Randomized Double-Blind Phase 2 Trial of Ibrutinib Versus Standard Treatment for COVID-19 Illness Requiring Hospitalization With Safety Lead-In
Phase: PHASE1
Conditions: Aplastic Anemia, Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Monoclonal B-Cell Lymphocytosis, Monoclonal Gammopathy of Undetermined Significance, Myelodysplastic Syndrome, Symptomatic COVID-19 Infection Laboratory-Confirmed
Sponsor: Jennifer Woyach

Ibrutinib for COVID 19 
 
1 
  TITLE: 
Randomized Double-Blind Phase 2 Trial of Ibrutinib versus Standard 
Treatment for COVID-19 Illness Requiring Hospitalization with Safety Lead-
In 
 
 
SPONSOR: 
 
 
 
The Ohio State University 
 
IND Principal Investigator: 
Jennifer A. Woyach MD 
 
LEAD CLINICAL INVESTIGATOR: Zeinab El Boghdadly MD 
 
 
 
 
PARTICIPATING INSTITUTIONS: The Ohio State University 
 
 
 
 
 
 
 
 
 
 
 
 
IND:  
 
 
 
149967 
 
 
 
VERSION: 
 
 
 
DATE:  
 
 
IRB Approval: 
1.0 
06/23/2020 
07/09/2020 
2.0 
12/14/2020 
08/04/2021 
 
 
 
 
 
 
 
 

Ibrutinib for COVID 19 
 
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TABLE OF CONTENTS 
1.  PROTOCOL SYNOPSYSIS ............................................................................................................................... 4 
2.  Study Objectives ........................................................................................................................................... 16 
2.1. Primary Objective ............................................................................................................................. 16 
2.2 
Secondary Objectives .................................................................................................................. 17 
3. 
Study Endpoints ......................................................................................................................................... 18 
4. 
BACKGROUND ............................................................................................................................................ 19 
4.1  
SARS-CoV-2 and COVID-19: ..................................................................................................... 19 
4.2  
Immune Response to SARS-CoV-2: ....................................................................................... 19 
4.3  
Cancer Strategies to Diminish Inflammatory, but not Immune Response: ........... 20 
4.4  
Targeting BTK as an Anti-infectious Strategy: .................................................................. 21 
4.5  
Risk Mitigation for Targeting BTKi in COVID-19 syndrome: ...................................... 21 
4.6  
Summary: ........................................................................................................................................ 22 
5. 
PATIENT SELECTION ............................................................................................................................... 23 
5.1. 
Inclusion Criteria .......................................................................................................................... 23 
5.2 Exclusion Criteria ............................................................................................................................... 24 
5.3.   
Inclusion of Women and Minorities ................................................................................. 25 
6.  REGISTRATION PROCEDURES ................................................................................................................ 25 
6.1.   
Informed Consent .................................................................................................................... 25 
6.2.   
Registration ................................................................................................................................ 25 
7.  TREATMENT PLAN ...................................................................................................................................... 26 
7.1.  
Overview and Design of Study ................................................................................................ 26 
7.1.1  
Phase 1b .................................................................................................................................. 26 
7.1.2  
Randomized Double-Blind Phase 2 Study ................................................................. 27 
7.2.  
Ibrutinib and Placebo Administration ................................................................................. 27 
7.3. Concomitant Medication Use Guidelines For Study Participants ................................... 28 
7.4  
Supportive Medications ............................................................................................................. 30 
7.5.  
Perioperative/Periprocedural Management ..................................................................... 31 
7.6.  
Duration of Treatment ............................................................................................................... 32 
7.7.  
Duration of Follow-up ................................................................................................................ 32 
7.8.  
Criteria for Removal from Study ............................................................................................ 32 
7.9.  
Duration of Study ......................................................................................................................... 32 
8.  DOSE DELAYS AND MODIFICATION (Only Applicable to Safety lead-in patients who do 
not have DLT, and Phase 2 Patients ................................................................................................... 32 
8.1.  
Guidelines for Dose Suspension or Modification Due to Adverse Events .............. 32 
8.2.  
Dose modification of study drug (Ibrutinib or placebo) for Hepatic Impairment
 
33 
9.  ADVERSE EVENT ASSESSMENT AND REPORTING ......................................................................... 34 
9.1.  
Safety Assessment Overview and Monitoring Timeframe ........................................... 34 
Maintenance of Safety Information .............................................................................................. 34 
9.2.  
Definition of an Adverse Event (AE) ..................................................................................... 34 
9.3.  
Definition of a Serious Adverse Event (SAE) ..................................................................... 35 

Ibrutinib for COVID 19 
 
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9.4.  
Definition of an Unlisted (Unexpected) Adverse Event................................................. 36 
9.5      Definition of an Adverse Event of Special Interest…………………………………………..35 
9.6.  
Adverse Event Grading and Attribution .............................................................................. 36 
9.7.  
Reporting of SAEs and Special Reporting Situations ...................................................... 37 
9.7.1.  All Adverse Events (AEs) .................................................................................................. 38 
9.8 Product Quality Complaint (PQC) ................................................................................................ 38 
9.9. Data and Safety Monitoring ........................................................................................................... 38 
10.  PHARMACEUTICAL INFORMATION ................................................................................................... 39 
10.1.  
Ibrutinib (PCI-32765, ImbruvicaTM) ................................................................................. 39 
10.1.1.  
Formulation and Storage ............................................................................................. 40 
10.1.2.  
Administration ................................................................................................................. 40 
10.1.3.  
Overdosage ........................................................................................................................ 40 
10.1.4. How Supplied .......................................................................................................................... 41 
11.  BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................................... 41 
12. STUDY CALENDARA ................................................................................................................................... 43 
13. STATISTICAL CONSIDERATIONS ......................................................................................................... 46 
14.  RETENTION OF RECORDS ...................................................................................................................... 50 
15.  REFERENCES ............................................................................................................................................... 50 
Appendices ........................................................................................................................................................... 55 
Appendix A:  INHIBITORS AND INDUCERS OF CYP3A................................................................ 55 
Appendix B: Preparation Worksheet for NG or OG Tube Administration of Ibrutinib .. 56 
Appendix C: Institutional guidelines for management of COVID-19 ..................................... 58 
 
 
 

Ibrutinib for COVID 19 
 
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1.  PROTOCOL SYNOPSYSIS 
IND Sponsor 
The Ohio State University 
Protocol Title 
Randomized Double-Blind Phase 2 Trial of Ibrutinib versus Standard 
Treatment for COVID-19 Illness Requiring Hospitalization with Safety 
Lead-In 
Protocol 
Number 
Protocol  
Phase of 
Development 
Phase 2 Randomized Adaptive Trial 
Rationale 
The SARS-CoV-2 virus, a novel coronavirus represents a serious human 
to human pathogenic virus and represents a current WHO pandemic 
pathogen. The clinical syndrome manifested by SARS-CoV-2 is termed 
COVID-19 with a common presentation of fever (89%), cough (68%), CT 
abnormalities (86%) and lymphocytopenia (84%) with nausea (5%) 
and diarrhea (4%) being uncommon. Severe disease that requires 
admission occurs in 20% and a subset of these patients require ICU care 
(6%), intubation (2.3%) or die (1.4%).   The death rate from COVID-19 
in different populations has ranged from 2.4% in China to 7.2% in Italy.  
Death rate from COVID-19 increases proportionally with older age, 
being highest among older patients and also those who are 
immunocompromised 
or 
have 
other 
co-morbidities 
or 
lymphocytopenia. Among hospitalized cancer patients with COVID-19 in 
China, a 38% frequency of mechanical ventilation or death occurred 
compared to 8% among patients without cancer. The systemic and 
pulmonary pathogenesis derived from clinical cases of ICU hospitalized 
COVID-19 cases and autopsy series demonstrate increased levels of 
plasma inflammatory cytokines including TNF-alpha, IL-6, and IL-2, and 
IL-10 and neutrophilic infiltration, macrophages, monocytes, minimal 
lymphocytes (CD4+ T-cells predominantly) and type 2 pneumocytes 
with viral particles. Other risk factors for severe COVID-19 illness is the 
presence of neutrophilia, organ dysfunction (elevated LDH), coagulation 
abnormalities, thrombocytopenia, and lymphocytopenia suggesting 
both findings observed in hemophagocytic syndrome, and immune 
deficiency.  
    To date, there have been no studies published that follow immune 
response serially in patients with SARS-CoV-2 infection and COVID-19 
syndrome.  Several studies have demonstrated cross comparative 
studies of moderate versus severe COVID-19 syndrome where 
differential decline in CD4 and CD8 cells occurs with increasing features 
of both exhausted T-cells (increased PD1, LAG3, CTLA4, and decreased 
intracellular gamma-interferon) and inflammatory cytokines.  These 
findings mimic other chronic virus and parasitic infections where 
inability of CD4 T-cells to generate cytotoxic gamma-interferon and T-

Ibrutinib for COVID 19 
 
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cell exhaustion contributes to failure of the host organism to clear viral 
infections.  Application of a therapeutic that enhances Th1 polarization, 
diminishes T-cell exhaustion and decreases TNF and IL6 production by 
both T-cells and monocytes would represent a potential novel 
therapeutic approach to COVID-19 syndrome. 
     In contrast to immune suppression predicting higher infection rate 
and morbidity with COVID-19, once this syndrome is active therapies 
directed at diminishing inflammation including corticosteroids, IL-6 
neutralizing 
antibodies, 
and 
hydroxychloroquine 
or 
hydroxychloroquine with azithromycin have demonstrated anecdotal 
benefit among ill patients. Patients recovering from COVID-19 syndrome 
demonstrate evidence of humoral neutralizing antibodies and SARS-
CoV-2 specific T-cells. Additionally, ill patients treated with plasma 
derived from patients who have developed COVID-19 and recovered 
with evidence of immune response have had evidence of clinical 
improvement.  This provides evidence that strategies that can disrupt 
the acute inflammatory response associated with respiratory failure 
while preserving immune function could serve to effectively treat 
patients with COVID-19.   
     Cancer based targeted therapies often seek to shut down 
inflammatory cytokine release while not compromising innate or 
adaptive immune response.  Examples of this include application of 
targeted agents directed at graft versus host disease while at the same 
time maintaining anti-leukemic activity in the setting of allogeneic stem 
cell transplant.  One such example of this is Ruxolitinib, a JAK2 inhibitor 
that was recently FDA approved for the use of acute graft versus host 
disease. JAK2 inhibitors also demonstrate profound reduction in 
cytokine production in myelofibrosis and other inflammatory diseases.  
Similarly, work by OSU investigators and then others has demonstrated 
ibrutinib, an irreversible inhibitor of BTK and ITK, has chronic graft 
versus host therapeutic potential in pre-clinical models and does not 
inhibit graft versus leukemia effect. As an irreversible ITK inhibitor, 
Ibrutinib has been shown to polarize CD4 cells to a Th1 phenotype in 
human CLL cells favoring gamma interferon production and in murine 
models enabling clearance of pathogens such as listeria monocytogenes 
and leishmania.  By enhancing T-cell function, ibrutinib has been shown 
to enhance other T-cell based therapies including TLR agonists, PD1 
blockade, and CAR-T cells.  The combination of CAR-T cells and ibrutinib 
in addition to being highly active was shown to also potentially diminish 
cytokine release syndrome as compared to an earlier report of 
administering CAR-T cells alone in CLL.  This was recapitulated 
experimentally in a murine model of CAR-T cell mediated cytokine 
release syndrome where ibrutinib improved survival by decreasing this 
complication while not abrogating T-cell expansion or killing.  Finally, in 
work performed by our own group in CLL we demonstrated that 

Ibrutinib for COVID 19 
 
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ibrutinib via ITK inhibition diminishes both activation induced death 
and reversed features of immune exhaustion, a common pathway that T-
cells become depleted in the setting of cancer or chronic viral infections.  
These favorable immune modulating features of ibrutinib establish it as 
a potential therapy to enhance Th1 polarization, diminished exhaustion, 
and improved T-cell immune response toward SARS-CoV-2. 
   Despite being an immune modulator, ibrutinib has not been 
administered clinically to treat infectious disease or abrogate 
inflammatory toxicity mediated by immune hyperactivation in the lung.  
However, there is significant pre-clinical data implicating BTK activation 
in acute pulmonary injury and subsequent ARDS.  BTK activation has 
been demonstrated to be an essential component of lung injury induced 
by infectious pathogens, sepsis, and hemorrhagic lung injury that is 
mediated by excessive inflammatory macrophages and neutrophils. 
Genetic knock down of BTK impaired this lung injury. Subsequent 
pharmacologic studies with ibrutinib have confirmed this.  Specifically, 
ibrutinib in the setting of murine pneumococcal pneumonia has also 
been shown to negatively influence both monocyte and granulocyte 
migration into the lung and also alveolar macrophage activation, 
cytokine release and plasma leakage. Antibiotic mediated killing of 
bacteria was not impaired.  A similar study with seasonal influenza A 
virus demonstrated ibrutinib administered intranasally to mice starting 
72 h after lethal infection with influenza A diminished weight loss and 
led to significant improved overall survival.  Additionally, ibrutinib 
treatment had a dramatic effect on morphological changes to the lungs 
including decreased alveolar hemorrhage, interstitial thickening, and 
the presence of alveolar exudate concomitant with diminished 
inflammatory mediators TNF-alpha, IL-1beta, IL-6, and MCP-1.  This 
murine study suggests that ibrutinib may be an effective therapy for not 
only influenza-induced lung injury but for treating other viral pathogens 
mediating lung dysfunction via excessive inflammation.  
   Collectively, these data support ibrutinib may diminish the lung 
pathology mediated by the SARS-CoV-2 virus and justify application of 
this approach for clinical investigation in patients with COVID-19 
syndrome.  Collectively, we put forth that ibrutinib as an agent that may 
1) diminish the excessive innate immune inflammatory pulmonary 
response to SARS-CoV-2 infection that causes need for intubation and 
often death; 2) helps to prevent/reverse the severe compromise of 
adaptive immune system by ameliorating lymphocytopenia, reducing 
exhaustion as measured by checkpoint molecule expression (PD-
1/CTLA4 etc.), and preserving the Th1/Tc1 function.  This ultimately 
will help to protect against HLH/MAS like symptoms, where deficiency 
in T cells or NK cells plays a key role and 3) Enhance or at least not 
compromise viral clearance based upon data by our group with listeria 
and Leishmania major and others with influenza.     

Ibrutinib for COVID 19 
 
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This clinical trial proposal seeks to test this hypothesis by administering 
ibrutinib therapy for hospitalized COVID-19 patients with a history of 
cancer.  Here we will determine if ibrutinib effectively diminishes the 
high observed frequency of respiratory failure or death.  If preliminary 
data suggest this approach shows promise in high risk cancer patients, 
we would broaden the eligibility to non-cancer patients after discussion 
with the Food and Drug Administration. 
   
Objectives 
Primary Objectives  
Safety Lead-In 
• To determine the feasibility and tolerability of administering 
Ibrutinib in COVID-19 infected patients  
Phase 2 
o To determine whether ibrutinib administration 
plus standard of therapy (Arm A) in cancer 
patients can diminish respiratory failure or death 
due to COVID-19 as compared to control 
population receiving placebo plus standard 
therapy (for example antiviral such as remdesivir 
or others, chloroquine, hydroxychloroquine, 
cytokine blocking peptides or small molecules) 
(Arm B). Respiratory failure is defined as any of 
the followings: 
 Endotracheal intubation and mechanical 
ventilation 
 Extracorporeal membrane oxygenation 
 High-flow nasal cannula 
oxygen delivery (i.e., 
reinforced nasal cannula 
delivering heated, 
humidified oxygen with 
fraction of delivered oxygen 
≥0.5 and flow rates of ≥30 
l/min) 
 Noninvasive positive pressure ventilation 
 Clinical diagnosis of 
respiratory failure without 
initiation of one of above 
measures only when clinical 
decision-making is driven 
solely by resource 

Ibrutinib for COVID 19 
 
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limitation or if patient has 
DNI (Do Not Resuscitate) 
status.  
Secondary Objectives 
• To determine time to clinical resolution of need for supplemental 
oxygen (i.e. maintenance of oxygen saturation of 93% or greater 
on room air with ambulation). 
• To determine rate of ICU admission and length of ICU admission 
for patients treated with ibrutinib (Arm A) versus control 
population receiving standard therapy (Arm B) 
• To determine rate of  shock requiring vasopressor support for 
patients treated with ibrutinib (Arm A) versus control population  
receiving standard therapy (Arm B) 
• To determine the rate of secondary infection (bacterial, fungal, 
viral) for patients treated with ibrutinib (Arm A) versus control 
population receiving standard therapy (Arm B) 
• To determine the time to hospital discharge for patients treated 
with ibrutinib (Arm A) versus control population receiving 
standard therapy (Arm B) 
• To determine grade 3 or higher toxicity observed in patients 
treated with ibrutinib (Arm A) versus control population 
receiving standard therapy (Arm B) 
• To determine time to mechanical ventilation, the number of days 
of mechanical ventilation per patient and total observed in 
patients treated with ibrutinib (Arm A) versus control population 
receiving standard therapy (Arm B) 
• To determine the overall survival at 3 and 12 months post-
enrollment. 
 
Exploratory Objectives 
• To examine the impact of baseline clinical features (e.g. type of 
cancer, active therapy), duration of symptoms prior to admission 
and laboratory features (e.g. T cell count) on outcome for patients 
treated on this therapeutic study 
• To determine the time to defervescence (oral temperature<100.5 
degrees F for a 48 hour time period) among patients treated with 

Ibrutinib for COVID 19 
 
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ibrutinib (Arm A) versus control population receiving standard 
(Arm B) therapy 
• To determine the proportion of patients with viral clearance at 
end of ibrutinib therapy, time of hospital discharge and follow  up 
thereafter among patients treated with ibrutinib (Arm A) versus 
control (Arm B) treatment  
• To determine the time and proportion of patients who develop 
IgM and IgG levels toward SARS-CoV-2 treated with ibrutinib 
(Arm A)  versus control treatment (Arm B) 
• To examine immune cell subsets for absolute number, activation, 
exhaustion markers, and presence of maturation arrest (NK cells) 
at baseline and over time among patients treated with ibrutinib 
(Arm A) versus control (Arm B) treatment 
• To examine T-cell repertoire over time among patients treated 
with ibrutinib (Arm A) versus control (Arm B) treatment   
• To 
determine the influence of epigenetic age, clonal 
hematopoiesis, and monoclonal B cell lymphocytosis (MBL on 
treatment outcome 
• To determine serial change in inflammatory markers as CRP, 
ferritin, D-Dimer and cytokines including IL6, IL1B, and TNF-
alpha serum levels over time among patients treated with 
ibrutinib (Arm A) versus control (Arm B) treatment. 
Trial Design       This study is a Phase 2 randomized double-blinded trial using a group 
sequential design with a lead-in cohort to better define safety and 
tolerability of ibrutinib combined with standard therapies for COVID-19 
in a high-risk cancer population. The lead-in cohort and randomized trial 
define two separate components of the study. 
Safety Lead-in Cohort 
This study will begin with a 12 patient lead-in component to establish 
safety and better characterize toxicity prior to the randomized 
component.  For safety purposes, patients will be enrolled in cohorts of 
3 for the first 6 patients, and patients will receive ibrutinib at a dose of 
420 mg daily.  Dose limiting toxicity (DLT) will be evaluated during the 
first 14 days of treatment.  
 
DLT would be considered to be any of the following:  
• Grade 4 hematologic toxicity that persists for 3 or more days that 
is considered at least possibly related to ibrutinib. 

Ibrutinib for COVID 19 
 
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• Grade 3 or higher non-hematologic toxicity that are considered at 
least possibly related to Ibrutinib with the exception of nausea, 
vomiting, diarrhea, or electrolyte abnormality, unless these 
persist for at least 3 days despite maximal supportive care 
• Any grade 3 or higher fungal or bacterial infection (excluding line 
infection, catheter-associated UTI, or C difficile infection), cardiac 
toxicity (with the exception of hypertension) or bleeding 
regardless of the attribution.  We note, though, that many 
patients in the hospital that develop infection of any grade will be 
treated with IV antibiotics, and that per CTCAE criteria, those 
graded 3 or higher would be those where IV antibiotics are 
indicated, not only for those where IV are chosen due to 
convenience. 
• Grade 3 or higher hemorrhage regardless of attribution, or Grade 
2 hemorrhage that is considered at least possibly related to 
ibrutinib and is considered to be significant by the treating 
physician in collaboration with the PI. 
 
• Non COVID-19 related neutropenic fever 
 
Enrollment to this dose level will stop if 2 of the first 3 evaluable patients 
or if at least 33% of subsequent evaluable patients (i.e, 2/6, 3/9, or 4/12) 
have DLT. If unacceptable toxicity is observed, Ibrutinib will decrease to 
280 mg daily, and another 12 patient lead-in will be evaluated at this 
lower dose level following the same stopping rules. If  toxicity is 
acceptable, the study will proceed to the randomized component.  
Patients who do not receive 14 days of Ibrutinib for reasons other than 
toxicity or DLT will be replaced for the purposes of the safety and 
tolerability assessment. 
Randomized Double-Blind Phase 2 Study 
The main study is a randomized, double-blind placebo-controlled trial. 
Following completion of the safety lead-in, patients in the phase 2 
portion will be randomized in a 1:1 fashion to receive ibrutinib plus 
standard treatment (Arm A) versus placebo plus standard treatment  
(Arm B) for COVID-19.   
Patients may receive any additional therapies that are not prohibited in 
the section on concomitant medications.   
In this trial, cycles will be 7 days in length.  Study drug will continue for 
2 cycles (14 days).  

Ibrutinib for COVID 19 
 
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Accrual 
Expectations, 
N 
78 
Inclusion/ 
Exclusion 
Criteria 
Inclusion Criteria 
1. Hospitalization for confirmed PCR positive COVID-19 infection 
2. Active cancer, defined as a solid malignancy either undergoing 
active therapy, receiving therapy within 1 year, or a hematologic 
malignancy under active therapy or observation. 
3. Age ≥ 18 
4. Patients with evidence of pulmonary involvement who meet any 
of the followings; presence of infiltrates on chest X-ray or CT scan 
or need for supplemental oxygen < 8L nasal cannula or pulse 
oximetry < 94% on room air.   
5. Biochemical values within the following limits: 
a. Creatinine clearance ≥ 25 ml/min by Cockcroft-Gault 
equation  
b. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless 
bilirubin rise is due to Gilbert’s syndrome or of non-hepatic 
origin  
c. Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 3 x ULN 
6. Hematology values must be within the following limits ( no need 
to hold growth factors or blood products transfusion): 
a. Absolute neutrophil count (ANC) ≥ 1000/mm3 independent 
of growth factor support 
b. Platelets ≥50,000/mm3  
7. Ability to swallow capsules or receive opened capsule content via 
nasogastric or enteral feeding tube as described in 7.2 
8. Ability to provide informed consent indicating that they 
understand the purpose of and procedures required for the 
study, including biomarkers, and are willing to participate in the 
study. If a patient is unable to provide informed consent (e.g. does 
not 
possess 
decisional 
capacity), 
a 
legally 
authorized 
representative may provide consent for the patient. 
9. Women of childbearing potential and men who are sexually 
active must be practicing a highly effective method of birth 
control during and after the study consistent with local 
regulations regarding the use of birth control methods for 

Ibrutinib for COVID 19 
 
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subjects participating in clinical trials. Men must agree to not 
donate sperm during and after the study. For females, these 
restrictions apply for 1 month after the last dose of study drug. 
For males, these restrictions apply for 3 months after the last 
dose of study drug. 
10. Women of childbearing potential must have a negative serum 
(beta-human 
chorionic 
gonadotropin 
[β-hCG]) 
or 
urine 
pregnancy test at Screening. Women who are pregnant or 
breastfeeding are ineligible for this study. 
Exclusion Criteria 
1.  Patients with new-onset malignancy requiring urgent initiation 
of systemic chemotherapy 
2. Active uncontrolled systemic bacterial or fungal or other viral 
infection  
3. Requires anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) 
4. Currently receiving BTK inhibitor therapy 
5. Actively receiving anti-cancer therapy (other than hormonal 
therapies).  All anti-cancer therapy (except hormonal therapies) 
must be stopped at the time of screening; can be resumed as soon 
as ibrutinib is discontinued.  Significantly T cell suppressive 
chemotherapy (defined as requiring PJP prophylaxis per 
standard guidelines) is not allowed for 3 months prior to 
enrollment. 
6. Clinically significant cardiovascular disease such as uncontrolled 
or symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of Screening, or any Class 
3 (moderate) or Class 4 (severe) cardiac disease as defined by the 
New York Heart Association Functional Classification  
7. Requirement for mechanical ventilation at screening  
8. Known bleeding disorders (e.g., Von Willebrand’s disease, 
platelet storage pool disorders, or hemophilia)  
9. Stroke or intracranial hemorrhage within 6 months of screening. 
10. Major surgery or non-healing wound within 4 weeks of 
enrollment. 
11. Concomitant administration of prohibited medications (See 
Appendices 
12. )  

Ibrutinib for COVID 19 
 
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13. Known history of human immunodeficiency virus (HIV), or active 
hepatitis B or C infection  
14. Disease significantly affecting gastrointestinal function and/or 
inhibiting small intestine absorption (malabsorption syndrome, 
resection of the small bowel, poorly controlled inflammatory 
bowel disease, etc.). 
15. Requires chronic treatment with strong CYP3A inhibitors or 
inducers. See appendix  A  for complete list of medications 
16. Participation in another clinical trial for COVID 19 (antiviral 
based trials accepting co-enrollment, emergency use or 
compassionate use or expanded access protocols are allowed) 
 
Length 
of 
Study 
Patients will be followed for 12 months or until death or withdrawal of 
study consent for further follow-up.  Following hospitalization, study 
visits may be by telephone or video encounters.  Patients will need to 
return to OSU for laboratory studies as outlined in the study calendar.  
Treatment 
Algorithm 
Phase 2: Patients will be randomized 1:1 to ibrutinib plus standard 
treatment (Arm A) versus placebo plus standard treatment (Arm B) 
Investigation
al Product 
Dose/Route/ 
Regimen 
Ibrutinib or Placebo 420 mg or 280 mg 
 
Doses described above will be given daily by mouth for 7 day cycles. 
Standard 
of 
care  
Patients will receive supportive care or directed therapies based on our 
institutional COVID-19 treatment recommendations. See appendix C  for 
details. This is an evolving matter and continuous updates to these 
recommendations will take place as new data arise. Details of supportive 
or targeted therapy will be reported for each patient.   
Study 
Assessments 
Biomarker and Correlatives 
The following biological specimens will be collected in this study and 
will be used to evaluate the association of exploratory systemic and/or 
tissue specific biomarkers with study drug response including efficacy 
and/or adverse events. Biomarker samples may be used for potential 
assay development of companion diagnostics.  Tests will include 
• Measurement of viral clearance in each treatment arm; 
• Measurement of immune cell subsets for absolute number, 
activation, exhaustion markers, and presence of maturation 
arrest (NK cells) at baseline and over time among patients 
treated with ibrutinib (Arm A) versus control (Arm B) treatment 

Ibrutinib for COVID 19 
 
14 
• Measurement of T-cell repertoire and IgM, IgA, IgG response to 
SARS-CoV-2 over time among patients treated with ibrutinib 
(Arm A)  versus control (Arm B) treatment;  
• Measurement of epigenetic age, clonal hematopoiesis, and MBL 
on treatment outcome 
• Measurement of serial change cytokines including (but not 
limited to) IL6, IL1B, TNF-alpha, IL-10 serum levels over time 
among patients treated with ibrutinib (Arm A) versus control  
(Arm B) treatment 
Statistics/ 
Sample 
Size 
Estimate 
Safety Lead-In: 12 patients will be enrolled as part of the safety lead-
in cohort. Enrollment to a dose level will stop if 2 of the first 3 
evaluable patients or if at least 33% of subsequent evaluable patients 
(i.e, 2/6, 3/9, or 4/12) have DLT.  
Randomized Phase 2: Allowing for roughly 10% over-accrual, we 
plan to randomize 66 high-risk patients with cancer to the two arms 
of the study in a 1:1 ratio utilizing a permuted block schedule. 
Randomization will be stratified on age (<60 years vs > 60 years) and  
presence of comorbidities (yes vs no) (comorbidities defined in 
Appendix C). The primary endpoint is the proportion of randomized 
patients with respiratory failure or death during hospitalization for 
COVID-19 infection within 30 days of registration. 
Based on the study in China, we assume that the event rate is 40% 
and that it can be reduced to 15% when Ibrutinib is given in addition 
to standard care for COVID-19. With 60 patients and using a standard 
group sequential design, there is 82.8% power to detect a reduction 
in the event rate under the alternative hypothesis and constraining 
the one-sided type I error to 20%. Power was calculated using a z-
test for the difference in two proportions, pooled variance, and 
adjustment for small sample sizes with the Casagrande-Pike-Smith 
correction (EAST v6.5; Cytel, Inc). There will be an interim analysis 
when 50% of randomized patients have been followed for 30 days 
from registration. The study will be stopped early if at the interim 
analysis the observed event rate is higher in the ibrutinib arm (Arm 
A) than in the control arm (Arm B). At the final analysis, data will be 
analyzed using a one-sided Fisher’s exact test and a promising signal 
declared if p<0.20 and the event rate is lower in the experimental 
arm.  
 
 
 

Ibrutinib for COVID 19 
 
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Although the actual reduction in the event rate could be larger than 
25%, it could also be as low as 20% and still be quite meaningful. 
Furthermore, there is uncertainty in the event rate of the control 
arm. For these reasons, we have incorporated increased flexibility at 
the time of the interim analysis to potentially increase the sample 
size if conditional power indicates promising results, and will thus 
implement an adaptive group sequential design (Chen, DeMets, Lan; 
2004).  
 
At the interim analysis, there are 4 possible outcomes: 1) the futility 
criteria are met and the trial stops early; 2) the conditional power is 
unfavorable (<50%), and enrollment continues to the full 60 patients 
without an increase in sample size; 3) the conditional power is in a 
promising zone (defined as conditional power >50% and < 82.8%), 
and sample size may be re-estimated with the original sample size 
updated to boost the power to a target of 82.8%, subject to a 
maximum sample size of 120; or 4) the conditional power is 
favorable (>82.8%), and enrollment continues to the full 60 patients 
without an increase in sample size. When using this procedure, no 
adjustment to the final test statistic or critical value from the original 
design is required to control the Type I error rate. In addition, if the 
conditional power is in the promising zone, we can choose not to 
increase the sample size beyond what was originally planned or by a 
flexible amount without penalty. 
Operating characteristics using the adaptive group sequential design 
is presented for four different scenarios:  
Scenario 1: Event rates in the ibrutinib and control groups are 15% 
and 40% 
Scenario 2: Event rates in the ibrutinib and control groups are 25% 
and 50% 
Scenario 3: Event rates in the ibrutinib and control groups are 20% 
and 40% 
Scenario 4: Event rates in the ibrutinib and control groups are 30% 
and 50% 
For each scenario, the power and expected sample size is also 
provided for the standard group sequential design. For example, 
under Scenario 4, the power of the adaptive group sequential design 
has increased by 11.7% at the cost of corresponding average sample 
size increases of 11 patients. It is important to note that under the 
standard group sequential design, the power would have been only 
64.7%. For the adaptive group sequential design, the conditional 
power falls in the promising zone 21.0% of the time, and for these 
simulations, the re-estimated sample size on average is 101 resulting 
in a boost in power to 89.2%.  

Ibrutinib for COVID 19 
 
16 
Operating characteristics were calculated based on 10,000 
simulations. For the purposes of the simulations, an efficacy 
boundary was defined using an alpha-spending function with 
Gamma(-30), a very conservative boundary to reflect the absence of 
an interim stopping rule for superiority. All sample size and power 
calculations used EAST v6.5 (Cytel, Inc). 
Scenario 
Interim Outcome 
Probability of 
Interim Outcome 
Power Conditional 
on Interim Outcome 
Expected Sample 
Size 
1 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD* 
3.5% 
13.1% 
13.0% 
70.4% 
100% 
0% 
71.8% 
97.8% 
97.9% 
91.0% / 82.8% 
30 
60 
111 
60 
66 / 58 
2 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD 
5.0% 
13.8% 
16.7% 
64.6% 
100% 
0% 
62.2% 
95.3% 
96.5% 
86.8% / 78.7% 
30 
60 
103 
60 
66 / 57 
3 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD 
8.0% 
19.8% 
15.9% 
56.3% 
100% 
0% 
56.9% 
92.1% 
94.7% 
79.3% / 68.0% 
30 
60 
112 
60 
66 / 55 
4 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD 
9.0% 
19.0% 
21.0% 
51.1% 
100% 
0% 
52.0% 
89.2% 
93.7% 
76.4% / 64.7% 
30 
60 
101 
60 
66 / 55 
All based on 10000 Simulations; GSD = standard group sequential design 
 
 
  
Publication of the results of this study will occur for the safety lead-
in cohort (report 1) and then the randomized phase 2 patient group 
(report 2). 
 
 
 
 
2.  Study Objectives 
 
2.1. Primary Objective 
 
Safety run-in 
• To determine the feasibility and tolerability of administering Ibrutinib in COVID-
19 infected patients  
Phase 2 
o To determine whether ibrutinib administration plus standard care  
for COVID-19 (Arm A) in cancer patients can diminish respiratory 

Ibrutinib for COVID 19 
 
17 
failure  or death as compared to untreated control population 
receiving placebo plus standard care (antiviral such as remdesivir or 
others, chloroquine, hydroxychloroquine, cytokine blocking peptides 
or small molecules) (Arm B). Respiratory failure is defined as any of 
the followings: 
 Endotracheal intubation and mechanical ventilation 
 Extracorporeal membrane oxygenation 
 High-flow nasal cannula oxygen delivery (i.e., 
reinforced nasal cannula delivering heated, 
humidified oxygen with fraction of delivered 
oxygen ≥0.5 and flow rates of ≥30 l/min) 
 Noninvasive positive pressure ventilation 
 Clinical diagnosis of respiratory failure without initiation of one 
of above measures only when clinical decision-making is driven 
solely by resource limitation or if patient has DNI (Do Not 
Resuscitate) status. 
2.2  Secondary Objectives 
 
• To determine time to clinical resolution of need for supplemental oxygen (i.e. 
maintenance of oxygen saturation of 93% or greater on room air with ambulation) or 
need for supplemental oxygen above baseline for those on home oxygen. 
• To determine rate of ICU admission and length of ICU admission for patients treated 
with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B) 
• To determine rate of  shock requiring vasopressor support for patients treated with 
ibrutinib (Arm A) versus control population receiving standard therapy (Arm B)  
• To determine the rate of secondary infection (bacterial, fungal, viral) for patients 
treated with ibrutinib (Arm A) versus control population receiving standard therapy 
(Arm B) 
• To determine the time to hospital discharge for patients treated with ibrutinib (Arm 
A) versus control population receiving standard therapy (Arm B) 
• To determine grade 3 or higher toxicity observed in patients treated with ibrutinib 
(Arm A) versus control population receiving standard therapy (Arm B) 
• To determine time to mechanical ventilation, the number of days of mechanical 
ventilation per patient and total observed in patients treated with ibrutinib (Arm A) 
versus control population receiving standard therapy (Arm B) 
• To determine the overall survival at 3 and 12 months post-enrollment. 
 
Exploratory Objectives 

Ibrutinib for COVID 19 
 
18 
• To determine the time to defervescence (oral temperature<100.5 degrees F for a 48 
hour time period) among patients treated with ibrutinib (Arm A) versus control 
population receiving standardtherapy (Arm B) 
• To examine the impact of baseline clinical features (e.g. type of cancer, active 
therapy), duration of symptoms prior to admission and laboratory features (e.g. T cell 
count) on outcome for patients treated on this therapeutic study 
• To determine the proportion of patients with viral clearance at end of ibrutinib 
therapy, time of hospital discharge and follow  up thereafter among patients treated 
with ibrutinib (Arm A) versus control (Arm B) treatment  
• To determine the time and proportion of patients who develop IgM and IgG levels 
toward SARS-CoV-2 treated with ibrutinib (Arm A)  versus control treatment (Arm B) 
• To examine immune cell subsets for absolute number, activation, exhaustion 
markers, and presence of maturation arrest (NK cells) at baseline and over time 
among patients treated with ibrutinib (Arm A) versus control (Arm B) treatment 
• To examine T-cell repertoire over time among patients treated with ibrutinib (Arm 
A) versus control (Arm B) treatment   
• To determine the influence of epigenetic age, clonal hematopoiesis, and monoclonal 
B cell lymphocytosis (MBL) on treatment outcome 
• To determine serial change in inflammatory markers as CRP, ferritin, D-Dimer and 
cytokines including IL6, IL1B, and TNF-alpha serum levels over time among patients 
treated with ibrutinib (Arm A) versus control (Arm B) treatment 
3. Study Endpoints 
 
3.1. 
Primary Endpoints 
Proportion of patients who develop respiratory failure (as defined elsewhere in the 
protocol) or death during hospitalization for COVID-19 infection within 30 days of 
registration 
 
3.2. 
Secondary Endpoints 
• 
Time from study initiation to 48 hours fever-free (<100.5 degrees F orally) 
• 
Duration of hospitalization  
• 
Time in ICU 
• 
Time to ICU admission  
• 
Number of days requiring supplemental oxygen (or supplemental oxygen above 
baseline levels) 
• 
Total days of mechanical ventilation 
• 
Time to mechanical ventilation 
• 
Shock and need for pressure support   

Ibrutinib for COVID 19 
 
19 
• 
Incidence of any infection (viral, fungal, bacterial) including opportunistic 
infections  
• 
Time to clinical resolution  
• 
Grade 3 or higher toxicity  
• 
Viral clearance at the end of therapy 
• 
Time to viral clearance 
• 
Overall survival at 3 and 12 months   
 
4. BACKGROUND 
4.1  
SARS-CoV-2 and COVID-19:  
The SARS-CoV-2 virus, a novel coronavirus originated from Wuhan China and represents 
a serious human to human pathogenic virus. SARS-Co-OV-2 has a variable phenotype 
ranging from asymptomatic carrier state to rapidly progressive acute respiratory 
distress syndrome.  The clinical syndrome manifested by SARS-CoV-2 is termed COVID-
19.  Both the infectiveness and pathogenic nature of this respiratory droplet transmitted 
RNA virus greatly exceeds that of influenza, likely as a consequence of no prior human 
exposure or available vaccine.  SARS-CoV-2 has rapidly spread throughout the world and 
was recently by the WHO as a pandemic pathogen.  Notably, SARS-COV-2 has common 
presentation of fever (89%), cough (68%), CT abnormalities (86%) and 
lymphocytopenia (84%) with nausea (5%) and diarrhea (4%) being uncommon. Severe 
disease that requires admission occurs in 20% and a subset of these patients require ICU 
care (6%), intubation (2.3%) or die (1.4%).1    The death rate from COVID-19 in different 
populations has been different from China (updated data, 2.4%) to Italy (7.2%).2,3.  Death 
rate from COVID-19 increases proportionately with older age, being highest among older 
patients and also those who are immunocompromised or have other co-morbidities or 
lymphocytopenia 1,3-5. Among hospitalized cancer patients with COVID-19 in China, a 
38% frequency of mechanical ventilation or death occurred compared to 8% among 
patients without cancer6. The systemic and pulmonary pathogenesis derived from 
clinical cases of ICU hospitalized COVID-19 cases and autopsy series demonstrates 
increased levels of plasma inflammatory cytokines including TNF-alpha, IL-6, and IL-2, 
and IL-10 and neutrophilic infiltration, macrophages, monocytes, minimal lymphocytes 
(CD4+ T-cells predominately) and type 2 pneumocytes with EM  viral particles. 7,8 Other 
risk factors for severe COVID-19 illness include the presence of neutrophilia, organ 
dysfunction (elevated LDH), coagulation abnormalities, thrombocytopenia, and 
lymphocytopenia suggesting both findings observed in hemophagocytic syndrome that 
often accompanies immune deficiency and dysregulation 1,9,10.  
 
4.2  
Immune Response to SARS-CoV-2:  
To date, there have been no studies published that serially follow immune response in 
patients with SARS-CoV-2 infection and COVID-19 syndrome.  Several studies have 
demonstrated cross comparative studies of moderate versus severe COVID-19 syndrome 
where differential decline in CD4 and CD8 T-cells occurs with increasing features of both 
exhausted T-cells (increased PD1, LAG3, CTLA4, and decreased intracellular gamma-
interferon) and inflammatory cytokines11-13..  These findings mimic other chronic virus 
and parasitic infections where inability CD4 T-cells to generate cytotoxic gamma-

Ibrutinib for COVID 19 
 
20 
interferon and T-cell exhaustion contributes to failure of the host organism to clear viral 
infections.  Application of a therapeutic that enhances Th1 polarization, diminishes T-cell 
exhaustion and decreases TNF and IL6 production by both T-cells and monocytes would 
represent a potential novel therapeutic approach to COVID-19 syndrome. 
In contrast to immune suppression predicting higher infection rate and morbidity with 
COVID-19, once this syndrome is active therapies directed at diminishing inflammation 
including corticosteroids, IL-6 neutralizing antibodies, and hydroxychloroquine or 
hydroxychloroquine with azithromycin have demonstrated anecdotal benefit among ill 
patients. Patients recovering from COVID-19 syndrome demonstrate evidence of 
humoral neutralizing antibodies14,15 and SARS-CoV-2 specific T-cells. Additionally, ill 
patients treated with plasma derived from patients who have developed COVID-19 and 
recovered with evidence of immune response have had evidence of clinical 
improvement16.  This provides evidence that strategies that can disrupt the acute 
inflammatory response associated with respiratory failure while preserving immune 
function could serve to effectively treat patients with COVID-19.   
 
4.3  
Cancer Strategies to Diminish Inflammatory, but not Immune Response:  
Cancer based targeted therapies often seek to shut down inflammatory cytokine release 
while not compromising innate or adaptive immune response.  Examples of this include 
application of targeted agents directed at graft versus host disease while at the same time 
maintaining anti-leukemic activity in the setting of allogeneic stem cell transplant17,18.  
One such example of this is Ruxolitinib, a JAK2 inhibitor that was recently FDA approved 
for the use of acute graft versus host disease. JAK2 inhibitors also demonstrate profound 
reduction in cytokine production in myelofibrosis and other inflammatory diseases19.  
Similarly, work by OSU investigators and then others has demonstrated ibrutinib, an 
irreversible inhibitor of BTK and ITK that is FDA approved for marketing for treatment 
of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, marginal zone lymphoma, 
and Waldenstrom’s macroglobulinemia, has chronic graft versus host therapeutic 
potential in pre-clinical models and does not inhibit graft versus leukemia effect20-22. As 
an irreversible ITK inhibitor, Ibrutinib has been shown to polarize CD4 cells to a Th1 
phenotype in human CLL cells favoring gamma interferon production and in murine 
models enabling clearance of pathogens such as listeria monocytogenes and Leishmania 
Major 23,24.  By enhancing T-cell function, ibrutinib has been shown to enhance other T-
cell based therapies including TLR agonists25, PD1 blockade26, and CAR-T cells27-29.  The 
combination of CAR-T cells and ibrutinib in addition to being highly active was shown to 
also potentially diminish cytokine release syndrome as compared to an earlier report of 
administering CAR-T cells alone in CLL30,31.  This was recapitulated experimentally in a 
murine model of CAR-T cell mediated cytokine release syndrome where ibrutinib 
improved survival by decreasing this complication while not abrogating T-cell expansion 
or killing32.  Finally, in work performed by our own group and others in CLL 
demonstrated that ibrutinib via ITK inhibition diminishes both activation induced death 
and reversed features of immune exhaustion, a common pathway that T-cells become 
depleted in the setting of cancer or chronic viral infections33,34.  These favorable immune 
modulating features of ibrutinib establish it as a potential therapy to enhance Th1 
polarization, diminished exhaustion, and improved T-cell immune response toward 
SARS-CoV-2.  Given the availability clinically of both less selective irreversible BTK 

Ibrutinib for COVID 19 
 
21 
inhibitors such as ibrutinib and more selective inhibitors (Zanabrutinib, acalabrutinib, 
and others), the question becomes which target is essential for immune modulation. 
Using the genetic XID BTK kinase inactive mouse, several groups have demonstrated 
favorable immune modulation including resistance to multiple organisms including 
Leishmania Major and other pathogens due to Th1 polarization and enhanced immune 
response35-37.  Our work and that of others in CLL patients suggest that even more 
selective BTK inhibitors such as acalabrutinib which lack inhibition of ITK have similar 
immune modulating potential in the setting of CLL33.  As such, from available work we 
would expect selective BTK inhibitors to be immune modulating, whereas dual inhibitors 
of BTK and ITK to have both immune modulatory and also ability to expand immune cell 
subsets based upon reversal of activation induced death by T-cells.   
 
4.4  
Targeting BTK as an Anti-infectious Strategy:   
Despite being an immune modulator, BTKi of any kind (selective BTK or BTK/ITK) has 
not been administered clinically to treat infectious disease or abrogate inflammatory 
toxicity mediated by immune in the lung.  However, there is significant pre-clinical data 
implicating BTK activation in acute pulmonary injury mediated by macrophages and 
neutrophils and subsequent acute respiratory distress syndrome.  BTK activation has 
been demonstrated to be an essential component of lung injury induced by infectious 
pathogens, sepsis, and hemorrhagic lung injury that is mediated by excessive 
inflammatory macrophages and neutrophils 38-40. Elegant genetic knock down of BTK 
impaired this lung injury 39,40. Subsequent pharmacologic studies with ibrutinib have 
confirmed this.  Specifically, ibrutinib in the setting of murine pneumococcal pneumonia 
has also been shown to negatively influence both monocyte and neutrophil influx into the 
lung and also alveolar macrophage activation, neutrophil influx, cytokine release and 
plasma leakage. Antibiotic mediated killing of bacteria was not impaired41.  A similar 
study with seasonal influenza A virus demonstrated ibrutinib administered intranasally 
to mice starting 72 h after lethal infection with influenza A diminished weight loss and 
led to improved overall survival (37).  Additionally, ibrutinib treatment had a dramatic 
effect on morphological changes to the lungs including decreased alveolar hemorrhage, 
interstitial thickening, and the presence of alveolar exudate concomitant with diminished 
inflammatory mediators TNF-alpha, IL-1beta, IL-6, KC, and MCP-1.  This murine study 
suggests that ibrutinib may be an effective therapy for not only influenza-induced lung 
injury but for treating other viral pathogens mediating lung dysfunction via excessive 
inflammation42.  Ibrutinib and potentially other irreversible BTK inhibitors that target 
BMX irreversibly as well may also have added advantage at diminishing inflammation 
induced by macrophages and monocytes as shown by both genetic and pharmacologic 
studies where this kinase regulates TLR4 activated expression of IL-6 or other pathways 
involving STAT 43-45.  Collectively, these data support ibrutinib or even a more selective 
BTKi may diminish the lung pathology mediated by the SARS-CoV-2 virus and justify 
application of this approach for clinical investigation in patients with COVID-19 
syndrome.  
 
4.5  
Risk Mitigation for Targeting BTKi in COVID-19 syndrome:   
Concern for administering ibrutinib or even more selective BTK inhibitors for the 
treatment of COVID-19 syndrome includes 1) impairment of humoral or cellular immune 

Ibrutinib for COVID 19 
 
22 
response to SARS-COV-2 virus; 2) overlapping cardiac toxicity that might occur with viral 
induced cardiac symptoms and also therapeutics such as chloroquine and 
hydroxychloroquine; 3) increased bleeding given the presence of thrombocytopenia with 
severe cases; 4) increase in alternative infections arising from the anti-inflammatory 
response to ibrutinib and other BTKi.  A small study examining the response of CLL 
patients on ibrutinib vaccinated against influenza A demonstrated protective titers in up 
to 74% of patients46.  In a prospective study performed by our own group in early stage 
CLL not requiring therapy, ibrutinib was administered concurrently with prenar-13 
vaccine and compared to sequential prevnar 13 followed by ibrutinib.  In the concurrent 
arm, 15/16 patients showed a significant increase in antibody titer following vaccination 
whereas in in the sequential arm 3/13 patients had an increase in antibody titer.  
Additionally, long-term treatment with both ibrutinib and acalabrutinib does not 
significantly impair humoral function and results in elevated serum IgA levels among 
non-heavily pretreated patients47,48.  This trial will include monitoring of IgM and IgG 
response to SARS-CoV2 among recovering patients as one of the secondary endpoints to 
assure diminished response is not noted.  With short exposure to ibrutinib (14 days for 
most), we do not anticipate this will occur and believe the risk population justifies this 
inclusion.  While cardiac toxicity consisting predominately of hypertension or atrial 
fibrillation and much lesser frequency of ventricular tachycardia and rare 
cardiomyopathy49-52.  The risk of atrial fibrillation is approximately 3-10% and occurs 
over an extended period of time.  Prolongation of QT is uncommon with ibrutinib. To 
minimize risk we will exclude patients with recent myocardial infarct, symptomatic 
congestive heart failure, and also poorly controlled or patients at high risk for ventricular 
arrhythmias.  Patients with COVID-19 are in the hospital and can be closely monitored 
for both arrhythmia and functional cardiac problems. Given the short period of ibrutinib 
treatment (14 days for most), the cardiac risks seem justifiable given the high mortality 
associated with hospitalized COVID-19 patients with cancer.  While serious bleeding has 
uncommonly been observed with ibrutinib therapy53-55, efforts to risk mitigate this by 
pausing therapy for surgical procedures and also avoiding anticoagulation with warfarin 
and other agents has greatly diminished this risk.  The pathology of lung and organ failure 
in COVID-19 syndrome can involve microthrombi that ibrutinib may have some 
protective effect against.  Indeed, a collective experience by our group at OSU with 
ibrutinib demonstrated that CLL patients had a very low level of venous or arterial 
thrombosis as compared to historical controls56.  To mitigate risk of serious CNS bleeding 
we will exclude patients with recent stroke (hemorrhagic), congenital or acquired 
bleeding diathesis.  Patients will be monitored for bleeding and if excessive events are 
noted the study will be put on hold and re-evaluated.  Finally, the concern for secondary 
infection with ibrutinib must be considered in the context of significant clinical 
experience with this agent in different lymphoid malignancies where over time the 
frequency of infections significantly diminishes.  However, heavily pre-treated patients 
and those who have received steroids concurrently are probably more at risk57,58.  Given 
the short duration of ibrutinib in this trial (14 days for most patients), we do not 
anticipate that the risk of such infections will be high.  We will monitor for these and 
adjust the trial if observed.        
   
 
4.6  
Summary:  

Ibrutinib for COVID 19 
 
23 
Collectively, this trial seeks to test the hypothesis that BTK inhibitors such as ibrutinib or 
other even more selective BTKi may 1) diminish the excessive innate immune 
inflammatory pulmonary response to SARS-COR-2 infection that causes need for 
intubation and often death; 2) helps to prevent/reverse the severe compromise of 
adaptive immune system by ameliorating lymphocytopenia, reducing exhaustion as 
measured by checkpoint molecule expression (PD-1/CTLA4 etc.), and preserving the 
Th1/Tc1 function.  This ultimately will help to protect against HLH/MAS like symptoms, 
where deficiency in T cells or NK cells plays a key role and 3) Enhance  or at least not 
compromise viral clearance based upon data by our group with listeria and Leishmania 
major and others with influenza A.   This clinical trial proposal seeks to test this 
hypothesis that by administering ibrutinib therapy for hospitalized COVID-19 patients 
with a history of cancer or a pre-cancer associated with high risk of infectious morbidity 
(monoclonal B-cell lymphocytosis, MGUS, and smoldering multiple myeloma, aplastic 
anemia, and myelodysplasia).   Here we will determine if ibrutinib effectively diminishes 
the high observed frequency of need for mechanical ventilation or death.  A randomized 
phase 2 study of hospitalized patients with COVID-19 syndrome and cancer/pre-cancer 
syndromes comparing active intervention with ibrutinib (Arm A) + standard of care 
versus standard of care (Arm B).  Cancer patients are chosen for this trial initially as they 
are at higher risk of poor outcome from SARS-CoV-2.  The dose of ibrutinib is chosen 
based upon the extensive CLL experience of the 420 mg and our own data demonstrating 
significant T-cell modulation when administered in this manner. Therapy will be given 
for 14 days with the potential of re-starting therapy if recurrent pulmonary symptoms 
recur.   This trial includes extensive risk mitigation to decrease potential risk of 
administering ibrutinib in this setting.   If preliminary data suggest this approach shows 
promise, we would consider broadening the eligibility to non-cancer patients at a later 
time in consultation with the FDA as a second cohort.    
 
 
 
5. PATIENT SELECTION 
5.1. 
Inclusion Criteria 
 
1. Hospitalization for confirmed PCR positive COVID-19 infection 
2. Active cancer, defined as a solid malignancy either undergoing active therapy, 
receiving therapy within 1 year, or a hematologic malignancy under active therapy or 
observation. 
3. Age ≥ 18 
4. Patients with evidence of pulmonary involvement who meet any of the followings; 
presence of infiltrates on chest X-ray or CT scan or need for supplemental oxygen < 
8L nasal cannula or pulse oximetry < 94% on room air.   
5. Biochemical values within the following limits: 
a. Creatinine clearance ≥ 25 ml/min by Cockroft-Gault equation  

Ibrutinib for COVID 19 
 
24 
b. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless bilirubin rise is due to 
Gilbert’s syndrome or of non-hepatic origin  
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN 
6. Hematology values must be within the following limits (no need to hold growth 
factors or transfusions): 
a. Absolute neutrophil count (ANC) ≥ 1000/mm3 independent of growth factor 
support 
b. Platelets ≥50,000/mm3  
7. Ability to swallow capsules or receive opened capsule content via nasogastric or 
enteral feeding tube as described in 7.2 
8. Ability to provide informed consent indicating that they understand the purpose of 
and procedures required for the study, including biomarkers, and are willing to 
participate in the study. If a patient is unable to provide informed consent (e.g. does 
not possess decisional capacity), a legally authorized representative may provide 
consent for the patient. 
9. Women of childbearing potential and men who are sexually active must be practicing 
a highly effective method of birth control during and after the study consistent with 
local regulations regarding the use of birth control methods for subjects participating 
in clinical trials. Men must agree to not donate sperm during and after the study. For 
females, these restrictions apply for 1 month after the last dose of study drug. For 
males, these restrictions apply for 3 months after the last dose of study drug. 
10. Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are 
pregnant or breastfeeding are ineligible for this study. 
5.2 Exclusion Criteria 
1. Patients with new-onset malignancy requiring urgent initiation of systemic 
chemotherapy. 
2. Active uncontrolled systemic bacterial or fungal or other viral infection  
3. Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon) 
4. Currently receiving BTK inhibitor therapy 
5. Actively receiving anti-cancer therapy (other than hormonal therapies).  All anti-
cancer therapy (except hormonal therapies) must be stopped at the time of screening; 
can be resumed as soon as ibrutinib is stopped. Significantly T cell suppressive 
chemotherapy (defined as requiring PJP prophylaxis per standard guidelines) is not 
allowed for 3 months prior to enrollment. 
6. Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by 

Ibrutinib for COVID 19 
 
25 
the New York Heart Association Functional ClassificationRequirement for mechanical 
ventilation at screening  
7. Requirement for mechanical ventilation at screening 
8. Known bleeding disorders (e.g., Von Willebrand’s disease, platelet storage pool 
disorders, or hemophilia)  
9. Stroke or intracranial hemorrhage within 6 months of screening. 
10. Major surgery or non-healing wound within 4 weeks of enrollment. 
Concomitant administration of prohibited medications (See Appendices 
11. )  
12. Known history of human immunodeficiency virus (HIV), or active hepatitis B or C 
infection  
13. Disease significantly affecting gastrointestinal function and/or inhibiting small 
intestine absorption (malabsorption syndrome, resection of the small bowel, poorly 
controlled inflammatory bowel disease, etc.). 
14. Requires chronic treatment with strong CYP3A inhibitors or inducers. See appendix  
A for complete list of medications 
15. Participation in another clinical trial for COVID 19 (antiviral based trials accepting co-
enrollment, compassionate or emergency use or expanded access protocols are 
allowed) 
 
5.3.   
Inclusion of Women and Minorities 
 
 
All genders, races, and ethnic groups are eligible for this trial and encouraged to participate.  
 
6.  REGISTRATION PROCEDURES 
 
6.1.   Informed Consent 
 
The patient must willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and 
discomforts. The consent process will either take place in-person or over a phone/video 
conferencing application. Any questions or clarifications will be addressed by the clinical 
research coordinator, a co-investigator, or a specific designee previously approved by the 
OSU Institutional Review Board (IRB) using forms approved by the IRB.  
 
 
6.2.   Registration  
 
This is a single center trial conducted at The Ohio State University (OSU).  Dr. Zeinab El 
Boghdadly, the lead clinical investigator, will coordinate protocol management with 

Ibrutinib for COVID 19 
 
26 
assistance from Drs. Jennifer Woyach and John Byrd, who will also have access to and 
responsibility for regulatory matters.  All patients for whom questions arise relative to 
eligibility for the study should be discussed with one of the principal investigators prior to 
entry onto the study. 
 
Patients will be registered by a clinical research coordinator, as per CTO standard practice. 
Because of the highly infectious nature of COVID-19 and need to conserve personal 
protective equipment, the study will be discussed with the patient by a study PI or co-I 
through a video or telephone conference, prior to the research coordinator initiating the 
consent process.    It is expected that most study laboratories will be available from standard 
of care procedures prior to study enrollment, and these can be used for screening studies as 
long as they are obtained within 3 days of screening. Patients with a positive SARS-CoV-2 
PCR result performed at any facility within 10 days of screening do not need to be retested 
given the known prolonged shedding nature of the viral infection.  
 
Patients will be registered after meeting all entry requirements, clearance by the Protocol 
Coordinator, and signing of the informed consent. 
 
Following registration, patients should begin protocol treatment within 48 hours.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator as 
soon as possible.  
 
 
 
7.  TREATMENT PLAN 
 
7.1.  
Overview and Design of Study 
7.1.1  Phase 1b  
This study will begin with a 12 patient lead-in cohort to establish safety and better 
characterize toxicity prior to the randomized component.  For safety purposes, patients will 
be enrolled in cohorts of 3 for the first 6 patients, and patients will receive ibrutinib at a dose 
of 420 mg daily.  Dose limiting toxicity (DLT) will be evaluated during the first 14 days of 
treatment.  
 
DLT would be considered to be any of the following:  
• Grade 4 hematologic toxicity that persists for 3 or more days that is considered at 
least possibly related to ibrutinib. 
• Grade 3 or higher non-hematologic toxicity that are considered at least possibly 
related to Ibrutinib with the exception of nausea, vomiting, diarrhea, or electrolyte 
abnormality, unless these persist for at least 3 days despite maximal supportive care 
• Any grade 3 or higher fungal or bacterial infection (excluding line infection, catheter-
associated UTI, or C difficile infection), cardiac toxicity (with the exception of 
hypertension) or bleeding regardless of the attribution.  We note, though, that many 

Ibrutinib for COVID 19 
 
27 
patients in the hospital that develop infection of any grade will be treated with IV 
antibiotics, and that per CTCAE criteria, those graded 3 or higher would be those 
where IV antibiotics are indicated, not only for those where IV are chosen due to 
convenience. 
• Non COVID-19 related neutropenic fever 
  
 
Further enrollment to this dose level will stop if 2 of the first 3 evaluable patients or if at least 
33% of subsequent evaluable patients (i.e, 2/6, 3/9, or 4/12) have DLT. If unacceptable 
toxicity is observed, Ibrutinib will decrease to 280 mg daily, and another 12 patient lead-in 
will be evaluated at this lower dose level following the same stopping rules. If toxicity is 
acceptable, the study will proceed to the randomized component.  Patients who do not 
receive 14 days of Ibrutinib for reasons other than toxicity or DLT will be replaced for the 
purposes of the safety and tolerability assessment. 
 
 
7.1.2  Randomized Double-Blind Phase 2 Study 
In the phase 2 portion of the study, patients will be randomized in a 1:1 fashion to receive 
ibrutinib plus standard care for COVID-19 versus placebo plus standard treatment for 
COVID-19. The study is double blinded and each patient will be assigned a randomization 
number by the James blind pharmacy.  The patient, treating physicians, study personnel, and 
outcome assessors will all remain blinded to group assignment until after the database is 
locked and blinded analysis is completed.Only the unblinded statistician and the pharmacy 
staff have access to the unblinded randomization list. 
 Patients may receive any additional therapies that are not prohibited in the section on 
concomitant medications.  In this trial, cycles will be 7 days in length.  Ibrutinib therapy will 
continue for 2 cycles (14 days). Dose of study drug should be held or modified for adverse 
events as outlined in Section 7. 
Patients who develop respiratory failure but are determined by the principal investigator to 
have clinical benefit from treatment may continue on for the full course of treatment. 
 
 
7.2.  
Ibrutinib and Placebo Administration 
The sponsor will provide both ibrutinib and matching placebo. Study participants will be 
dispensed  ibrutinib daily (ARM A) and matching capsule placebo (ARM B) through the 
investigational pharmacy at OSU.The matching placebo will be identical in size and shape, 
but do not contain ibrutinib.  
 
Ibrutinib or placebo will be administered as capsules (3x140mg capsules) orally once daily 
with water.  The capsules are to be taken around the same time each day with 8 ounces 
(approximately 240 mL) of water.  The capsules  should be swallowed intact and should not 

Ibrutinib for COVID 19 
 
28 
be crushed and patients should not attempt to open capsules or dissolve them in water.  
Patients requiring mechanical ventilation who cannot swallow capsules can have capsules 
crushed under water and administered through nasogastric or orogastric tube in 
collaboration with OSU pharmacy as outlined in Appendix B. Each dose of study drug should 
be taken at approximately the same time every day.   
 
Patients may NOT consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruit during the study. 
 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same 
day with a return to the normal schedule the following day.  The subject should not take extra 
capsules to make up the missed dose.  Missed doses will not be made-up.  If vomiting occurs 
no replacement dose is to be given. 
 
If patients are discharged from the hospital prior to completing the course of study drug, the 
remainder drug to complete two cycles of therapy will be sent home with the patient at 
discharge and a pill diary will be used. 
 
Medication administration records will be used to determine compliance with study therapy. 
 
 
7.3. Concomitant Medication Use Guidelines For Study Participants  
 
Warfarin is excluded throughout the trial as is grapefruits and grapefruit juice, 
starfruit,  and Seville oranges. Cancer therapy is also prohibited during the study.  
Medications allowed with caution are found in Appendices 
A.  All concomitant medications need to be documented in the electronic medical record. 
Standard of Care COVID 19 Therapy 
All standard of care therapy for COVID 19 that is not specifically prohibited in the protocol 
is acceptable and encouraged.  Current standards of care can be found in Table 2 of Appendix 
C. It is acknowledged that standards of care are likely to change during the course of the 
study.  Standard of care therapy should be considered in the context of toxicities expected 
with ibrutinib, and therapies that are expected to have overlapping toxicities should be used 
with caution. 
 
Anticoagulants and Anti-platelet agents 
 
Laboratory studies have shown that in vitro ibrutinib can prevent platelets from aggregating 
normally.  While serious bleeding has been uncommon in patients treated to date, it is 
possible that treatment with the study drug could increase the risk of bruising or bleeding, 
particularly in subjects receiving oral anticoagulants or antiplatelet agents.  Besides 
warfarin, which is prohibited, patients on the study may receive any other anticoagulants or 
antiplatelet agents at prophylactic or therapeutic doses. Subjects receiving anticoagulants 
and/or antiplatelet agents in conjunction with ibrutinib should be observed closely for any 
signs of bleeding or bruising and ibrutinib should be withheld in the event of any significant 

Ibrutinib for COVID 19 
 
29 
bleeding events.  Patients receiving both therapeutic anticoagulation and anti-platelet agents 
should be considered at higher risk for bleeding. 
 
Inhibitors or inducers of CYP3A 
 
As ibrutinib is primarily metabolized by CYP3A. Concomitant use of ibrutinib and 
drugs that strongly or moderately inhibit CYP3A can increase ibrutinib exposure, 
these should be avoided as possible.  Avoid grapefruit and Seville oranges during 
ibrutinib treatment as these contain moderate inhibitors of CYP3A.  Strong inhibitors 
of ibrutinib should be avoided during the course of the trial. Dose adjustment of 
ibrutinib due to concomitant use of CYP3A inhibitors should follow Table 1 below as 
applicable. See Appendices 
A for a summary of cautionary medications.  
 
 
Table 1:  Ibrutinib Dose Modification Guidance for Co-Administration with CYP3A 
Inhibitors 
 

Ibrutinib for COVID 19 
 
30 
Co-administered Drug 
Recommended Ibrutinib Dose for 
the Duration of the Inhibitor Usea 
Recommended Ibrutinib Dose 
for the Duration of the Study IF 
THE STARTING STUDY 
DOSE IS 280 mg 
Mild CYP3A inhibitors 
420 mg once daily. No dose 
adjustment required. 
280 mg daily.  No dose adjustment 
required 
Moderate CYP3A inhibitors  
280 mg once daily.  
140 mg once daily 
Voriconazole 200 mg twice daily 
Posaconazole suspension 100mg 
once daily, 100 mg twice daily, 
or 200 mg twice daily 
140 mg once daily. 
70 mg once daily 
Posaconazole at higher dosesb 
70 mg once daily. 
Discontinue ibrutinib 
Other strong CYP3A inhibitors 
 
Avoid concomitant use and consider 
alternative with less CYP3A 
inhibitory potential. 
If these inhibitors will be used short-
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib. 
If the benefit outweighs the risk and 
long-term dosing is required (more 
than seven days), reduce ibrutinib 
dose to 140 mg once daily for the 
duration of the inhibitor use. 
Avoid concomitant use and 
consider alternative with less 
CYP3A inhibitory potential. 
If these inhibitors will be used 
short-term (such as anti-infectives 
for seven days or less), interrupt 
ibrutinib.  
If the benefit outweighs the risk 
and long-term dosing is required 
(more than seven days), reduce 
ibrutinib dose to 140 mg once 
daily for the duration of the 
inhibitor use. 
a. 
Monitor for adverse reactions to ibrutinib (IMBRUVICA) and interrupt or modify dose as recommended (see 
Dosage and Administration). 
b. 
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, 
posaconazole IV injection 300 mg once daily, posaconazole delayed-release tablets 300 mg once daily).  
 
A list of common CYP3A inhibitors and inducers is provided in Appendix A. For further 
information, please refer to the current version of the ibrutinib IB and examples of inhibitors, 
inducers, and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-
table/. 
 
Tocilizumab has the potential to reduce ibrutinib concentrations, and thus should be used 
with caution  
 
 
 
 
 
7.4  
Supportive Medications  
 
Colony Stimulating Factors 

Ibrutinib for COVID 19 
 
31 
 
Colony stimulating factors including filgrastim (G-CSF; Neupogen) and peg-filgrastim (peg-
GCSF; Neulasta) may be employed for primary and secondary prophylaxis according to 
American Society of Clinical Oncology (ASCO) Guidelines.   
 
 
Corticosteroids 
 
Use of corticosteroids is currently recommended for patients with COVID 19 and hypoxia, 59 
Use of dexamethasone (or equivalent corticosteroid) at doses of 6 mg daily for 10 days is 
allowed.  Further use of corticosteroids for COVID 19 is discouraged but use for management 
of unrelated chronic medical illnesses (e.g. COPD exacerbation) will be allowed at doses 
equivalent to ≤20 mg prednisone daily. 
 
Anti-Emetics 
 
Prophylactic and other antiemetic therapy will be given at the discretion of the treating 
physician but should not routinely include corticosteroids. 
 
Antimicrobial Prophylaxis  
 
Prophylaxis for varicella zoster virus (VZV), herpes simplex virus (HSV), or pneumocystis 
pneumonia (PJP) prophylaxis is allowed, but not required or recommended.  
 
7.5.  
Perioperative/Periprocedural Management  
 
The following guidance should be applied during the perioperative period for patients who 
require surgical intervention or an invasive procedure while receiving ibrutinib: 
 
For any planned surgery or invasive procedure requiring sutures or staples for closure, 
ibrutinib should be held for at least 7 days prior to the intervention and should be held at 
least 7 days after the procedure, and restarted at the discretion of the investigator when the 
surgical site is reasonably healed and without serosanguinous drainage or the need for 
drainage tubes. 
 
For planned minor procedures (such as needle biopsy, thoracentesis, or paracentesis) 
ibrutinib should be held for at least 3 days prior to the procedure and should not be restarted 
for at least 3 days after the procedure.  It is not necessary to hold ibrutinib for bone marrow 
biopsies, intubation or central line placements. 
 
For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure or 3 days for 
an urgent minor procedure, or at the discretion of the investigator. 
 
 

Ibrutinib for COVID 19 
 
32 
7.6.  
Duration of Treatment  
 
Study treatment will continue for a total of 2 cycles (14 days). Therapy will also be 
discontinued if  
 
• Toxicity requiring unacceptable dose suspension or reduction as outlined in Section 
7.1. 
• Patient voluntarily withdraws from the study 
• The treating physician decides it is no longer in the best interest of the patient to 
continue study treatment 
 
 
7.7.  
Duration of Follow-up  
 
Patients will be followed for up to 12 months or until death or withdrawal of consent from 
study assessments and all further follow-up.  Patients who discontinue therapy should 
continue to be followed for study assessments according to the study calendar.  Following 
hospitalization, study visits will be telephone or video encounters.  Patients will need to 
return to OSU when feasible for laboratory studies as outlined in the study calendar and in 
line with institutional criteria for discontinuation of isolation at the outpatient setting.  
 
7.8.  
Criteria for Removal from Study 
 
Patients will be removed from the study if they die or if they withdraw consent from study 
assessments and all further follow-up. Discontinuation of therapy alone is not sufficient for 
removal from study. Date of study removal and reason will be documented in the case report 
form.  
For subjects who withdraw consent, there must be clear documentation of whether the 
subject withdraws consents to treatment only (i.e. agrees to follow-up) or withdraws 
consent to treatment and follow-up. 
7.9.  
Duration of Study 
 
The study will end 12 months after the final patient is enrolled. 
 
8.  DOSE DELAYS AND MODIFICATION (Only Applicable to Safety lead-in patients who 
do not have DLT, and Phase 2 Patients  
 
8.1.  
Guidelines for Dose Suspension or Modification Due to Adverse Events 
 
Adverse events (AEs) will be assessed and graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.  Laboratory 
toxicities will be formally evaluated on days 8, 15, 22, and 29, unless determined to be 
clinically irrelevant by the principal investigator.  These labs will be done ± 3 days. 
 

Ibrutinib for COVID 19 
 
33 
Treatment with study drug should be interrupted for any grade 3 or higher non-hematologic 
toxicity with at least possible association to ibrutinib, with the exception of electrolyte 
abnormalities, nausea, vomiting, or diarrhea, alopecia, or hypertension that can be managed 
with supportive medications.   
 
Treatment with study drug should be interrupted for any grade 4 hematologic toxicity (or 
increase in grade by 2 levels if baseline toxicity exists) with at least possible association to 
ibrutinib with the exception of neutropenia that can be managed with growth factors, 
anemia/thrombocytopenia responsive to transfusion, or lymphocytosis/lymphocytopenia. 
 
Once the toxicity has resolved to grade 1 or baseline, study drug can be restarted at the 
original dose. If toxicity recurs, the dose should be held and then decreased by one dose level 
as outlined in Table 2.   
 
If drug needs to be held > 14 days and still considered possibly drug-related, study drug 
should not be restarted. 
 
Table 2:  Dose De-Escalation Schedule for Toxicity 
 
Dose De-Escalation Schedule for Toxicity 
Dose Level 
Study drug 
Level 1 – Starting Dose 
420 mg/day (Days 1-14) 
Level 2 
280 mg/day 
Level 3 
140 mg/day 
Level 4 
Discontinue 
 
 
8.2.  
Dose modification of study drug (Ibrutinib or placebo) for Hepatic Impairment 
 
Patients who develop grade 2 increase in bilirubin or ALT/AST should have study drug dose 
reduced to 2 capsules (equivalent to 280 mg daily) for either arms.  If liver function tests 
return to grade 1 levels, study drug   can be increased to 3 capsules (equivalent to 420 mg 
daily). Patients who develop grade 3 or higher increase in bilirubin or AST/ALT or who have 
evidence of hepatic failure should have study drug  discontinued permanently. 
 
 
 
 
 
8.3 Unblinding Procedures 
Unblinding can be done only in cases of an emergency leading to a life threatening 
unexpected adverse event that is at least possibly related to the investigational agent and for 
which unblinding would influence treatment decisions. As well, unblinding would be 
considered in a situation where knowledge of the arm would determine whether a procedure 

Ibrutinib for COVID 19 
 
34 
could be performed emergently (because of risk of bleeding).  In any case of unblinding, the 
patient will be discontinued from the protocol drug.  
 
9.  ADVERSE EVENT ASSESSMENT AND REPORTING 
 
9.1.  
Safety Assessment Overview and Monitoring Timeframe 
 
To monitor the toxicity of study treatment and ensure safety of subjects enrolled in this 
interventional study adverse events (AEs) will be assessed at each study visit and described 
and graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0.  In general, AEs and serious adverse event (SAEs) 
should be reported as a diagnosis instead of symptoms if possible at the time of reporting. 
 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will 
be reported appropriately.  Each reported AE or SAE will be described by its duration (i.e. 
start and end dates), regulatory seriousness criteria if applicable, suspected relationship to 
the study drug, and actions taken.  
 
The study period during which all AEs and SAEs must be reported begins after the patient is 
randomizes and ends at 30 days post completion of treatment.  After this period 
investigators should only report SAEs that are attributed to prior study treatment.   
 
Maintenance of Safety Information 
 
All safety data should be maintained in a clinical database in a retrievable format. The 
INSTITUTION and PRINCIPAL INVESTIGATORS shall provide all adverse events, both serious 
and non-serious, in report format. However, in certain circumstances more frequent 
provision of safety data may be necessary, e.g. to fulfill a regulatory request, and as such the 
data shall be made available within a reasonable timeframe. 
 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to study drug (ibrutinib or placebo) are to be documented by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to study 
drug. 
 
All (serious and non-serious) adverse events reported for study drug  should be followed-up 
in accordance with clinical practice. 
 
9.2.  
Definition of an Adverse Event (AE) 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational medicinal product (IMP) or other protocol-imposed 

Ibrutinib for COVID 19 
 
35 
intervention regardless of attribution.  The event does not necessarily have a causal 
relationship with that treatment or usage. 
 
This includes the following: 
 
• An exacerbation or an unexpected increase in frequency or intensity of a pre-existing 
condition (other than condition under investigation) including intermittent or 
episodic conditions. 
• Significant or unexpected worsening or exacerbation of the condition/indication 
under investigation. 
• A suspected drug interaction. 
• An intercurrent illness. 
• Any clinically significant laboratory abnormality. 
 
An AE does not include:  
 
• Anticipated day-to-day fluctuations of any pre-existing conditions including the 
disease under study. 
• Signs and symptoms of the disease under study that do not represent a significant 
worsening or exacerbation. 
• Expected progression of the disease under investigation.  
 
9.3.  
Definition of a Serious Adverse Event (SAE) 
 
An AE that meets one or more of the following criteria/outcomes is classified as serious:  
 
• Death. 
• Life threatening. 
• Disabling/incapacitating. 
• Results in new hospitalization or prolongs a hospital stay. 
• A congenital abnormality. 
• Other serious medical events may also be considered SAEs if it is an important 
medical event that may not be immediately life threatening or result in death or 
hospitalization, but based upon appropriate medical and scientific judgment may 
jeopardize the patient or may require medical or surgical intervention to prevent one 
of the other serious outcomes listed in the definition above. 
 
Death for any reason must be reported as a SAE. 
 
A SAE does not include:  
 
• Progression of the underlying infection or syndrome (COVID-19). 
• Hospitalization for a routine clinical procedure or treatment as required by the 
protocol.  

Ibrutinib for COVID 19 
 
36 
• Hospitalization for non-medical reasons (i.e., social admissions, hospitalizations for 
social, convenience, or respite care).  
 
 
9.4.  
Definition of an Unlisted (Unexpected) Adverse Event 
 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ibrutinib, the expectedness of an adverse event 
will be determined by whether or not it is listed in the Investigator's Brochure. 
 
9.5 
Definition of an Adverse Event of Special Interest  
 
Adverse events of special interest are events that Janssen is actively monitoring as a result 
of a previously identified signal (even if non-serious). These adverse events are: 
• Major Hemorrhage 
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or 
greater in severity or that results in 1 of the following: intraocular bleeding 
causing loss of vision, the need for a transfusion of 2 or more units of red 
cells or an equivalent amount of whole blood, hospitalization, or 
prolongation of hospitalization. 
• Intracranial Hemorrhage 
Any intracranial hemorrhage adverse event, including subdural 
hematoma/hemorrhage, epidural hematoma/hemorrhage and intracerebral 
hemorrhage, of any grade severity, will be captured as an event of special 
interest. 
• Other Malignancies  
In addition to all routine AE reporting, all new malignant tumors, including 
solid tumors, skin malignancies and hematologic malignancies, are to be 
reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for overall 
survival. 
 
Any adverse event of special interest should be recorded on a Serious Adverse Event 
Report Form and be reported to Janssen within 24 hours of becoming aware of the 
event. 
 
 
9.6.  
Adverse Event Grading and Attribution 
 
All patients must be carefully monitored for AEs, including clinical laboratory tests.  AEs 
should be assessed in terms of their seriousness, intensity, and relationship to the study 
drug.  For consistency, events are to be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site: 
 

Ibrutinib for COVID 19 
 
37 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If CTCAE criterion does not exist for a particular AE, the investigator should use the grade or 
adjectives as described below: 
 
• Grade 1: Mild.  Does not interfere with patient’s usual function. 
• Grade 2: Moderate.  Interferes to some extent with patient’s usual function. 
• Grade 3: Severe.  Interferes significantly with patient’s usual function. 
• Grade 4: Life-Threatening.  Results in a threat to life or in an incapacitating disability. 
 
The investigator will make a judgment regarding whether or not the AE was related to study 
drug, as outlined in Table 5  For the purpose of safety analyses all AEs that are classified as 
possibly related will be considered treatment-related events. 
 
Table 5. Criteria for Attribution of Adverse Events 
Attribution 
Criteria 
Not related 
The lack of a temporal relationship of the event to study 
treatment makes a causal relationship not reasonably 
possible, or other drugs, therapeutic interventions, or 
underlying conditions provide a sufficient explanation. 
Possibly related 
The temporal relationship of the event to study 
treatment makes a causal relationship reasonably 
possible, and the event is equally explained by exposure 
to the study treatment than by other drugs, therapeutic 
interventions, or underlying conditions. 
 
9.7.  
Reporting of SAEs and Special Reporting Situations 
 
Overview 
As the sponsor of the Study, Institution and Principal Investigators shall be solely 
responsible for complying, within the required timelines, any safety reporting obligation to 
competent Health Authorities, IRB/ECs and any participating (co or sub) investigators, as 
defined in applicable laws and regulations.  Safety data includes adverse events, product 
quality complaints (PQCs), and special situations including pregnancies. 
 
The institution and principal investigator will provide safety information to Janssen on 
adverse events, special situations including pregnancies and product quality complaints. 
 
Management of Safety Data 
This Study has been designated as an interventional study. As such, all adverse events, 
special situations including pregnancies and product quality complaints will be reported as 
described in this exhibit from the time a subject has signed and dated an Informed Consent 
Form (ICF) until 30 days after the last documented use of a product under study within the 

Ibrutinib for COVID 19 
 
38 
study. All subsequent AEs and SAEs will be collected after this period if the Principal 
Investigator considers the AE/SAE to be causally-related to the use of the study drug. 
 
 
9.7.1.  All Adverse Events (AEs) 
 
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 30 days after the last dose of 
therapy.  Serious adverse events, including those spontaneously reported to the investigator 
within 30 days after the last dose of study drug, must be reported.  
 
All events that meet the definition of a serious adverse event will be reported as serious 
adverse events, regardless of whether they are protocol-specific assessments. 
 
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
drug, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as "upper respiratory infection"). Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to study therapy. All measures 
required for adverse event management must be recorded in the source document. 
 
The sponsor assumes responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The sponsor must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the 
protocol unless otherwise required and documented by the IEC/IRB. 
 
9.8 Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or delivery system.  
Not all PQCs involve a subject.  Lot and batch numbers are of high significance and need to 
be collected whenever available. 
 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit 
 
 
9.9. Data and Safety Monitoring 
 

Ibrutinib for COVID 19 
 
39 
This study will be monitored both by the investigators and The OSU Data and Safety 
Monitoring Committee (DSMC), a multidisciplinary board that will monitor the safety and 
conduct of this trial to ensure patient safety, data quality, and data timeliness.    The outcome 
of the DSMC review of  the Lead-in component of the study will be shared with PCYC/Janssen.  
 
The OSU Comprehensive Cancer Center DSMC is composed of a multidisciplinary team with 
expertise reviewing clinical trial data and adverse events.  Information to be provided to the 
committee may include: up-to-date participant accrual; dosing information; all grade 2 or 
higher adverse events that have been reported across all sites as well as a summary of all 
deaths occurring within 30 days of the last day of the treatment period. In addition to safety 
results, all response/efficacy information (including laboratory results, scans etc.) will be 
reviewed to better assess the risk/benefit of the study intervention.  Should any major 
concerns arise, the DSMC, after meeting in a closed session, will offer recommendations 
regarding whether or not to suspend or amend the study.   
 
The DSMC will review all serious adverse events in real time.  Outside of concerns regarding 
adverse events (including SAEs reviewed by the DSMC), the DSMC will review safety data at 
the next DSMC meeting after the first 12 patients have completed therapy and thereafter 
every time 30 additional patients have completed therapy (e.g. 12 patients, 42 patients, 78 
patients) or every 3 months, whichever comes more quickly.  .    
 
The study investigators will conduct continuous review of data and will hold weekly 
teleconferences to discuss toxicities throughout the course of the trial.  Any disagreement 
among the Co-Investigators as to the safety of the trial will be escalated to the DSMC. 
Frequency and severity of adverse events will be reviewed by the principal investigator and 
compared to what is known about the agent from other sources; including published 
literature, and scientific meetings to determine if the trial should be terminated before 
completion.   
 
All reportable Serious Adverse Events (SAE) will also be reported to the OSU Cancer IRB as 
per the policies of the IRB. 
 
10.  PHARMACEUTICAL INFORMATION 
 
10.1.  Ibrutinib (PCI-32765, ImbruvicaTM) 
 
Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK).  It is a white to off-white solid 
with the empirical formula C25H24N6O2 and a molecular weight 440.50.  Ibrutinib is freely 
soluble in dimethyl sulfoxide, soluble in methanol, and practically insoluble in water.  The 
chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4 
d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one. 
 

Ibrutinib for COVID 19 
 
40 
10.1.1.  
Formulation and Storage 
 
Ibrutinib and placebo will be supplied as capsules.  Capsules are provided as a hard gelatin 
capsule containing 140mg of ibrutinib or placebo.  
 
Bottles should be stored at room temperature 20°C to 25°C (68°F to 77°F) with excursions 
permitted between 15°C and 30°C (59°F to 86°F).   
 
The investigational pharmacy at OSU will dispense a 14 day supply of capsules on day 1.  This 
supply will be used to administer daily doses while the patient is admitted.  If a patient is 
discharged before the completion of the 14 days of therapy, the remaining supply will be 
sent home with the patient along with a pill diary.  
 
10.1.2.  
Administration 
 
The study drug will be administered in the form of 3 capsules orally once daily (either 
placebo or ibrutinib). The Ibrutinib arm will receive 420mg (3 X 140-mg capsules) orally 
once daily.  The capsules are to be taken around the same time each day with 8 ounces 
(approximately 240 mL) of water.  The capsules should be swallowed intact and patients 
should not attempt to open capsules or dissolve them in water.  Patients requiring 
mechanical ventilation who cannot swallow pills can have capsules opened and 
administered through nasogastric or orogastric tube in collaboration with OSU pharmacy.  
In this case, please see preparation worksheet (Appendix B).  Each dose of  study drug should 
be taken at approximately the same time every day.   
 
 
 
Patients may NOT consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruit during ibrutinib treatment. 
 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same 
day with a return to the normal schedule the following day.  The subject should not take extra 
capsules to make up the missed doses.  If vomiting occurs no replacement dose is to be given. 
 
10.1.3.  
Overdosage 
 
Any dose of study drug administered in excess of that specified in this protocol is considered 
to be an overdose. Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as a SAE in the appropriate time frame and documented as clinical sequelae to an 
overdose, and would lead to unblinding.  
 
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received 
up to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 
1680 mg. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST 

Ibrutinib for COVID 19 
 
41 
and ALT) after a dose of 1680 mg. Subjects who ingested more than the recommended 
dosage should be closely monitored and given appropriate supportive treatment.  
 
10.1.4. How Supplied 
 
Ibrutinib and matched placebo will be supplied by Janssen. 
 
 
 
11.  BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Correlative laboratory studies for this trial will focus on the modulation of immune response 
to SARS-CoV-2, clearance of virus, and modulation of immune cells in response to ibrutinib, 
and select senescence markers (i.e. clonal hematopoiesis, epigenetic age, and others) that are 
examined to be predictive of outcome. These results, using descriptive analyses, will be 
correlated between the ibrutinib plus supportive care and the placebo arm, and baseline 
values and change in values will be correlated with the primary or secondary outcomes. 
Samples will be collected at the following times: 
 
• Screening  
• Day 2 immediately pre-dose 
• Cycle 2 Day 1 
• End of Ibrutinib (±3 days)  
• 1, 3, 6,  and 12 months post study entry (±14 days) 
 
In order to prevent viral transmission, patients who are discharged from the hospital will 
have follow-up labs collected at the OSU outpatient laboratory if they meet criteria for 
discontinuation of isolation at the outpatient setting.  If they do not meet criteria for safe 
discontinuation of isolation per OSU guidelines, laboratory studies will not be obtained, and 
this will not be considered a protocol deviation. Samples for assays not performed in the 
clinical pathology laboratories (CPL) will be sent to the Experimental Hematology 
Laboratory (EHL) for analysis. 
 
These samples will be used for the following assays: 
• Measurement of viral clearance using PCR (from nasal pharyngeal swab in viral media) 
and serologic antibody testing (CPL): 
• Measurement of immune cell subsets for absolute number, activation and exhaustion 
markers, and maturation using clinical immunome panel (CPL, EHL) at baseline and 
over time 
• Measurement of senescence including epigenetic age (EHL), targeted sequencing for 
the presence of clonal hematopoiesis (EHL), and others at baseline (this will be done 
on residual DNA from material derived from immunophenotype/T-cell repertoire) 
• Measurement of B/T-cell repertoire and IgM, IgA and IgG response to SARS-CoV-2 
(CPL/EHL)  

Ibrutinib for COVID 19 
 
42 
• Measurement of cytokines including IL6, IL1β, TNF-α, and serum  alternative multi-
cytokine panel to be performed broadly in EHL (CPL/EHL) 
• Measurement of serial and post-treatment T-cells to isolate and expand SARS-CoV2 
specific T-cells, B-cells and other immune senescent changes  (EHL) 
 
Samples for the EHL will be collected and in some cases processed by the clinical trials 
processing laboratory (CTPL). 
 
We will also collect samples to evaluate ibrutinib pharmacokinetics (PK).  This will 
include trough measurements after the first dose (day 2 pre-dose) and at steady state.  
For this, approximately 5 mL of blood will be collected in sodium heparin (green top) 
tubes, placed on ice and immediately centrifuged at 1,200 x g for 10 minutes to isolate 
plasma. Plasma will be frozen in two separate vials and stored in a -70°C (or less) freezer. 
Each sample will be labeled with the protocol number, patient number, reference time 
point relative to the protocol, date and time the sample was obtained. 
 
To perform these analyses, the following samples will be collected at each time point: 
 
Assay 
Screeni
ng 
Day 1 24 
hours 
(prior to 
second 
ibrutinib 
dose) 
C2D1 
(prior to 
ibrutinib 
dose) 
End of 
Rx 
1 
month 
From start 
2 
month 
From start  
3 
month 
From start  
6 
month 
From start  
12 
month 
From start  
Serologic 
antibody 
testing 
CPL  
1 EDTA 
(3ml) 
 
CPL  
1 
EDTA 
(3ml) 
CPL  
1 EDTA 
(3ml) 
CPL  
1 
EDTA 
(3ml) 
CPL  
1 
EDTA 
(3ml) 
CPL  
1 
EDTA 
(3ml) 
CPL  
1 
EDTA 
(3ml) 
CPL  
1 
EDTA 
(3ml) 
C5b-9 level 
CPL  
1 EDTA 
(3ml)  
 
CPL  
1 
EDTA 
(3ml) 
CPL  
1 EDTA 
(3ml) 
CPL  
1 
EDTA 
(3ml) 
 
 
 
 
Epigenetic 
age/clonal 
hematopoiesis/COVID 
T-cells, cytokines    
CTPL 
5 (8 ml 
ACD) 
 
CTPL 
5 (8 ml 
ACD) 
CTPL 
5 (8 ml 
ACD) 
CTPL 
5 (8 ml 
ACD) 
 
CTPL 
5 (8 ml 
ACD) 
 
CTPL 
5 
(8 
ml 
ACD) 
Ibrutinib PK 
 CTPL  1 
NaHep 
(5 
mL 
green 
top) 
CTPL  1 
NaHep (5 
mL green 
top) 
 L 
 
1 
NaHep (5 
mL green 
top) 
 
 
 
 
 
 
 
 
To protect patient identity, samples sent to EHL will be coded and stored with a subject 
identification number.  The key linking the subject identification number to the individual 
patient identifying information will be available only to investigators and qualified honest 
brokers.  This key will be password protected.  Samples not immediately used will be stored 
in the Experimental Hematology Laboratory.  Any remaining tissue will be stored for future 
use in the CLL Experimental Hematology Laboratory.  Future use will be only that which 
relates specifically to the biology of COVID-19 and treatment with ibrutinib 

Ibrutinib for COVID 19 
 
43 
12. STUDY CALENDARA 
 
 
Screening 
Cycle 1 
Day 1I 
Cycle 2 
Day 1I 
End of 
Treatment 
(day 14  + 
up to 3 days 
if 
outpatient) 
1 month 
post 
enrollment J 
2  months 
post 
enrollment J 
3 months 
post 
enrollment J 
6 months 
post 
enrollment J 
12 months post 
enrollment J 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
XK 
XK 
XK 
XK 
Physical Exam 
X 
X 
X 
X  
 
 
 
 
 
Vital SignsB 
X 
X 
X 
X 
 
 
 
 
 
EKGC 
X 
X 
X 
X 
 
 
 
 
 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry,D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT/INR, D-
dimer, fibrinogen, 
LDH 
X 
X  
X 
X 
X 
 
 
 
 
Hepatitis B,C 
ScreeningE 
X 
 
 
 
 
 
 
 
 
CRP, ferritin, 
troponin 
X 
X (daily) 
X (daily) 
X 
X 
 
 
 
 
IL6, IFNγ, TNF 
X 
 
X 
X 
 
 
 
 
 
Serum or Urine 
Pregnancy Testing 
X 
 
 
 
 
 
 
 
 
Flow cytometry 
(Immunome) 
X 
 
X 
X 
 
 
 
 
 
Total serum IgG, 
IgA, and IgM 
X 
 
 
X 
 
X 
X 
X 
X 
Nasopharyngeal 
SARS-CoV-2 PCRF 
X 
 
 
X 
X ( if negative 
will stop 
X ( if negative 
will stop 
X ( if negative 
will stop 
 
X ( if negative will 
stop further 
testing) 

Ibrutinib for COVID 19 
 
44 
further 
testing) 
further 
testing) 
further 
testing) 
Peripheral Blood 
for Correlative 
Laboratory StudiesG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ibrutinib or placebo 
 
X 
 
 
 
 
 
 

Ibrutinib for COVID 19 
 
45 
 
A. All research coordinator contact (consent, adverse events, concomitant medications) 
will be either by phone or over videoconference.  Physical examination will be 
performed by the inpatient treatment team and does not have to be study personnel. 
For study participants who are discharged prior to completing 14 days, no daily labs 
will be performed at the outpatient setting and C2D1 labs will be performed on the 
day of discharge.  Study participants will follow institutional inpatients/outpatient 
isolation initiation and discontinuation measures.  
B. Should include Oxygen saturations and O2 requirement. Consider continuous cardiac 
monitoring, especially for patients receiving concomitant medications with cardiac 
effects 
C. Consider continuous cardiac monitoring, especially for patients receiving 
concomitant 
medications 
with 
cardiac 
effects. 
All 
patients 
receiving 
hydroxychloroquine will be placed on telemetry as part of our standard institutional 
practice guidelines.  
D. Includes chem 10 and liver function panel.  Should consider doing chemistry panel 
and CBC daily. 
E. Includes hepatitis C Ab, hepatitis B antibody, surface antigen, and core 
antigen.  Patients with positive surface antigen or core antibody should have hepatitis 
B DNA tested. Those with a positive core antibody and negative surface antigen may 
start treatment while awaiting hepatitis B DNA result given its long turnaround time. 
If the latter is positive, the study drug will be stopped.  
F. Will use currently available clinical methods, which may evolve during the course of 
the study. A positive COVID 19 PCR test at any facility within 10 days of screening is 
allowed.  
G. Please see section 11 for details on required samples.  The correlative samples will be 
collected from standard clinical material that comes through the flow cytometry 
laboratory under Dr. Gerard Lozanski.  Material (plasma, DNA, RNA) will be 
transferred to the EHL for studies not performed in clinical pathology. 
 
H. Ibrutinib will be administered daily for patients on the ibrutinib arm (Arm A) for a 
total of 2 cycles (14 days). Placebo will be administered to patients on the standard 
care arm (ARM B)  
 
I. During study drug administration, CBC and BMP should be collected daily.  Liver 
function tests should be performed at least twice weekly. 
 
J. Post-discharge evaluations may be conducted by phone or videoconference. 
Laboratory studies will be obtained in the OSUCCC outpatient labs if patient meet 
criteria for discontinuation of isolation.    Patients who are unable to return to OSU 
will be allowed to have labs performed locally and correlative/COVID related samples 
shipped to OSU if possible.  This has to be approved by the study team. Labs can be 
performed ± 7 days for timepoints after day 14. 
 

Ibrutinib for COVID 19 
 
46 
K. Toxicity will continue to be assessed during phone assessments every other week in 
patients who do not have all toxicities that are possible drug-related resolved at the 
1 month follow-up point. 
 
 
13. STATISTICAL CONSIDERATIONS 
This study will enroll high-risk cancer patients testing positive for COVID-19, to be 
treated with ibrutinib plus standard of care therapy for COVID-19 or placebo plus 
standard of care therapy for COVID-19. There will be two components of the trial: 1) a 
safety lead-in component to evaluate the feasibility and tolerability of administering 
ibrutinib with standard therapy for COVID-19 and 2) a double-blinded randomized 
component to assess efficacy of ibrutinib with standard therapy for COVID-19 versus 
placebo plus standard therapy for COVID-19. 
 
Safety Lead-in Cohort 
This study will begin with a 12 patient lead-in cohort to establish safety and better 
characterize toxicity.  Patients will receive Ibrutinib at a dose of 420mg daily. For safety 
purposes, patients will be enrolled in cohorts of 3 for the first 6 patients, with a pause in 
study enrollment after each cohort to assess for dose-limiting toxicity (DLT). DLT will be 
evaluated during the first 14 days of treatment.  
 
DLT would be considered to be any of the following:  
• Grade 4 hematologic toxicity that persists for 3 or more days that is considered at 
least possibly related to ibrutinib. 
• Grade 3 or higher non-hematologic toxicity that are considered at least possibly 
related to Ibrutinib with the exception of nausea, vomiting, diarrhea, or electrolyte 
abnormality, unless these persist for at least 3 days despite maximal supportive care 
• Any grade 3 or higher fungal or bacterial infection (excluding line infection, catheter-
associated UTI, or C difficile infection) or cardiac toxicity (with the exception of 
hypertension) regardless of the attribution.  We note, though, that many patients in 
the hospital that develop infection of any grade will be treated with IV antibiotics, and 
that per CTCAE criteria, those graded 3 or higher would be those where IV antibiotics 
are indicated, not only for those where IV are chosen due to convenience. 
• Grade 3 or higher hemorrhage regardless of attribution, or Grade 2 hemorrhage that 
is considered at least possibly related to ibrutinib and is considered to be significant 
by the treating physician in collaboration with the PI. 
• Non COVID-19 related neutropenic fever 
 
Enrollment to this dose level will stop if 2 of the first 3 evaluable patients or if at least 
33% of subsequent evaluable patients (i.e, 2/6, 3/9, or 4/12) have DLT. If unacceptable 
toxicity is observed, Ibrutinib will decrease to 280 mg daily, and another 12 patient lead-

Ibrutinib for COVID 19 
 
47 
in will be evaluated at this lower dose level following the same stopping rules. If 
acceptable toxicity is observed, the study will proceed to the randomized component.  
Patients who do not receive 14 days of Ibrutinib for reasons other than toxicity or DLT 
will be replaced for the purposes of the safety and tolerability assessment. 
Randomized Phase 2 
The main study is a randomized, double-blind placebo-controlled trial. The primary 
endpoint of the phase 2 component is the proportion of randomized patients with 
respiratory failure or death during hospitalization for COVID-19 infection within 30 days 
of registration. Respiratory failure is defined as any of the following: 1) endotracheal 
intubation and mechanical ventilation, 2) extracorporeal membrane oxygenation, 3) 
high-flow nasal cannula oxygen delivery (i.e., reinforced nasal cannula delivering heated, 
humidified oxygen with fraction of delivered oxygen ≥0.5 and flow rates of ≥30 l/min), 
noninvasive positive pressure ventilation, or 4) clinical diagnosis of respiratory failure 
without initiation of one of above measures only when clinical decision-making is driven 
solely by resource limitation or if patient has DNI (Do Not Resuscitate) status.   Patients 
will be randomized to each treatment arm in a 1:1 ratio utilizing a permuted block 
schedule. Randomization will be stratified on age (<60 years vs > 60 years) and presence 
of comorbidities (yes vs no) (comorbidities defined in Appendix C). 
 
Design and Sample Size: Based on a study in China, we assume that the event rate is 40% 
with standard care and that the event rate can be reduced to 15% when Ibrutinib is added 
to standard care for COVID-19. With 60 patients and using a standard group sequential 
design, there is 82.8% power to detect a reduction in the event rate under the alternative 
hypothesis and constraining the one-sided type I error to 20%. Power was calculated 
using a z-test for the difference in two proportions, pooled variance, and adjustment for 
small sample sizes with the Casagrande-Pike-Smith correction (EAST v6.5; Cytel, Inc).  
There will be an interim analysis when 50% of randomized patients have been followed 
for 30 days from registration. The study will be stopped early if at the interim analysis 
the observed event rate is higher in the ibrutinib arm (Arm A) than in the control arm 
(Arm B). We will plan to over-accrue by about 10% for a total accrual goal of 66 patients. 
 
Although the actual reduction in the event rate could be larger than 25%, it could also be 
as low as 20% and still be quite meaningful. Furthermore, there is uncertainty in the 
event rate of the control arm. For these reasons, we have incorporated increased 
flexibility at the time of the interim analysis to potentially increase the sample size if 
conditional power indicates promising results, and will thus implement an adaptive 
group sequential design (Chen, DeMets, Lan; 2004).  
 
At the interim analysis, there are 4 possible outcomes: 1) the futility criteria are met and 
the trial stops early; 2) the conditional power is unfavorable (<50%), and enrollment 
continues to the planned sample size without an increase in sample size; 3) the 
conditional power is in a promising zone (defined as conditional power >50% and < 
82.8%), and sample size may be re-estimated with the original sample size updated to 
boost the power to a target of 82.8%, subject to a maximum sample size of 120; or 4) the 
conditional power is favorable (>82.8%), and enrollment continues to the planned 

Ibrutinib for COVID 19 
 
48 
sample size without an increase in sample size. When using this procedure, no 
adjustment to the final test statistic or critical value from the original design is required 
to control the Type I error rate. In addition, if the conditional power is in the promising 
zone, we can choose not to increase the sample size beyond what was originally planned 
or by a flexible amount without penalty.  
 
Operating characteristics using the adaptive group sequential design is presented for 
four different scenarios:  
Scenario 1: Event rates in the ibrutinib and control groups are 15% and 40% 
Scenario 2: Event rates in the ibrutinib and control groups are 25% and 50% 
Scenario 3: Event rates in the ibrutinib and control groups are 20% and 40% 
Scenario 4: Event rates in the ibrutinib and control groups are 30% and 50% 
 
For each scenario, the power and expected sample size is also provided for the standard 
group sequential design. For example, under Scenario 4, the power of the adaptive group 
sequential design has increased by 11.7% at the cost of corresponding average sample 
size increases of 11 patients. It is important to note that under the standard group 
sequential design, the power would have been only 64.7%. For the adaptive group 
sequential design, the conditional power falls in the promising zone 21.0% of the time, 
and for these simulations, the re-estimated sample size on average is 101 resulting in a 
boost in power to 89.2%.  
 
Operating characteristics were calculated based on 10,000 simulations. For the purposes 
of the simulations, an efficacy boundary was defined using an alpha-spending function 
with Gamma(-30), a very conservative boundary to reflect the absence of an interim 
stopping rule for superiority. All sample size and power calculations used EAST v6.5 
(Cytel, Inc). 
 
 
Scenario 
Interim 
Outcome 
Probability of 
Interim 
Outcome 
Power 
Conditional on 
Interim Outcome 
Expected Sample 
Size 
1 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD* 
3.5% 
13.1% 
13.0% 
70.4% 
100% 
0% 
71.8% 
97.8% 
97.9% 
91.0% / 82.8% 
30 
60 
111 
60 
66 / 58 
2 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD 
5.0% 
13.8% 
16.7% 
64.6% 
100% 
0% 
62.2% 
95.3% 
96.5% 
86.8% / 78.7% 
30 
60 
103 
60 
66 / 57 
3 
Futility 
Unfavorable 
Promising 
8.0% 
19.8% 
15.9% 
0% 
56.9% 
92.1% 
30 
60 
112 

Ibrutinib for COVID 19 
 
49 
Favorable 
All Trials / GSD 
56.3% 
100% 
94.7% 
79.3% / 68.0% 
60 
66 / 55 
4 
Futility 
Unfavorable 
Promising 
Favorable 
All Trials / GSD 
9.0% 
19.0% 
21.0% 
51.1% 
100% 
0% 
52.0% 
89.2% 
93.7% 
76.4% / 64.7% 
30 
60 
101 
60 
66 / 55 
All based on 10000 Simulations; GSD = standard group sequential design 
 
Primary Endpoint Analysis: All randomized patients will be included in the primary 
endpoint analysis and analyzed in the treatment arm to which they were randomized 
(ITT population). The data will be analyzed using a one-sided Fisher’s exact test and a 
promising signal declared if p<0.20 and the event rate is lower in the experimental arm. 
Since the primary endpoint is to be measured within the first 30 days of registration, we 
do not expect that primary endpoint information will be missing. However, if there is data 
missing, the patient will be considered a treatment failure. 
 
Sensitivity analyses include comparison between treatment arm when adjusting for 
stratification factors and other important variables such as type of cancer or more refined 
categories of standard of care therapy via logistic regression.  If there are events for 
respiratory failure based on clinical diagnosis without an objective measure and driven 
solely by resource limitation or if patient has DNI (Do Not Resuscitate) status, a 
sensitivity analysis will compare arms excluding patients with these events. Sensitivity 
analyses will be performed for the ITT population and for eligible patients who receive 
their assigned therapy without a major protocol violation. 
 
Adverse Event Stopping Rules: If there is no concerning safety signal in the lead-in cohort, 
and the study is able to continue to the randomized component as planned, we have 
included a plan for comparing toxicity at the interim analyses (first 30 patients across 
both arms).  Accrual will be temporarily suspended to this study and discussion of the 
data with co-investigators and the data safety monitoring board will occur if we observe 
adverse events that satisfy the following criteria:  
 
• If the percentage of grade 3/4 all-cause adverse events is at least 15% higher in the 
ibrutinib arm than in the standard of care arm.  This would also include grade 2 
hemorrhage if considered significant by the treating physician in collaboration with PI.  
• If the percentage of grade 4 all-cause adverse events is at least 15% higher in the 
ibrutinib arm than in the standard of care arm 
• If the percentage of grade 5 treatment-related adverse events is at least 5% higher in 
the ibrutinib arm than in the standard of care arm 
 
We note that the above stopping rules may be adjusted at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the adverse event 
profile of the treatment(s) under investigation. The study team may choose to suspend 

Ibrutinib for COVID 19 
 
50 
accrual because of unexpected adverse event profiles that have not met the specified 
rules above.  
 
Secondary Endpoints: At the final analysis, all adverse events will be summarized by 
grade, type, and attribution (regardless of attribution and treatment-related) for each 
arm. Time-to-event endpoints such as time to discharge  and overall survival will be 
estimated for each arm using the method of Kaplan-Meier. Medians estimates and/or 
estimates at specific time points will be provided with 95% confidence intervals. The 
proportion of patients with viral clearance at the time of hospital discharge will be 
estimated with 95% confidence intervals for each arm. For all biomarkers, descriptive 
statistics (e.g., means, medians, standard deviations, interquartile range) and graphical 
displays will be used to characterize central tendency and variability over time. Values 
will be log transformed as appropriate to reflect biologic plausibility. We will evaluate for 
statistical trends over time among the biologic measurements, with multiple 
measurements per patient, using mixed effects models. Lastly, associations between 
baseline characteristics and the primary endpoint will be evaluated with logistic 
regression, adjusting for arm. These analyses will be largely descriptive, as a result of a 
limited sample size. 
 
14.  RETENTION OF RECORDS 
 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of clinical trials 
and the distribution of investigational drug, patient records, consent forms, laboratory test 
results, and medication inventory records must be retained for 2 years after the last 
marketing application approval in an ICH region or after at least 2 years have elapsed since 
formal discontinuation of clinical development of the investigational product.  All state and 
local laws for retention of records also apply. 
 
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Ibrutinib for COVID 19 
 
55 
Appendices 
Appendix A:  INHIBITORS AND INDUCERS OF CYP3A 
NOTE: Itraconazole and ketoconazole can be replaced with voriconazole for study subjects. 
 
 

Ibrutinib for COVID 19 
 
56 
Appendix B: Preparation Worksheet for NG or OG Tube Administration of Ibrutinib 
PREPARATION WORKSHEET FOR IBRUTINIB  
Preparation Worksheet for Ibrutinib for each dose that is prepared. 
 
IP Preparation Steps for Ibrutinib 140 mg  
Preparation Date: 
Subject No.   
 
  
dd/   
mmm/   
yyyy 
HH: 
mm 
Preparation area: 
PREPARATION OF THE DRUG PRODUCT 
INSTRUCTIONS 
RECORD 
1.   Confirm the preparation area is clean and 
cleaning is performed according to site 
procedure. 
  
/  
 
Performed by 
Date 
2.   Ensure the dispensing labels are prepared  
3.   Remove 3 capsules from the bottle. 
Medication Kit Number:   
 
4.   Record the time the capsules are removed 
from the bottle. 
dd / 
mmm / 
yyyy 
HH: 
mm 
5.   Open the 3 capsules and place their 
contents into a glass beaker. Tap the 
capsule bodies and caps against the side 
of the beaker to remove any excess 
material remaining within the capsule 
bodies and caps. 
6.   Prepare a glass beaker filled with 30 mL of 
water, add to the beaker with the capsule 
contents, and swirl/mix until the contents are 
uniform. 
Volume of water in beaker (mL):   
 
7.   Allow the dispersion to stand for at least 15 
minutes. 
Standing Start: 
     HH:     mm 
Standing End: 
     HH:     mm 
8.   Affix an 18 gauge needle to a 60 mL 
syringe, briefly swirl the beaker, and draw 
the dispersed capsule contents into the 
syringe. 

Ibrutinib for COVID 19 
 
57 
9.   Prepare a glass beaker filled with 10 mL of 
water, add to the empty container to rinse, 
and draw up into the same syringe. 
Volume of water in beaker (mL):   
 
10.   Prepare a glass beaker filled with 10 mL of 
water, add to the empty container to rinse a 
second time, and draw up into the same 
syringe, leaving air between solution and 
plunger. 
Volume of water in beaker (mL):   
 
11.  Invert the syringe several times to ensure 
capsule material remains suspended and 
does not stick to the sides of the syringe. 
 
 
 
12.  Draw the plunger back slightly to evacuate 
the tip. Close the syringe with a tip cap. 
13. 
Shake 
the 
syringe 
vigorously 
for 
approximately 1 min and allowed to stand for 
at least 30 minutes to allow for complete 
dispersion prior to dose administration. 
Standing Start: 
  
HH: 
mm 
Standing End: 
    HH: 
mm 
14. Fill in the variable text fields of the 
previously prepared dispensing labels and 
affix the label on the barrel of the syringe. 
15. Calculate expiry: Expiry time is 4 hours 
after the capsules are removed from the 
bottle. 
Expiry date: 
dd / 
mmm / 
yyyy 
HH: 
mm 
16. Place the syringe in a tray or a suitable 
container in a horizontal position. 
Attestation of Dose Preparation steps 1- 
16 
  
/  
 
Performed by 
Date 
  
/  
 
Checked by 
Date 
The prepared syringe is ready to be 
provided to the dose Administrator 

Ibrutinib for COVID 19 
 
58 
Appendix C: Institutional guidelines for management of COVID-19 
 
 
 
 
 

Ibrutinib for COVID 19 
 
59 
Comorbidities: obesity, asthma, chronic heart, lung, kidney, or liver disease; poorly controlled diabetes 
mellitus; pregnancy; or active malignancy 
 
Please refer to https://osu.app.box.com/s/sgvwyweea5xx7mjoghfimcaeakpq52hv for most updated version 
of institutional COVID 19 guidelines 
 
 
 
 
 
 
 
 
 
 
 
*The appendix in the tables refer to an external document