 or hospital discharge day soluble P-selectin as 
the outcome variable, using baseline soluble P-selectin and treatment group as the covariates. A 
soluble P-selectin greater than assay will be imputed as 150% of upper limit of assessment.   
  
 
  Analysis of Secondary Endpoints  
The secondary endpoints of other biomarkers (including VWF, D-dimer, CRP) at baseline, day 3, 
day 7 and day 14, and the secondary endpoint of soluble P-selectin at day 7 and day 14 will be 
summarized with descriptive statistics.  For the assessment of the secondary endpoints, 
comparison of the changes in biomarkers from baseline to day 14 between the two groups will be 
made using the similar methods as with the primary endpoint above, after log-transforming 
baseline and follow-up values of other biomarkers (including VWF, D-dimer, and CRP).   
  
The secondary endpoint of the World Health Organization (WHO) Ordinal Scale for COVID-19 
Trials up to  day 14 will be summarized by reporting the number and proportion of patients in each 
treatment group in each WHO category, and analyzed by ordinal logistic regression with patient’s 
baseline score and randomized treatment as the model covariates. Consistency of any detected 
associations across the range of the ordinal scale will be assessed using the Brant test. Analysis 
of the repeated measurements of WHO Ordinal Scale (collected daily from day 3 to day 14) will 
be analyzed using a mixed-effects ordinal logistic regression model with treatment, study day, and 
baseline score as fixed effects and patient id as a random effect.   
  
  
 
  Analysis of Exploratory Endpoints  
The secondary endpoints of other biomarkers (IL-6, TNF-alpha, factor 8, soluble ICAM1, 
soluble VCAM-1, CCL2, troponin isoforms T or I, NT-pro-BNP, PCSK9) at baseline, day 3, day 
7, day 14 and hospital discharge day will be summarized with descriptive statistics.  For the 
assessment of the secondary endpoints, comparison of the changes in biomarkers from 
baseline to day 14 between the two groups will be made using the similar methods as with the 
primary endpoint above.   
The secondary endpoints of individual clinical endpoints (time to resolution of fever, time 
to liberation from supplemental oxygen, time to mechanical ventilation, time to in hospital death, 
time to arterial or venous vascular event or ischemic stroke, time to hospital discharge) will be 
summarized by Kaplan-Meier curves and compared using log-rank tests and univariate Cox 
models.  


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  Missing data  
This is a well-designed trial with many safeguards in place for assuring complete data, therefore 
the extent of missing data is expected to be minimal. The primary analysis will use patients with 
available baseline, day 3 and/or hospital discharge day data. Where data are missing, sensitivity 
analyses will be done using several assumptions to evaluate the sensitivity of the statistical 
results to the possible effects on the non-completers. To the extent possible, the reasons for 
missing data will be documented and evaluated. Using this information, assumptions about the 
missing data mechanism will be assessed and these assumptions will be used to impute 
missing values under a variety of scenarios. In multiple imputations, the missing values will be 
replaced with values consistent with several possible scenarios. If the missing data are 
extensive, model-based approaches will be considered to estimate effects under various 
assumptions regarding missing data. Missing data analysis will follow the guideline promulgated 
in the National Research Council report [National Research Council. The Prevention and 
Treatment of Missing Data in Clinical Trials. 2010. Washington, DC: The National Academies 
Press.].  
  
 
  Interim Analysis  
Formal interim analyses for efficacy and futility will not be performed.  
  
 
  Level of Significance and Sample Size  
The primary analysis will focus on between-arm changes in soluble P-selectin.  Based on a trial 
design with two-sided α=0.05, assuming a standard deviation (SD) of 30 ng/ml and a 10% drop 
out rate, a sample size of 40 subjects (20 per treatment arm) will ensure 83% power to detect a 
between-group difference of 30 ng/ml and 93% power to detect a between-group difference of 35 
ng/ml.    
  
 Stopping Rules for Termination of the Trial   
The study will be monitored by the Data and Safety Monitoring Board (DSMB) as described in 
Section 12.15.  However, there will be no formal interim analyses for efficacy or futility and thus 
no stopping rules for termination of the trial. The DSMB may suggest premature termination of 
the study based on safety concerns regarding crizanlizumab in patients with thrombosis or 
bleeding.  In addition, early termination of this trial may occur because of a regulatory authority 
decision, withdrawal of study approval by clinical site IRBs, or investigational product safety 
problems, or overwhelming efficacy in the opinion of the DSMB. Novartis retains the right to 
withdraw support of the trial prior to the completion of enrollment of the targeted number of 
subjects, but will exercise these rights only for valid scientific or administrative reasons.   
  
 Spurious Data Procedures  
Consistency checks and range checks will be built into the data management system. This will 
allow many errors to be identified and corrected at the time of data entry. Queries regarding any 
problems with data will be sent to site coordinators regularly throughout the course of the trial. 
The site will also be monitored during the study. Therefore, spurious data are expected to be 
rare. Any data which are judged by the medical monitors to be definitely incorrect, and which 
cannot be resolved, will be set to missing.   
  
The study report will indicate the number of subjects who have missing data on each study 
endpoint. For covariate-adjusted analyses, the number of subjects who have missing data on 
the covariates will be reported.  
  


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Throughout the study, the rate, timing, and reasons for subject withdrawal will be monitored by 
site and treatment arm.   
  
 Deviation Reporting Procedures  
Any modifications or deviations from the statistical plan described in this protocol will be 
documented in a "Revised Statistical Plan" document.   
  
 Subjects to be Included in Analyses  
Data analysis of primary and secondary outcomes will follow an intention-to-treat principle.  
However, adverse event reporting will include those who have received any dose of treatment 
according to the treatment actually received. All subjects that are randomized will be included in 
data analysis.   
  
 Measures to Minimize and Avoid Bias  
  
 
12.14.1  
Randomization  
Randomization will be carried out using permuted blocks of size 4. Subjects will 
be randomized in a 1:1 ratio to crizanlizumab 5.0 mg/kg IV once or placebo IV 
once.  
  
Subjects will be randomized using a validated Web-based Randomization 
System (eSOCDAT) only accessible to designated site personnel. eSOCDAT will 
allocate numbered study treatment pack number(s) which should be used for the 
subject concerned. Details on how to randomize a subject will be found in the 
respective user manual. The randomization plan will be kept strictly confidential, 
accessible only to authorized persons, until the time of unblinding. If a subject 
discontinues from the study, neither the subject identification number nor the 
allocated study treatment pack numbers will be reused, and the subject will not 
be allowed to be re-randomized in the study.   
  
Since the Johns Hopkins Investigational Drug Service will be supplying the 
placebo, the Johns Hopkins Investigational Drug Service will not be blinded to 
the identity of the study drug and placebo.  Although the Johns Hopkins 
Investigational Drug Service will know the identity of the vials containing study 
drug or placebo, it will not be informed of the identity of the patients receiving 
placebo or study drug, and will not have access to endpoint data.  
  
 
12.14.2  
Masking  
Subjects, site investigators and study personnel, and persons performing 
surveillance will remain blinded to the identity of the treatment from the time of 
randomization until database lock. Randomization data are kept strictly 
confidential until the time of unblinding, and will not be accessible by anyone 
involved in the study except as required by the Data and Safety Monitoring Board 
(DSMB), or in the case of subject emergencies, for which unblinding is deemed 
absolutely necessary. The identity of investigational product will be concealed 
through over encapsulation by the Johns Hopkins Investigational Drug Service.  
In addition, the 100 ml saline pouches will be placed in an amber colored outer 
pouch.  
  


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 Data and Safety Monitoring Board (DSMB)  
The Data and Safety Monitoring Board (DSMB) will oversee the trial across the single study site. 
The DSMB is comprised of experienced members (core plus ad hoc) with expertise required to 
oversee this trial. The DSMB members will review protocol-specific reports created by study 
statisticians using data pulled from eSOCDAT.  These reports summarizing the data by 
treatment arm, coded as A vs B, will include an overview of study objectives, a review of actual 
and projected accrual rates, an evaluation of subject demographics for balance of 
randomization, and a summary of the number and seriousness of adverse events. Actual 
treatment associated with the coded treatment arms will be provided to the DSMB members at 
the time of each review.  These reports will allow the DSMB to independently judge whether the 
overall integrity and conduct of the protocol remain acceptable based on data provided and 
reported by the study statistician. The DSMB will make recommendations to the Principal 
Investigator that could include actions of continuation, modification, suspension, or termination.  
  
In providing oversight for the conduct of this study, the DSMB will meet at a minimum of every  
week during the six-month study to review all adverse events. Additional meetings may be 
scheduled as determined by the DSMB or requested by the study team. There will be no 
prespecified stopping rules either for efficacy, harm or futility. All serious adverse events will be 
reported to the DSMB and IRB in accordance with their reporting guidelines. We will forward the 
communication of the DSMB recommended actions and all pertinent regulatory information to 
the FDA, appropriate Institutional Review Board(s), and the Novartis when applicable.  
  
  
13.0  ETHICS AND PROTECTION OF HUMAN SUBJECTS  
  
 
  Ethical Standard   
The trial will be conducted in accordance with Good Clinical Practice (GCP) guidelines, the rules 
and regulations of the Institutional Review Board(s), and applicable state and federal regulatory 
agency requirements and laws.  
  
 
  Institutional Review Board (IRB)   
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any subject is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented in the study.    
  
 
  Informed Consent Process  
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. Extensive discussion of risks and possible 
benefits of study participation will be provided to subjects and their families, if applicable.  A 
consent form describing in detail the study procedures and risks will be given to the subject.  
Consent forms will be IRB-approved, and the subject is required to read and review the 
document or have the document read to him or her. The investigator or designee will explain the 
research study to the subject and answer any questions that may arise.  The subject will sign 
the informed consent document prior to any study-related assessments or procedures.  
Subjects will be given the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. They may withdraw consent at any time throughout the course of 
the study. A copy of the signed informed consent document will be given to subjects for their 
records. The rights and welfare of the subjects will be protected by emphasizing to them that the 


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quality of their clinical care will not be adversely affected if they decline to participate in this 
study. The consent process will be documented in the clinical or research record.    
  
 
  Exclusion of Women, Minorities and Children (Special Populations)  
Crizanlizumab for COVID-19 aims to enroll a representative proportion of minority subjects. 
Children, pregnant women, prisoners, and institutionalized individuals will not be enrolled. 
Children are excluded because their phenotype differs from that of an adult, which could 
confound response results. Pregnant women are excluded because of regulations barring them 
from this type of research.  
  
  
14.0  TRIAL MANAGMENT AND COMMUNICATION PLAN   
  
 
  Monitoring IRB Approvals  
The participating institution must provide for the review and approval this protocol and the 
associated informed consent documents and recruitment material by an appropriate IRB 
registered with the OHRP. Any amendments to the protocol or consent materials must also be 
approved before they are placed into use. In the US, only institutions holding a current US 
Federal-wide Assurance issued by OHRP may participate.   
  
The IRB approval letters will be collected by the CCC and will be required for the study site to be 
certified as ready to enroll subjects. The date of each IRB approval will be recorded and the 
single study site will need to inform the CCC about any changes to the IRB approval and all IRB 
renewals. In the event of a lapse in a site’s IRB approval, the site will be responsible to obtain 
clearance from their IRB to continue to collect follow-up data on subjects enrolled, but no 
additional subjects can be enrolled from that site until full IRB approval is reinstated.  
  
 
  Monitoring of Modifications  
Modifications to the protocol can only be made by the steering committee. Protocol 
modifications that affect study design or endpoints in any substantial manner may need to be 
reviewed by the DSMB.   
  
Modifications to the protocol will be communicated to the study site by the CCC. When 
modifications of the protocol are made that require the site to resubmit the protocol to a local 
IRB, the site will be required to provide evidence of IRB re-approval before they can enroll 
subjects under the new protocol.   
  
 
  Problem Management  
Issues that arise at the study site regarding the conduct of the study must be reported by site 
personnel to the CCC. The CCC will be responsible for maintaining contact with the single study 
site.   
  
 
  Communication  
The Steering Committee will meet weekly during the course of the trial.  The study site will be 
updated with study information by means of webinars, conducted prior to study enrollment and 
on an ad hoc basis as needed.   
  
  
15.0  DATA COLLECTION AND QUALITY ASSURANCE  
  


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  Data Management Responsibilities   
The DCC, SOCAR, Dr. Solomon and Dr. Claggett and the staff at the Brigham and Women’s 
Clinical Trials Endpoints Center will be responsible for implementing and maintaining quality 
control and quality assurance systems with written standard operation procedures (SOPs) to 
ensure that trial is conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice (International Conference on 
Harmonization E6), and all applicable federal, state, provincial, and local laws, rules, and 
regulations relating to the conduct of the clinical trial.   
  
The Clinical Site may be subject to review and/or inspection by the Institutional Review Board 
(IRB), the US Food and Drug Administration (FDA), and/or to quality assurance audits 
performed by the DCC or CCC.  
  
It is important that the Investigator(s) and the relevant clinical site personnel be available during 
the monitoring period and possible audits or inspections, and that sufficient time is devoted to 
the process.  
  
 
  Clinical Trial Data Management System  
  
eSOCDAT will be the e-clinical solution used to collect and mange subjects and logistic 
metadata for the current trial.  eSOCDAT is a web-based tool and can be accessed worldwide 
via an internet browser. eSOCDAT is FDA 21 CFR Part 11 compliant and is fully compliant with 
Good Clinical Practice (GCP) and other applicable rules and regulations for the validation of 
computerized systems used to collect and manage data for a clinical research study.  
  
The single study site can only access data for their own subjects. All clinical data required by the 
protocol is entered using a unique subject assigned number and no personal identifying 
information is entered or stored other than dates of birth and service.  
  
All data entered through eSOCDAT will be stored on servers hosted by SOCAR Research  
(‘’SOCAR’’) SA.  SOCAR Research is fully compliant with ISO/IEC 27002 (previously known as  
ISO 17799:205) standards. Direct access to SOCAR’s servers is restricted to authorized  
SOCAR personnel only via login credentials. Customers have no access to the server itself.  All 
SOCAR’s employees are granted access only to computer and networking areas necessary to 
perform their duties. Each installation is separate, and cannot be accessed from any other 
installation. Connection to a hosted instance is encrypted by means of secure socket layer. The 
application server and database server are secured via firewall, hardened to remove 
nonessential access credentials, and strong password compliance. Hosted systems are 
constantly monitored for latencies and intrusion.  
  
  
  
 
  Data Management Procedures  
Data will be collected and entered into eSOCDAT at each site participating in the trial.  
eSOCDAT provides real-time field level validations, context sensitive help and automatic query 
generation. Data entry forms use browser based logic to enforce proper validations of all data 
fields and proper skip patterns within study data forms. Interim background data submittals 
prevent loss of data due to interruption of internet connections.  
  


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The CTDMS is programmed to validate data entry fields as the data are entered. Validations are 
question-by-question checks that give immediate feedback to help catch data entry errors, form 
completion errors, and out-of-range values. Reports of outstanding edits, generated upon 
completion of data entry, will enable continuous cleaning of data at each site. Detailed 
procedures are outlined in the Data Management Plan.  
  
If the DCC observes inconsistent data or patterns of protocol violations or missing data, site staff 
will be contacted to address the finding.   
  
 
  Direct Access to Source Data   
As noted above, source documents for verification of entry criteria may be queried by the DCC.  
The investigator will make available to the DCC source documents as requested. The  
verifications of CRF data will be made by direct review of source documents for a small 
percentage of subjects as described above. It may be necessary to have access to the 
complete medical record in some instances.   
  
 
  Specimen Collection Management  
Ensuring the accuracy of blood specimens for this trial is paramount. The Johns Hopkins 
Hospital has quality control methods in place to ensure this accuracy. Aliquot tubes are linked, 
and tracked to allow tracing back to the original parent tube. The complete electronic chain of 
custody in place will allow the data management system to monitor and report on the critical 
processes involved in specimen collection, shipping and results..  
  
15.5.1 Data Use and Banking   
During the study, the Ancillary Studies Committee will be responsible for reviewing and 
approving requests for de-identified data sets from potential research collaborators 
outside of the Executive Committee investigators. Data will be stripped of all PHI in 
compliance with the HIPAA Privacy rule. Collaborators will be required to complete an 
agreement (a Data Transfer Agreement or recharge agreement) that states data will only 
be released for use in disclosed research, as well as provide documentation of IRB 
approval or exemption from their institution for receiving the data. Datasets will be 
provided to researchers by the DCC using SAS transport files and using a secure FTP 
site. Data use is limited to studying endothelial function and cardiovascular disease. 
Data must be returned or destroyed when analysis is complete.  
  
After this research study is over and the main results have been published, a complete 
de-identified data set will be banked at the Brigham and Women’s Hospital and at The 
Johns Hopkins Hospital, including the following data: medical history and medications, 
vital signs, side effects or other health issues that occurred during the study, health 
status. Directly identifiable information will be removed and keys linking codes to subject 
identity will be destroyed, making data withdrawal impossible. The banked data will not 
be sent to researchers outside of Hopkins or the Brigham. The banked data will be used 
for future research about COVID-19 and vascular inflammation and thrombosis.  
  
  
  
 
  Confidentiality of Data  
By signing this protocol, the Investigator affirms that trail information will be maintained in 
confidence and such information will be divulged to the IRB or similar expert committee, 
affiliated institution, and employees only under an appropriate understanding of confidentiality 


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with such board or committee. Data generated by this clinical trial will be considered confidential 
by the Investigator, except to the extent that it is included in a publication.   
  
 
  Confidentiality of Subject Records  
By signing the protocol, the Investigator agrees that the IRB, or Regulatory Agency  
representative may consult and/or copy study documents in order to verify CRF data. By signing 
the consent form, the subject agrees to this process. If study documents will be photocopied 
during the process of verifying CRF information, the subject will be identified by unique code 
only and full names and similar identifying information (such as medical record number or social 
security number) will be masked.  
  
The Clinical Site Investigators will ensure that the identity of subjects will be protected. All study 
records will be maintained in a secure fashion with access limited to essential study personnel 
only. All study documents submitted to the Coordinating Center will have identifiers removed 
other than dates of birth and service and subjects will be identified with a study-specific 
identification number only. The Clinical Site Investigators will maintain, in a secure location, an 
enrollment log that includes subject identifying information and links subjects to their 
studyspecific identification number.   
  
 
  Protocol Deviations  
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical  
Practice, or Manual of Procedures requirements.  The noncompliance may be on the part of the 
subject, the investigator, or study staff.    
  
Investigators may only implement a deviation from or a change to the protocol to eliminate an 
immediate hazard(s) to subjects without prior IRB approval.    
  
All deviations from the protocol must be addressed in study subject source documents and 
promptly reported to Network Study Manager or Clinical Coordinating Center.  As a result of 
deviations, corrective actions are to be developed by the study staff and implemented promptly.  
  
  
16.0  PUBLICATION POLICY  
  
Publications derived from this study should include input from the Principal Investigator, Steering 
Committee, and other Investigators in the trial. No results will be released publicly before completion of 
the final analysis regarding the primary endpoint of this study without the approval of the Steering 
Committee. The statistical analysis will be performed according to the pre-specified analysis plan. 
Subsequent to the multi-center publication, or 24-months after completion of the trial, whichever comes 
first, an Investigator may publish the results of the trial independently, subject to approval of the Steering 
Committee.  
  
A manuscript of each proposed presentation and publication shall be submitted to Novartis for review 
prior to submission to anyone who is not employed by the Institution and not under an obligation of 
nondisclosure and non-use at least substantially identical to that imposed on the Principal Investigator by 
this Agreement in order to permit Novartis to (1) evaluate the manuscript for accuracy, (2) ascertain 
whether Confidential Information is being improperly disclosed, (3) provide Confidential Information which 
may not have yet been made available by Novartis and (4) provide input for consideration regarding the 
content and/or conclusion(s) of the manuscript.  Novartis shall be afforded a review period of fifteen (15) 


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Working Days for manuscripts not exceeding two (2) double-spaced pages in length (or the equivalent 
thereof) and forty-five (45) Working Days for all other manuscripts.    
  
  
  
17.0  REFERENCES  
1. 
World Health Organization R&D Blueprint COVID-19 Therapeutic Trial Synopsis. World Health  
Organization,  
2020.  
at  
https://www.who.int/blueprint/priority-diseases/key-action/COVID- 
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf.)  
2. 
Henry BM, Vikse J. Clinical Characteristics of Covid-19 in China. N Engl J Med 2020;382:1860-1.  
3. 
Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N 
Engl J Med 2020;382:727-33.  
4. 
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and 
Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020.  
5. 
Myers LC, Parodi SM, Escobar GJ, Liu VX. Characteristics of Hospitalized Adults With COVID-19 in an 
Integrated Health Care System in California. JAMA 2020.  
6. 
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic 
staging proposal. J Heart Lung Transplant 2020;39:405-7.  
7. 
Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. 
Thromb Res 2020;190:62.  
8. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in 
patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.  
9. 
Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe 
novel coronavirus pneumonia. J Thromb Haemost 2020.  
10. 
Klok FA, Kruip M, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic 
complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res 2020.  
11. 
Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU 
patients with COVID-19. Thromb Res 2020.  
12. 
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 
2020;395:1417-8.  
13. 
Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell 
Disease. N Engl J Med 2017;376:429-39.  
1. 
World Health Organization R&D Blueprint COVID-19 Therapeutic Trial Synopsis. World Health 
Organization, 2020. at https://www.who.int/blueprint/priority-diseases/key-action/COVID- 
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf.)  
2. 
Henry BM, Vikse J. Clinical Characteristics of Covid-19 in China. N Engl J Med 2020;382:1860-1.  
3. 
Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N 
Engl J Med 2020;382:727-33.  
4. 
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and 
Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020.  
5. 
Myers LC, Parodi SM, Escobar GJ, Liu VX. Characteristics of Hospitalized Adults With COVID-19 in an 
Integrated Health Care System in California. JAMA 2020.  
6. 
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic 
staging proposal. J Heart Lung Transplant 2020;39:405-7.  
7. 
Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. 
Thromb Res 2020;190:62.  
8. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in 
patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.  
9. 
Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe 
novel coronavirus pneumonia. J Thromb Haemost 2020.  


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10. 
Klok FA, Kruip M, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic 
complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res 2020.  
11. 
Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU 
patients with COVID-19. Thromb Res 2020.  
12. 
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 
2020;395:1417-8.  
13. 
Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell 
Disease. N Engl J Med 2017;376:429-39.  
1. 
World Health Organization R&D Blueprint COVID-19 Therapeutic Trial Synopsis. World Health 
Organization, 2020. at https://www.who.int/blueprint/priority-diseases/key-action/COVID- 
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf.)  
2. 
Henry BM, Vikse J. Clinical Characteristics of Covid-19 in China. N Engl J Med 2020;382:1860-1.  
3. 
Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N 
Engl J Med 2020;382:727-33.  
4. 
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and 
Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020.  
5. 
Myers LC, Parodi SM, Escobar GJ, Liu VX. Characteristics of Hospitalized Adults With COVID-19 in an 
Integrated Health Care System in California. JAMA 2020.  
6. 
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic 
staging proposal. J Heart Lung Transplant 2020;39:405-7.  
7. 
Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. 
Thromb Res 2020;190:62.  
8. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in 
patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.  
9. 
Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe 
novel coronavirus pneumonia. J Thromb Haemost 2020.  
10. 
Klok FA, Kruip M, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic 
complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res 2020.  
11. 
Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU 
patients with COVID-19. Thromb Res 2020.  
12. 
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 
2020;395:1417-8.  
13. 
Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell 
Disease. N Engl J Med 2017;376:429-39.