A Pilot Study of Duvelisib to Combat COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: Washington University School of Medicine

Protocol Version: 11/30/2020 
 
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A Pilot Study of Duvelisib to Combat COVID-19 
 
Washington University School of Medicine 
Division of Infectious Disease & 
Division of Oncology 
660 South Euclid Avenue, Box 8007 
St. Louis, MO 63110 
 
Protocol #: 202007009 
Version Date:  11/30/2020 
 
Principal Investigator: 
John DiPersio, MD, PhD 
Email: jdipersi@wustl.edu 
 
 
 
 
 
Phone:  (314) 454-8491 
 
 
Co- Principal Investigator: Erik Dubberke, MD, MSPH 
edubberk@wustl.edu 
314-454-8293 
 
Co- Principal Investigator: Dr. Nitin Anand, MD 
 
 
 
 
Missouri Baptist Medical Center 
nitin.anand@bjc.org 
 
Statistician:  
 
Mark Fiala, MSW 
 
Study Drugs:  
 
Duvelisib  
 
IND#: 
150555 
NCT#: 
NCT04372602 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless 
law or regulations require such disclosure.  Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by 
them. 
 

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A Pilot Study of Duvelisib to Combat COVID-19 
 
Protocol Revision History 
 
Initial Version 
 
 
 
 
 
 
 
 
08/11/2020 
Amendment 1 
 
 
 
 
 
 
 
 
10/21/2020 
Amendment 2 
 
 
 
 
 
 
 
 
11/30/2020 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 

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PROTOCOL SUMMARY 
 
Title: 
A Pilot Study of Duvelisib to Combat COVID-19 
Study Description: 
Patients with a diagnosis of COVID-19 with critical disease 
manifestations will be randomly assigned to receive duvelisib or 
placebo 
Objectives: 
Primary Objective: 
To evaluate the efficacy of duvelisib for the treatment of COVID-
19 disease manifestations. 
 
Secondary Objectives: 
To evaluate the safety and tolerability of duvelisib for the treatment 
of COVID-19 disease manifestations. 
Endpoints: 
Primary Endpoint: 
• 28 day overall survival 
Secondary Endpoints: 
• Hospital and ICU length of stay 
• Duration of ventilator 
• Duration of vasopressors 
• Duration on renal replacement therapy 
• Viral kinetics 
• Adverse Events 
Study Population: 
Twenty-eight patients (approximately 14 per arm) over the age of 
18 with a diagnosis of COVID-19 with advanced disease 
manifestations including one or more of the following: extensive 
lung involvement, respiratory failure, shock, or cardiac 
dysfunction. 
Phase: 
Pilot Phase 2 
Description of 
Sites/Facilities 
Enrolling: 
This is a multi-center study open at Washington University School 
of Medicine and Missouri Baptist Medical Center. 
Description of Study 
Intervention: 
Patients will receive either duvelisib 25mg or placebo for 10 
days. Both participants and researchers will be blinded.  
Study Duration: 
18 months 
Participant Duration: 
6 months  

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Table of Contents 
 
PROTOCOL SUMMARY .............................................................................................................. 4 
1.0 
BACKGROUND AND RATIONALE ............................................................................... 7 
 
COVID-19 and Cytokine Release Syndrome ................................................................. 7 
 
Lessons and Preclinical Data from CART-releated CRS ............................................... 7 
 
Gene edited CART model for the Mitigation of CRS .................................................... 8 
 
PI3K Inhibition Potently Mitigates CRS in Pre-clinical CART Model .......................... 9 
 
PI3K Inhibition to Mitigate Pathogenesis of Advanced COVID-19 ............................ 10 
2.0 
OBJECTIVES ................................................................................................................... 11 
 
Primary Objective ......................................................................................................... 11 
 
Secondary Objectives .................................................................................................... 11 
 
Objectives and Endpoints Table ................................................................................... 11 
3.0 
PATIENT SELECTION ................................................................................................... 12 
 
Inclusion Criteria .......................................................................................................... 12 
 
Exclusion Criteria ......................................................................................................... 13 
 
Inclusion of Women and Minorities ............................................................................. 13 
4.0 
REGISTRATION PROCEDURES .................................................................................. 13 
 
Confirmation of Patient Eligibility ............................................................................... 13 
 
Screen Failures .............................................................................................................. 13 
5.0 
STUDY TREATMENT .................................................................................................... 14 
 
Overview ....................................................................................................................... 14 
 
Dose Modifications ....................................................................................................... 14 
 
Supportive Care ............................................................................................................ 15 
 
Viral Load Monitoring .................................................................................................. 17 
 
Worsening COVID-19 Symptomology ........................................................................ 17 
 
Duration of Therapy ...................................................................................................... 17 
 
Duration of Follow-up .................................................................................................. 18 
 
Lost to Follow-Up ......................................................................................................... 18 
6.0 
PHARMACEUTICAL INFORMATION ......................................................................... 18 
 
Duvelisib ....................................................................................................................... 18 
7.0 
SCHEDULE OF ASSESSMENTS ................................................................................... 20 
8.0 
CORRELATIVE STUDIES ............................................................................................. 22 
 
Sample Collection ......................................................................................................... 22 
 
Sample Processing ........................................................................................................ 22 
 
Planned Correlative Studies .......................................................................................... 22 
9.0 
DATA SUBMISSION SCHEDULE ................................................................................ 24 
10.0 
REGULATORY AND REPORTING REQUIREMENTS .............................................. 24 
 
Sponsor-Investigator Reporting Requirements ............................................................. 25 
 
Secondary Site Reporting Requirement ................................................................... 28 
 
Exceptions to Expedited Reporting .............................................................................. 28 
11.0 
DATA AND SAFETY MONITORING ........................................................................... 29 
12.0 
STATISTICAL CONSIDERATIONS.............................................................................. 30 
 
Determination of Sample Size ...................................................................................... 30 
 
Statistical Analysis Plan ................................................................................................ 30 

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Study Termination ........................................................................................................ 31 
13.0 
MULTICENTER REGULATORY REQUIREMENTS ............................................. 32 
14.0 
REFERENCES ................................................................................................................. 33 
Appendix A: Mean Arterial Pressure (MAP) Formula ................................................................. 35 
Appendix B: Creatinine Clearance (Cockcroft-Gault) Formula ................................................... 36 
APPENDIX C: Definitions for Adverse Event Reporting ............................................................ 37 
APPENDIX D: Reporting Timelines ............................................................................................ 39 
APPENDIX E: Washington University Serious Adverse Event Reporting Cover Sheet ..... 41 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
 
COVID-19 and Cytokine Release Syndrome 
 
Coronavirus disease 2019 (COVID-19) is an unprecedented international pandemic caused 
by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] The spread of 
the virus and the incidence of the disease are accelerating at exponential rates. Despite 
public health campaigns to quench the spread, delays in testing have allowed for 
dissemination that is undetected and unaccounted. Aggressive measures are being taken to 
develop vaccines and therapies, but even relaxation of regulatory measures are unlikely to 
expedite their development to allow for rapid widespread dissemination. Mortality in 
patients with severe and critical disease is exceedingly high. In Wuhan, mortality 28-day 
mortality for those admitted to the ICU was over 60%.[1] In New York City, initial 
mortality rates for those requiring mechanical ventilation was over 75% for those age 65 
years and under, and 97% for those over 65 years-old.[2] These staggering statistics 
highlight a population with a significant unmet need. It is imperative that existing therapies 
be evaluated for repurposing in order to manage and potentially reverse the sequela of 
COVID-19.  
 
Emerging evidence suggests that this novel coronavirus, like others, induces an overactive 
and ineffective immune cascade associated with acute lung pathology, acute myocarditis, 
and cytokine storm mediated by cytokines such as interleukins 2, 6, and 8, TNF-alpha, 
interferon-γ, and G-CSF.[3] This aberrant immune response is thought to be the principal 
contributor to the morbidity and mortality of COVID-19. Additionally, studies of viral 
kinetics suggest that viral peaking occurs a number of days prior to the apex of symptoms, 
further suggesting that decompensation is an immunopathogenic response related to innate 
immune cells.[4] Numerous anecdotal reports describe the onset of severe symptomatology 
with refractory pyrexia occurring one to two weeks after initial viral prodrome, consistent 
with this theory. As such, a number of agents, including IL-6 inhibitors and JAK inhibitors, 
are aiming to disrupt these immune pathways in COVID clinical trials.  
 
 
Lessons and Preclinical Data from CART-releated CRS 
 
Chimeric antigen receptor T-cell (CART) therapy has been limited by life threatening 
toxicities in over 50% of patients.  Toxicities primarily manifest as cytokine release 
syndrome (CRS) characterized by an early phase with fever, hypotension, increasing 
oxygen requirements and elevations of cytokines including IFNγ, GM-CSF, TNF, IL-10, 
and IL-6 and a later phase associated with life-threatening or life-ending neurologic events. 
IL-6, unlike IFNγ, is often but not always elevated early during CRS and current 
management strategies rely on administration of the IL-6 receptor antagonist tocilizumab, 
which is effective at blocking the early events of CRS but ineffective at controlling life 
threating CNS CRS.[5]  A clinical strategy to prevent CRS without attenuating CART 
mediated anti-tumor activity is essential for the safe use of CART as a curative therapy for 
hematological malignancies.  Enhancing the safety and efficacy of CART therapy though 
the amelioration of CRS will dramatically improve outcomes and expand clinical 

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application of adoptive T cell therapy. The same processes may underlie the terminal 
clinical manifestations of COVID-19 where patients suffer from progressive fever, 
increasing oxygen requirements, bleeding and clotting due to the activation of the 
coagulation cascade and eventual respiratory failure.[6]  These events are often associated 
with elevation of biomarkers such as elevated IL-6, CRP, D-Dimers and ferritin levels, 
which are comparable to those seen in CART-related CRS.[7]   
 
 
Gene edited CART model for the Mitigation of CRS 
 
We hypothesized that the generation 
of CART cells, engineered through 
CRISPR/Cas9 gene editing to delete 
IFNγ, or other selected genes known 
to mediate inflammatory interactions 
between CART and target cells and 
macrophages (source of IL-6 and 
other inflammatory cytokines) may 
ameliorate 
CRS, 
preventing 
downstream IL-6 secretion from 
macrophages.  We had previously 
shown that inhibitors of JAK1/2 
could block the production of IL-6 
and 
CRS 
symptoms 
when 
immunocompetent mice were treated 
with anti-murine CD3 in vivo (Fig 1). 
We hypothesized that the generation 
of CART cells, engineered through 
CRISPR/Cas9 gene editing to delete 
IFNγ will completely ameliorate 
CRS, preventing downstream IL-6 secretion from macrophages and dendritic cells.  To test 
this hypothesis we developed an 
in vitro assay to assess the effect 
of IFNy deletion in human T 
cells on the release of CRS 
related cytokines, specifically 
IL-6.  Using CRISPR/Cas9, 
IFNy was genetically deleted in 
human primary T cells (>80% 
deletion).  IFNy deficient T cells 
were stimulated in the presence 
of immature dendritic cells, prior 
to cytokine quantification by 
ELISA (+24hrs).  Contrary to 
expectations, deletion of IFNy, 
significantly 
increased 
IL-6 
Fig 2 
Fig 1 

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secretion from immature dendritic cells.  These data suggest that IFNy is not the key 
mediator released by activated CART for the induction of IL-6 by iDCs/macrophages (Fig 
2) 
 
 
PI3K Inhibition Potently Mitigates CRS in Pre-clinical CART Model 
 
Using unbiased CRISPR/Cas9 screens in which we have deleted several hundred genes 
involved in pathways of inflammation in CART19 cells, we have explored several other 
genes of interest..  Although these studies are still in progress we have identified several 
pathways/genes involving co-stimulatory pathways signaling through phosphoinositide 3-
kinase (PI3K) in macrophages.  One of these pathways includes the CD40-CD40L 
pathway.  CRISPR/Cas9 genetic deletion of CD40L in CART resulted in normal CART 
function but no production of IL-6 when incubated with iDC (data not shown).  We 
phenocopied these results by blocking both CD40L on CART and CD40 on iDC using 
antibodies to each.  Of note is that one pathway of CD40 signaling in macrophages includes 
PI3K signaling specifically PI3Kγ signaling.  We tested the pharmacologic inhibition of 
PI3K using a dual PI3K-δγ inhibitor duvelisib.  Duvelisib, which is currently FDA 
approved for the treatment of chronic lymphocytic leukemia (CLL) had a potent effect on 
IL-6 production (even more potent that antibodies to CD40L) while having no impact on 
CART function, similar to CD40L-CD40 blockade and JAK1/2 blockade (Fig 3) Of 
interest is that the combination of a JAK1/2 inhibitor and duvelisisb completely a  brogated 
IL-6 production in our in vitro CAR model (Fig 4).   
 
Fig 3 

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PI3K Inhibition to Mitigate Pathogenesis of Advanced COVID-19 
 
PI3K-δγ inhibition with duvelisib could potentially avert CRS related to COVID-19, while 
preserving cytotoxic T-lymphocyte, as we have seen in preclinical work on CART therapy.. 
Many of the cytokines reduced by duvelisib are ones demonstrated to be significantly 
elevated in patients with COVID-19, including IL-1beta, IL-6, IL-8, MIP-1α, MIP-1β, IL-
10, and TNFα, supporting a potential role in mitigating CRS.[8, 9] Duvelisib may also 
positively impact the respiratory pathology associated with COVID-19 causing acute 
respiratory distress syndrome. In a murine model of acute pulmonary inflammation, PI3Kδ 
inhibition has been demonstrated to decrease IL-17 production and decrease pathogenic 
neutrophil recruitment to the lung.[10] Duvelisib has also demonstrated significant 
reductions in pro-inflammatory cytokines and neutrophil infiltration in in vivo models of 
asthma and pulmonary inflammation.[11] Lastly, duvelisib may potentiate the elimination 
of SARS-CoV-2 through preferential macrophage polarization and inhibiting viral 
persistence. Duvelisib has been demonstrated to polarize macrophages to the M1 
phenotype which is responsible for pathogen elimination.[12] Such macrophage 
polarization has been demonstrated in primary samples from clinical trials of duvelisib.[13] 
Additionally, PI3K/Akt signaling has been shown to be a requirement for persistent SARS-
CoV-1 infection in vitro in Vero E6 cells, which inhibition of PI3K can disrupt.[14, 15] 
 
The exceedingly high mortality rates of severe and critical COVID-19 warrant the 
identification and evaluation of novel therapies that could potentially mitigate the advanced 
disease manifesations. Based on preclinical data from our institution and others,we 
hypothesize that PI3K  inhibition with duvelisib could potentially quell aberrant 
hyperactivtation of the innate immune system, preferentially polarize macrophages, reduce 
pulmonary inflammation, and limit viral persistence, thereby improving patient outcomes. 
 
 
 
Fig 4A 
Fig 4B 

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2.0 
OBJECTIVES 
 
 
Primary Objective 
 
To evaluate the efficacy of duvelisib for the treatment of COVID-19 disease 
manifestations. 
 
 
Secondary Objectives 
 
To evaluate the safety and tolerability of duvelisib for the treatment of COVID-19 disease 
manifestations. 
 
 
Objectives and Endpoints Table 
 
Objectives 
Endpoints 
Justification for Endpoints 
Primary 
 
 
To evaluate the efficacy of 
duvelisib for the treatment 
of 
COVID-19 
disease 
manifestations. 
Primary:  
28 day overall survival 
 
 
 
The expected survival of 
these patients with 
advanced COVID-19 
symptoms is poor and 
studies are currently needed.  
Secondary: 
Hospital and ICU length of 
stay and duration of 
ventilator, vasopressors, 
and renal replacement 
therapy 
In addition to improving 
survival, duvelisib may 
reduce the need for these 
interventions.  
Secondary 
 
 
To evaluate the safety and 
tolerability of duvelisib 
for the treatment of 
COVID-19 disease 
manifestations. 
Viral kinetics 
Duvelisib and similar 
treatments which modulate 
cytokine signaling have the 
potential to reduce immune 
function which could result 
in increasing viral loads.  
Adverse events 
Adverse events are common 
with duvelisib for its 
indicated purpose. It is 
unclear if similar adverse 
events are observed in this 
population.  
 
 

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3.0 
PATIENT SELECTION 
 
 
Inclusion Criteria 
 
1. A diagnosis of advanced COVID-19 as defined both of the following: 
a. as a positive test for SARS-CoV-2 RNA detected by RT-PCR collected from the 
upper respiratory tract (e.g. nasopharyngeal, nasal, oropharyngeal swab, or saliva) 
and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or 
bronchoalveolar lavage), analyzed by a CLIA certified lab with an FDA approved 
assay. [11] 
b. Critical disease manifested by any of the following: 
i. Chest imaging with ≥ 50% lung involvement 
ii. Respiratory failure requiring invasive mechanical ventilation, non-invasive 
mechanical ventilation (eg. BiPAP, OptiFlow), supplementary oxygen with ≥ 6 
LPM, or extracorporeal membrane oxygenation (ECMO) 
iii. Shock – defined as mean arterial pressure ≤ 65 mmHg unresponsive to 25ml/kg 
isotonic intravenous fluid resuscitation and/or requiring vasopressor support 
(See Appendix A) 
iv. Cardiac dysfunction defined by: 
1. New global systolic dysfunction with ejection fraction ≤ 40% 
2. Takotsubo cardiomyopathy 
 
2. Patients who have received prior investigational or off-label agents for COVID-19 does 
not exclude eligibility. 
 
3. At least 18 years of age at the time of study registration 
 
4. Adequate hematologic function defined as absolute neutrophil count ≥ 1000/mm3 and 
platelet count ≥ 50,000/mm3 without growth factor or transfusion support for 7 days 
prior to screening. 
 
5. Creatinine-clearance ≥ 15 mL/minute or receiving renal replacement therapy (See 
Appendix B) 
 
6. Aminotransferase (AST/ALT) levels <3x the upper limit of normal 
 
7. Able to understand and willing to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable) 
 
8. Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, or women who have had a tubal ligation) are required 
to have a negative pregnancy test and use two forms of acceptable contraception, 
including one barrier method, during participation in the study treatment period. 
 

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9. Male patients if engaging in sex with a women of childbearing potential are required 
to use two forms of acceptable contraception, including one barrier method, during 
participation in the study and throughout the evaluation period.  
 
Exclusion Criteria 
 
1. Known allergy or intolerance to duvelisib or another PI3K inhibitor. 
 
2. Known or suspected active viral (including CMV, HIV, hepatitis B, and hepatitis C), 
bacterial, mycobacterial, or fungal infection other than COVID-19. CMV viral load 
will be assessed at screening and those with viremia will be excluded. Other virologic 
testing not required unless infection is suspected.  
 
3. Pregnant and/or breastfeeding.   
 
4. Any uncontrolled intercurrent illness that would put the patient at greater risk or limit 
compliance with study requirements in the opinion of the investigator.  
 
 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
The study is limited to adults over the age of 18 as the safety of duvelisib in minors has not 
been established.  
 
 
4.0 
REGISTRATION PROCEDURES 
 
 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. 
Registering MD’s name 
2. 
Patient’s race, sex, and DOB 
3. 
Three letters (or two letters and a dash) for the patient’s initials 
4. 
Copy of signed consent form 
5. 
Completed eligibility checklist, signed and dated by a member of the study team 
6. 
Copy of appropriate source documentation confirming patient eligibility 
 
 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 

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respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
 
5.0 
STUDY TREATMENT 
 
 
Overview 
 
Patients will be randomly assigned in a double-blind fashion to receive either duvelisib 
25mg or placebo twice daily for up to 10 days. Patients who have significant clinical 
improvement prior to day 10 and are going to be discharged from the hospital may 
discontinue the treatment early with investigator permission.  
 
 Blocks of 10 patients will be used to allocate patients to duvelisib or placebo.  Due to 
differences in color between the duvelisib and placebo capsules, we will employ methods 
in this trial to maintain the blinding of the investigator to the best of our ability (e.g. having 
the drug dispensed by alternative personnel). If this study were to lead to a pivotal trial, 
matched placebos would be manufactured for such a trial. 
 
Treatment is dosed orally and can be administered with or without food. For patients unable 
to administer orally, a duvelisib suspension will be administered through a 
nasogastric/orogastric tube. In this event, the capsule(s) will be opened and the dose will 
be placed in 40mL water and stirred until dissolved. The suspension should be administered 
using an appropriate syringe within 6 hours after preparation. Following administration, 
the tube should be rinsed with approximately 75 mL of water. 
 
If a dose is missed by fewer than 6 hours, administer the missed dose right away and take 
the next dose as usual.  If a dose is missed by more than 6 hours, the patient should not take 
an additional dose, but should take the next usual prescribed dose.  
 
 
Dose Modifications 
 
Participants will be evaluated for toxicity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 5.0. Dose 
modifications for treatment-emergent adverse events are listed in the table below. If the 
dose is reduced for toxicity, escalation may occur at the discretion of the treating physician 
following resolution/stabilization of the toxicity.      
 
Treatment-Emergent 
Adverse Event  
Management for Duvelisib/Placebo 
Neutropenia  
Grade ≤ 3  
No change.  
Grade 4 
Hold treatment until < Grade 2. When resumed, reduce treatment 
by one dose level. 
Thrombocytopenia 
Grade ≤ 3 
No change.  

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Grade 4 
Hold treatment until < Grade 3. When resumed, reduce treatment 
by one dose level. 
Anemia 
Any 
Dose delay is not required for anemia, unless deemed necessary 
by the treating physician. Transfusions and/or erythrocyte 
stimulating agents are allowable. 
Pneumonitis 
Grade 1 
No change. 
Grade 2 
If suspected related to treatment, treat with systemic steroid 
therapy and hold treatment until < Grade 1 OR patient returns to 
baseline (where patient had a predetermined abnormal baseline). 
When resumed, reduce treatment by one dose level. 
 
If unrelated to treatment, no change unless deemed necessary by 
the treating physician. 
Grade > 3 
Discontinue.  
Viral Load Elevation 
Increase in viral load of 
>0.5 log on two 
consecutive days, or >1 log 
increase in one day 
See section 5.4. If viral load elevation is suspected to be related 
to treatment, hold treatment until patient returns to baseline 
(where patient had a predetermined abnormal baseline). 
Permission required from the principal investigator prior to re-
treatment. If resumed, reduce treatment by one dose level. 
All other events  
Grade ≤ 2 
No change.  
Grade 3  
If suspected related to treatment, hold treatment until < Grade 1 
OR patient returns to baseline (where patient had a predetermined 
abnormal baseline). When resumed, reduce treatment by one 
dose level. When resumed, reduce treatment by one dose level. 
 
If unrelated to treatment, no change unless deemed necessary by 
the treating physician. 
Grade 4  
For Grade 4 lab abnormalities:  
Hold treatment until < Grade 1 OR patient returns to baseline 
(where patient had a predetermined abnormal baseline). 
Permission required for the principal investigator prior to re-
treatment.  
 
For Grade 4 treatment-related adverse events with clinical 
manifestation (eg. life-threatening colitis, cutaneous reactions, 
infections): 
Discontinue study treatment 
 
5.2.1 Duvelisib/Placebo Dose Levels 
 
1  
25 mg twice daily 
-1 
15 mg twice daily 
-2 
Discontinue 
 
 
Supportive Care 
 

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Patients should receive full supportive care, including but not limited to intravenous fluids, 
transfusions of blood and blood products, antibiotics, antivirals, antibacterial agents, and 
antiemetics, when appropriate at the discretion of the treating clinician. 
 
5.3.1 Recommended Prophylaxis Medications 
 
Patients should receive prophylaxis for Pneumocystis jirovecii (PJP) during study 
treatment. Following completion of study treatment, continue PJP prophylaxis until 
the absolute CD4+ T cell count is greater than 200 cells/μL.  
 
CMV prophylaxis may be considered in patients deemed high risk per institutional 
guidelines, although is not mandatory. CMV viral load monitoring will occur for 
seropositive patients. 
 
5.3.2 Prohibited/Discouraged Medications 
 
Strong CYP3A inducers should be avoided as they decrease duvelisib area under 
the curve (AUC) which may reduce duvelisib efficacy.   
 
Strong CYP3A inhibitors should be avoided as they increase duvelisib AUC which 
may increase the risk of duvelisib toxicities. If strong CYP3A inhibitors are 
clinically necessary, the dose of duvelisib should be reduced to 15 mg BID. 
 
Other drugs that are sensitive CYP3A4 substrates should be avoided as 
administration of duvelisib increases AUC of these drugs which may increase the 
risk of toxicities. If sensitive CYP3A4 substrates are clinically necessary, it is 
recommended to reduce the dose of the sensitive CYP3A4 substrate and monitor 
for signs of toxicities.  
 
5.3.3 Standard of Care Therapy 
 
The standard of care for patients with severe or critical COVID-19 continues to 
evolve and may be defined differently due to local practice habits and the 
availability or shortage of therapies.  
 
Ventilatory strategies and management of critical illness should proceed 
according to instutional standards, as should the use of remdesivir. 
 
Patients who are not already receiving a corticosteroid should be started on a dose 
of at least dexamethasone 6mg daily oral or intravenously at the time of screening 
(Day -1) and continue through Day +10 or beyond, unless contraindicated, per 
results of the RECOVERY Trial.[19]  
 
5.3.4 Investigational or Off-Label Treatments for COVID-19  
 

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Patients who have received other investigational or off-label agents previously are 
eligible for study and these agent(s) may be continued at the discretion of the 
treating physician. 
 
During study treatment, screening through Day 10, the addition of investigational 
or off-label agents for patients on the study is discouraged. However, physicians 
who believe use of such agents is warranted should discuss with the principal 
investigator. If such agents are administered, patients are permitted to continue on 
duvelisib. 
 
 
Viral Load Monitoring 
 
All patients will have three consecutive days of viral load monitoring prior to receiving 
duvelisib, on Screening day, Day -1, and Day 1 (see Section 7.0), to establish the baseline 
viral load and trend. For patients with an increase in viral load of >0.5 log on two 
consecutive days, or >1 log increase in one day, clinical judgement should be used to 
determine if any continued rising viral load is susprected to be related to study treatment. 
If suspected to be related to study treatment, follow dose modifications as outlined in 
section 5.2. If thought to be unrelated to study treatment,  i.e. keeping with baseline trend, 
no change unless deemed necessary by the treating physician. 
 
 
Worsening COVID-19 Symptomology 
 
Patients with clinically worsening symptoms of COVID-19 may be removed from study 
treatment at any time per discretion of the treating physician and additional treatments may 
be commenced. However, patients should continue to be followed as per the protocol 
calendar in section 7.0.    
 
 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient/surrogate no longer wishes continuation of the protocol 
therapy, the protocol therapy should be discontinued and the reason(s) documented in the 
case report forms.  
 
Patients will be removed from the study for any of the following reasons: 
 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of the study drug 
• General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 

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• Lost to follow-up 
• Patient/surrogate withdraws consent 
• Investigator removes the patient from study 
• Investigator decides to close the study 
 
 
Duration of Follow-up 
 
All patients will be followed as according to the protocol calendar in Section 7.0 for the 
duration unless the patient withdraws consent or is lost-to-follow-up. Following the safety 
follow-up visit, patients will continued to be monitored for survival and late-onset toxicity 
every 3 months for up to 6 months. For these long-term follow-up visits, a telephone visit 
can be made in lieu of a physical visit. 
 
 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
• The study team will attempt to contact the participant and reschedule the missed 
visit within 1 week and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
• Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6.0 
PHARMACEUTICAL INFORMATION 
 
 
Duvelisib 
 
6.1.1 Description 
 
Duvelisib is a dual inhibitor of phosphatidylinositol 3-kinases PI3K-δ and PI3K-γ. 
Duvelisib is a white-to-off-white crystalline solid with the empirical formula 
C22H17ClN6O•H2O and a molecular weight of 434.88 g/mol.  Hydration can vary 
with relative humidity.  Duvelisib contains a single chiral center as (S) enantiomer.  
Duvelisib is soluble in ethanol and practically insoluble in water.  Duvelisib is 

Protocol Version: 11/30/2020 
 
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described chemically as a hydrate of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-  
chloro-2-  phenylisoquinolin-1(2H)-one. 
 
6.1.2 Dose Forms and Strengths 
 
Duvelisib capsules are for oral administration and are supplied as white to off-white 
opaque and Swedish orange opaque capsules (25 mg, on anhydrous basis) or pink 
opaque capsules (15 mg, on anhydrous basis), and contain the following inactive 
ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and 
microcrystalline cellulose.  Capsule shells contain gelatin, titanium dioxide, black 
ink, and red iron oxide. 
 
Plaebos are supplied as matching size white to off-white opaque capsules 
containing the inactive aboves.  
 
6.1.3 Storage and Stability 
 
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions are permitted 
between 15°C and 30°C (59°F and 86°F).  
 
6.1.4 Availability 
 
Duvelisib is commercially available by prescription. For this study, duvelisib or 
placebo will be supplied without charge to the participants by Verastem Oncology, 
the maker of duvelisib.  
 
6.1.5 Preparation 
 
Not applicable for capsule administration. For nasogastric/orogastric tube 
administration see Section 5.1.  
 
6.1.6 Administration 
 
Please see Section 5.1. 
 
6.1.7 Warnings and Precautions 
 
Fatal and/or serious diarrhea or colitis occurred in 18% of duvelisib-treated 
patients. Monitor for the development of severe diarrhea or colitis.  
 
Fatal and/or serious cutaneous reactions occurred in 5% of duvelisib-treated 
patients.  
 
Fatal and/or serious pneumonitis occurred in 5% of duvelisib-treated patients. 
Monitor for new/evolving pulmonary symptoms and interstitial infiltrates. 

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7.0 
SCHEDULE OF ASSESSMENTS 
 
 
 
Screening1 
 
 
Study Treatment Days 
 
Safety Follow-
Up11 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
15 
29 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam w/ vital signs and O2 
saturation2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APACHE II Score 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
SOFA Score 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
CBC2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D-Dimer10 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
aPTT and PT/INR10 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
Fibrinogen10 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
C-reactive peptide2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 viral load 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative immunoglobulins 
(IgA, IgG, IgM) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune competence assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CMV IgG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV DNA PCR (CMV seropositive pts) 
X 
 
 
 
 
 
 
 
 
X8 
 
 
 
 
Serum βhCG4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiagram5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma troponin and NT-proBNP5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duvelisib/placebo6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PJP prophylaxis7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Correlative studies9 
X12 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
Adverse event monitoring 
 
 
Continuously 
1 – Within 7 days of registration 
2 – Performed daily while inpatient or per local SOC. If outpatient, visits may occur within +/- 2 days from schedule 
3 – Performed daily through Day +10 then weekly thereafter by NP or OP  
4 – Women of childbearing potential only 
5 – Not required at Screening if patient meets Inclusion Criterion 1 by other measures.  Repeated on study if clinically indicated.   
6 – Duvelisib or placebo will be administered twice daily for up to 10 days.  See section 5.0 for treatment administration details.  
7 -  Continued until CD4+ T cells >200 cells/μL. Choice of agent per institutional guidelines and patient tolerance. 
8 – CMV viral load monitoring should occur at screening, and on D8 in patients who are CMV seropositive (positive IgG at screening). CMV prevention/treatment should 
follow institutional guidelines. 
9 – Collected on the first 10 patients enrolled onto study. A variance of +/- 2 days for correlative collection will be permitted.  
10 – Performed as scheduled or more frequently if clinically indicated for coagulopathy monitoring 
11 – Outpatient follow-up visits  may be performed by telemedicine/telephone encounter without lab assessment in situations  that preclude in-person visits (eg. discharge 
to skilled nursing facility, lack of transportation,  persistent COVID precautions) 
12 – May occur anytime from screening through Day 1 pre-dose. 

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8.0 
CORRELATIVE STUDIES 
 
Correlative studies will be collected and analyzed for the frist 10 patients enrolled onto the trial.  
 
 
Sample Collection 
 
Peripheral blood (20 ml) will be collected into EDTA (pink or lavender top) vacutainer 
tubes and 10 mL will be collected into serum (red top) vacutainer tubes at the following 
time points (a variance of +/- 2 days will be permitted for correlative collections):  
• Screening (May occur anytime from screening through Day 1 pre-dose) 
• Day 2  
• Day 4 
• Day 8 
• Day 10 
• Day 15 
• Day 29 
 
 
Sample Processing 
 
EDTA tubes will be processed to obtain double-spun plasma and peripheral blood 
mononuclear cells (PBMCs); serum tubes will be processed to obtain serum.   
 
 
Planned Correlative Studies 
 
8.3.1 Monitoring anti-SARS-Cov2 antibody responses in Duvelisib-treated 
COVID-19 patients  
 
Rationale of the study  
The production of neutralizing antibodies represents an important host defence 
mechanism against systemic dissemination of SARS-CoV2. Our understanding of 
the molecular determinants controlling in B cells the strength and quality of the 
antibody response against SARS-CoV2 during the acute phase of infection remains 
largely unknown. Also, we have limited information on the molecular effectors that 
control in B cells the production of specific classes (ie. IgM, IGG, IGA) and 
subclasses (IGG1, IGG2, IGG3, IGG4) of antibodies during SARS-CoV2 infection. 
The latter information is crucial to understand which factors trigger the production 
of antibody classes and subclasses with neutralizing activity rather than those 
exerting pro-inflammatory functions by binding to Fc receptors on macrophages 
and natural killer cells, or by complement fixation. Finally, the identification of 
molecular determinants contributing to the establishment of long-lived antigen-
specific memory B cells and antibody-secreting plasma cells during the acute phase 
of SARS-Cov2 infection represents a key step to possibly modulate the duration of 
anti-viral responses.  
 

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PI3K signalling is a strong candidate for controlling key functions of B cells related 
to the production of antigen-specific antibodies during both T-cell dependent and 
independent anti-viral immune responses. Therefore, Duvelisib inhibition of PI3K 
catalytic function offers the opportunity to understand whether such treatment can 
influence the quality and quantity of the antibody response raised against SARS-
CoV2 during the acute phase of the infection. Specifically, Duvelisib may influence 
the extent of B cell activation in response to SARS-CoV2 recognition, by 
modulating B cell receptor (BCR) signalling, which in turn controls B cell 
proliferation and terminal differentiation [16.17). Duvelisib exposure may also 
influence immunoglobulin isotype switching [17] This effect may lead to a 
substantial shift in the classes and subclasses of antibodies produced during the 
viral infection. In particular, Duvelisib treatment may change the ratio between 
neutralizing IGG1 antibodies and pro-inflammatory IGG3 antibodies produced 
during the acute phase of SARS-CoV2 infection. Duvelisib interference of PI3K 
signalling may enhance the process of antibody somatic hypermutation in antigen-
specific B cells recruited into germinal centers (GC), in the frame of a conventional 
T-cell dependent anti-SARS-Cov2 immune response [17]. Whether enhanced 
antibody diversification ignited in GC B cells by Duvelisib, positively impacts on 
the average affinity of antibodies raised against SARS-Cov2 remains to be 
determined. Finally, Duvelisib treatment, during the acute phase of SARS-Cov2 
infection, could exert a crucial impact on the net output of germinal centers 
represented by the generation of long-lived memory B cells and plasma cells 
producing high-affinity anti-virus antibodies [17,18].   
 
Aim of the investigations and experimental plan 
The proposed studies aim to obtain a comprehensive understanding of the effects 
of Duvelisib treatment on the antibody response raised against SARS-CoV2 in the 
acute phase of infection. Specifically, we will measure the effects of Duvelisib 
treatment on the concentration of all classes (IGM, IGG, IGA) and subclasses 
(IGG1, IGG2, IGG3, IGG4), IGA1 and IGA2) of serum anti-SARS-CoV2 Spike 
RBD-specific antibodies, respectively at Day-2, Day-4, Day-8, Day-15, and Day-
29 of infection. Through serum neutralization tests, we will also estimate at the 
same time points, the effects of Duvelisib on the extent of production of anti-SARS-
Cov2 neutralizing antibodies. Finally, flow cytometric determinations will establish 
whether Duvelisib treatment impacts.  on the frequency of circulating RBD-binding 
long-lived CD27+ IgM- and Ig-switched memory B cells and CD38+CD138+ 
plasma cells/plasma blasts, assessed at the different time points after the infection.  
 
Methods 
The laboratory of Dr S. Casola (The FIRC Institute of Molecular Oncology, IFOM, 
Milan) has developed an in-house ELISA-based serological assay to measure 
serum/plasma levels of the entire spectrum of antibody classes and subclasses 
(IGM, IGG1, IGG2, IGG3, IGG4, IGA1/A2) raised against the Receptor Binding 
Domain (RBD) of the SARS-CoV2 Spike protein, produced in recombinant 
fashion. In particular, the assay will ensure the measurement of absolute amounts 

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(i.e concentration) of IGM- and IGG1-specific anti-RBD antibody titers. An 
ELISA-based competition assay will be employed to quantify the neutralizing 
activity of the serum of SARS-Cov2-infected patients.  To perform the serological 
tests mentioned above, we will need between 0.5 and 1.0 ml of fresh or -20°C -
stored serum (or plasma).  One-two ml of fresh or cryopreserved peripheral blood 
mononuclear cells will be needed to estimate by flow cytometry the frequency of 
antigen-specific memory B cells and plasma cells revealed after staining the cells 
with a tetramer form of fluorescent labelled recombinant RBD.  
 
8.3.2 Additional analyses 
 
Analysis will include, but are not limited to, the evaluation of cytokine expression 
via multiplex cytokine array or other markers/predictors of response.  
 
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
Medical History Form 
Treatment History Form 
Medical Assessment Form 
Lab Form 
At Baseline 
Medical Assessment Form 
Lab Form 
As Scheduled in Section 7.0  
28 Day Overall Survival Form At Day 28 or Death  
Adverse Events 
Continuous from baseline through safety follow-up visit  
MedWatch Form 
See Section 10.0 for reporting requirements 
SAE / CIOMS Form 
See Section 10.0 for reporting requirements for Canada 
End of Treatment Form 
At the completion of study follow-up 
Death Form 
At time of death 
  
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
10.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix C for definitions and Appendix D for a grid of reporting 
timelines. 

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Adverse events will be tracked from start of treatment through Day 29.  All adverse events must 
be recorded on the toxicity tracking case report form (CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 9 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 10.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may be found in Section 10.2. 
 
 
 
Sponsor-Investigator Reporting Requirements 
 
10.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
10.1.2 Reporting to Verastem 
 
All initial and follow-up SAEs to include unanticipated problems and pregnancies, 
must be reported to Verastem, Inc. Safety and Pharmacovigilance via PPD at 
rtpsafety@ppdi.com within 24 hours of knowledge of the event concerning the 
Verastem, Inc. product. Reports should be submitted in English via the sponsor-
investigator internal SAE/pregnancy forms, MedWatch or CIOMS forms.  
 
Pregnancy per se is not considered an AE unless there is cause to believe that the 
study interventions may have interfered with the effectiveness of a contraceptive 
medication or if the outcome of the pregnancy meets SAE criteria (miscarriage or 
congenital anomaly/birth defect, etc.), in which case it should be reported in the 
same manner and timelines as an SAE. In addition, any infant death or congenital 
anomaly occurring after 30 days that the Investigator suspects is related to the in-
utero exposure to the study interventions should also be reported as an SAE. 
Hospitalization for normal delivery of a healthy newborn is not an SAE.  
 
Since duvelisib has not been evaluated in pregnant or nursing women, the treatment 
of pregnant women or WCBP who are not using highly effective contraception is 
contraindicated. 
 

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Pregnancies occurring in subjects or partners of male subjects during the study 
intervention period and until 30 days after the subject’s last dose of study 
interventions are considered immediately reportable events. If a pregnancy occurs 
in a subject, study interventions must be discontinued immediately. The pregnant 
woman should be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. The Investigator will 
observe the pregnant woman until completion of the pregnancy and must notify 
Verastem of the outcome within 24 hours of the Investigator’s knowledge of the 
pregnancy outcome using a Pregnancy Outcome Form. This notification includes 
pregnancies resulting in live, “normal” births. 
 
SAE reports must contain the following minimum information: 
• 
At least one identifiable reporter 
• 
One single identifiable patient 
• 
At least one suspect adverse reaction  
• 
At least one suspect medicinal product 
• 
The sponsor-investigator’s assessment of causality for the event 
 
All such occurrences listed in this section shall be reported to Verastem using an 
approved local regulatory form and/or SAE form provided by Verastem and sent 
by facsimile or email to the following: 
 
 
Facsimile:  888-529-3580 
 
 
Email: rtpsafety@ppdi.com 
 
FDA submissions of IND safety reports should be reported to the contact 
information provided above and reported to Verastem in the same timeframe as the 
submission. Copies of any correspondence or telephone conversation logs with the 
applicable Regulatory Authorities regarding all SAE(s), irrespective of association 
with the Study Drug(s), within a reasonable time frame must be provided to 
Verastem, Inc. Safety and Pharmacovigilance. The sponsor-investigator will 
provide additional information about SAEs or Safety Information upon request. 
 
An aggregate listing of all SAEs and pregnancies reported by the site will be sent 
monthly by Verastem to the sponsor-investigator site for the site’s reconciliation. 
Discrepancies between Verastem and sponsor-investigator site’s records will be 
investigated by the sponsor-investigator site. The sponsor-investigator will send an 
updated SAE/pregnancy forms, MedWatch or CIOMS to Verastem or designee to 
resolve identified discrepancies. 
 
10.1.3 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 

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is the responsibility of the Washington University Sponsor-Investigator to report to 
the FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix C for definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix C) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix C) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 

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information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
10.1.1 Reporting to Secondary Sites 
 
The Washington University Sponsor-Investigator (or designee) will notify the 
research team at each secondary site of all unanticipated problems involving risks 
to participants or others that have occurred at other sites within 10 working days 
of the occurrence of the event or notification of the Sponsor-Investigator (or 
designee) of the event.  This includes events that take place both at Washington 
University and at other secondary sites, if applicable. Refer to Section 16.0 
(Multicenter Regulatory Requirements) for more information. 
 
 
 
Secondary Site Reporting Requirement 
 
The research team at each secondary site is required to promptly notify the Washington 
University Sponsor-Investigator and designee of all serious adverse events (refer to 
Appendix F, Section D) within 1 working day of the occurrence of the event or notification 
of the secondary site’s PI of the event.  This notification may take place via email if there 
is not yet enough information for a formal written report (using a FDA Form 3500a 
(MedWatch) and Washington University’s cover sheet (Appendix H)).  A formal written 
report must be sent to the Washington University Sponsor-Investigator and designee within 
4 calendar days (for fatal or life-threatening suspected adverse reactions) or 11 calendar 
days (for serious unexpected adverse reactions) of the occurrence of the event or 
notification of the secondary site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.  
The research team at Washington University is responsible for reporting all applicable 
events to the FDA and AstraZeneca as needed. 
 
 
 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 10.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
 

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11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish  Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members 
are subject to the Washington University School of Medicine policies regarding standards of 
conduct. Individuals invited to serve on the DSMB will disclose any potential conflicts of interest 
to the trial principal investigator and/or appropriate university officials, in accordance with 
institution policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB 
must also be disclosed.  
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician and will be reviewed by the DSMB. The first DSM report will be completed 3 months 
or following the completion of the 10th enrollment, whichever comes first. Subsequent reports will 
be completed every 3 months thereafter or after completion of the 20th and 28th enrollments, 
whichever is sooner  for as long as patients are actively receiving treatment on study. The DSM 
report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site  
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date and accrual by site 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities at all participating sites 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 

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Further DSMB responsibilities are described in the DSMB charter. 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
This is a double-blinded randomized pilot phase II study. The purpose of this study is to provide 
hypothesis generating data on the efficacy and toxicity duvelisib for the treatment of COVID-19. 
The total accrual goal is 28 patients, approximately 14 in each arm. Blocks of 10 patients will be 
used to allocate patients to either duvelisib or placebo. The projected enrollment time frame is 3 
months (approximately 9 patients per month).  
 
 
Determination of Sample Size 
 
The primary endpoint is 28 day overall survival (OS). While outcomes data are still 
developing, observational studies in other areas demonstrate 28-day OS to be poor but 
highly variable, from approximately 10-40%. [12–14] The variability is outcomes makes a 
priori sample size calculations difficult, but as this pilot study is designed to generate 
hypotheses rather than show superiority, sample size considerations were based largely on 
feasibility and detecting a clinically meaningful effect rather than statistical significance. 
For duvelisib to have clinically meaningfully efficacy, we estimate that 28-day OS is >60% 
in this patient population. Based on this assumption, a sample size of 28, 14 in each arm, 
would allow us to detect an improvement in 28-day OS from approximately 20% to 60%, 
with >80% power at a one-sided type I error of <0.20. If 28 day survival in the placebo 
cohort is considerably higher, for example 40%, we would only have approximately 40% 
power in detecting a statistical-significant difference. In either event, additional 
confirmatory studies that are adequately powered would be needed to more accurately 
assess the efficacy of duvelisib for the treatment of COVID-19.  
 
 
Statistical Analysis Plan 
 
The primary endpoint is 28 day overall survival (OS) and will be treated as a binary 
outcome for the purposes of the primary analysis and will be described using descriptive 
statics with the corresponding 95% confidence intervals. This will be an intent-to-treat 
analysis, and all patients randomized will be included in the analysis. The assumption is 
that all patients will be followed for at least 28 days. Patients who are lost to follow-up for 
any reason prior to this point will be included in the analysis and considered treatment 
failures and treated the same as a death. The 28 day OS of each cohort, duvelisib versus 
placebo, will be compared using Fisher’s exact test of independence.   
 
In addition to the primary analysis, OS will be treated as a time-to-event variable and will 
be described using Kaplan-Meier product limit estimators of event time curves and, if 
reached, medians with 95% confidence intervals. Cox proportional hazards models may be 
used to adjust for potential confounding effects. These analyses are considered exploratory, 
and we acknowledge that the proposed sample size will have low power for such 
adjustment. 

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The analyses of secondary end points are all exploratory in nature. Secondary endpoints of 
efficacy include: hospital and ICU length of stay and duration of ventilator (for those on a 
ventilator at the time of randomization), vasopressors, and renal replacement therapy. 
Kaplan-Meier product limit estimators of event time curves and, if reached, medians with 
95% confidence intervals, and compared between cohorts using the Log-Rank test. For 
these analyses, patients will be censored at Day 28 or at death, whichever is earlier. 
Secondary end points of toxicity are viral kinetics and adverse events. The rate of viral load 
elevation and other adverse events of interested will be summarized using descriptive 
statistics and compared using Fisher’s Exact tests.  
 
Demographic and clinical characteristics of the sample and of each cohort will be 
summarized using descriptive statistics. For continuous variables, the number of patients, 
mean, standard deviation, median, minimum, maximum, and quartiles will be provided. 
For 
categorical 
variables, 
the 
number 
and 
percent 
of 
patients 
in 
each 
demographic/characteristic category will be summarized with 95% confidence intervals. 
 
 
Study Termination 
 
Early stopping criteria for virologic failure are described above. In addition, at any time the 
study may be discontinued by the sponsor due to excessive toxicity, enrollment issues, etc. 
In this event, all participating sites, physicians, and patients will be notified and alternative 
treatment plans will be arranged.  
 
 
 

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13.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 

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14.0 
REFERENCES 
1.  
Wang D, Hu B, Hu C, et al (2020) Clinical Characteristics of 138 Hospitalized Patients 
With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 
https://doi.org/10.1001/jama.2020.1585 
2.  
Richardson S, Hirsch JS, Narasimhan M, et al (2020) Presenting Characteristics, 
Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the 
New York City Area. JAMA. https://doi.org/10.1001/jama.2020.6775 
3.  
Zumla A, Hui DS, Azhar EI, et al (2020) Reducing mortality from 2019-nCoV: host-
directed therapies should be an option. Lancet 395:e35–e36. 
https://doi.org/10.1016/S0140-6736(20)30305-6 
4.  
To KK-W, Tsang OT-Y, Leung W-S, et al (2020) Temporal profiles of viral load in 
posterior oropharyngeal saliva samples and serum antibody responses during infection by 
SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 
https://doi.org/10.1016/S1473-3099(20)30196-1 
5.  
Brudno JN, Kochenderfer JN (2016) Toxicities of chimeric antigen receptor T cells: 
recognition and management. Blood 127:3321–3330. https://doi.org/10.1182/blood-2016-
04-703751 
6.  
Yang X, Yu Y, Xu J, et al (2020) Clinical course and outcomes of critically ill patients 
with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational study. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(20)30079-5 
7.  
Mehta P, McAuley DF, Brown M, et al (2020) COVID-19: consider cytokine storm 
syndromes and immunosuppression. Lancet. https://doi.org/10.1016/S0140-
6736(20)30628-0 
8.  
Xie S, Chen M, Yan B, et al (2014) Identification of a role for the PI3K/AKT/mTOR 
signaling pathway in innate immune cells. PLoS One 9:e94496–e94496. 
https://doi.org/10.1371/journal.pone.0094496 
9.  
Vangapandu H V, Jain N, Gandhi V (2017) Duvelisib: a phosphoinositide-3 kinase δ/γ 
inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs 26:625–632. 
https://doi.org/10.1080/13543784.2017.1312338 
10.  
Way EE, Trevejo-Nunez G, Kane LP, et al (2016) Dose-Dependent Suppression of 
Cytokine production from T cells by a Novel Phosphoinositide 3-Kinase Delta Inhibitor. 
Sci Rep 6:30384. https://doi.org/10.1038/srep30384 
11.  
Winkler DG, Faia KL, DiNitto JP, et al (2013) PI3K-δ and PI3K-γ Inhibition by IPI-145 
Abrogates Immune Responses and Suppresses Activity in Autoimmune and Inflammatory 
Disease Models. Chem Biol 20:1364–1374. 
https://doi.org/10.1016/j.chembiol.2013.09.017 

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12.  
Vergadi E, Ieronymaki E, Lyroni K, et al (2017) Akt Signaling Pathway in Macrophage 
Activation and M1/M2 Polarization. J Immunol 198:1006 LP – 1014. 
https://doi.org/10.4049/jimmunol.1601515 
13.  
Horwitz SM, Koch R, Porcu P, et al (2018) Activity of the PI3K-δ,γ inhibitor duvelisib in 
a phase 1 trial and preclinical models of T-cell lymphoma. Blood 131:888–898. 
https://doi.org/10.1182/blood-2017-08-802470 
14.  
Mizutani T, Fukushi S, Saijo M, et al (2005) JNK and PI3k/Akt signaling pathways are 
required for establishing persistent SARS-CoV infection in Vero E6 cells. Biochim 
Biophys Acta 1741:4–10. https://doi.org/10.1016/j.bbadis.2005.04.004 
15.  
Mizutani T, Fukushi S, Saijo M, et al (2004) Importance of Akt signaling pathway for 
apoptosis in SARS-CoV-infected Vero E6 cells. Virology 327:169–174. 
https://doi.org/10.1016/j.virol.2004.07.005 
16. 
Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell 
malignancies. Nat Rev Immunol 2013;13:578-91 
17. 
Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, Calame K, et al. 
Regulation of class-switch recombination and plasma cell differentiation by 
phosphatidylinositol 3-kinase signaling. Immunity 2006;25:545-57 
18. 
Avery DT, Kane A, Nguyen T, Lau A, Nguyen A, Lenthall H, et al. Germline-activating 
mutations in PIK3CD compromise B cell development and function. J Exp Med 
2018;215:2073-95 
19. 
The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with 
Covid-19 — Preliminary Report. N Engl J Med. 2020 
 
 
 
 
 
 

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Appendix A: Mean Arterial Pressure (MAP) Formula 
 
 

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Appendix B: Creatinine Clearance (Cockcroft-Gault) Formula 
 
 
 
 

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APPENDIX C: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 

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o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 

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APPENDIX D: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
FDA 
Verastem Oncology 
Serious AND 
unexpected suspected 
adverse reaction 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
Report to Verastem 
at the same time as 
the FDA. 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
Report no later than 7 
calendar days after 
initial receipt of the 
information 
Report to Verastem 
at the same time as 
the FDA. 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  
If the event results in the death of 
a participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
 
Report to Verastem 
at the same time as 
the FDA. 
Pregnancy (within 30 
days after last dose) 
 
 
Report to Verastem 
at the same time as 
the FDA. 
Overdose 
 
 
Report to Verastem 
at the same time as 
the FDA. 
Major deviation 
Report within 10 working days.  
If the event results in the death of 
a participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.   
 
 
Protocol exception 
Approval must be obtained prior 
to implementing the change 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
that list in the protocol 
or IB 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
Report to Verastem 
at the same time as 
the FDA. 
Complaints 
If the complaint reveals an 
unanticipated problem involving 
risks to participants or others OR 
noncompliance, report within 10 
working days.  If the event results 
in the death of a participant 
enrolled at WU/BJH/SLCH, 
 
 

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Expedited Reporting Timelines 
Event 
HRPO 
FDA 
Verastem Oncology 
report within 1 working day.  
Otherwise, report at the time of 
continuing review. 
Breach of 
confidentiality 
Within 10 working days. 
 
 
Incarceration 
If withdrawing the participant 
poses a safety issue, report within 
10 working days.   
 
If withdrawing the participant 
does not represent a safety issue 
and the patient will be withdrawn, 
report at continuing review. 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
FDA 
Verastem 
Oncology 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks 
to participants or others, report 
summary information at the time of 
continuing review 
The most current toxicity 
table from the DSM report 
is provided to the FDA 
with the IND’s annual 
report. 
 
Minor deviation 
Report summary information at the time 
of continuing review. 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem involving risks 
to participants or others OR 
noncompliance, report within 10 
working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the 
time of continuing review. 
 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
 
 
 
 

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APPENDIX E: Washington University Serious Adverse Event Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Event Start Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date