Conditions: CoronaVirus Induced Disease-2019 (COVID-19)
Keywords: CoronaVirus Induced Disease-2019 COVID-19 Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Pulmonary Injury Ibrutinib Imbruvica Respiratory failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Lung failure is the main cause of death related to COVID-19 infection. The main objective of this study was to evaluate if ibrutinib is safe and can reduce respiratory failure in participants with COVID-19 infection.

Detailed description:
This was a Phase 2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the addition of ibrutinib to supportive care in hospitalized participants who presented with COVID-19- related pulmonary distress requiring supplemental oxygen. Participants were randomized in a 1:1 ratio to receive placebo + supportive care, denoted as SOC or standard-of-care, or ibrutinib 420 mg + SOC, with randomization stratified by prescription for remdesivir.

Participants were to be treated with either placebo or ibrutinib in addition to supportive care for up to 28 days unless they met treatment discontinuation criteria and were to be followed for 58 days following start of therapy or until death, whichever occurred first. Treatment could have been stopped at the discretion of the treating physician after 14 days if the participant was clinically stable and had been off supplemental oxygen for \> 48 hours.

Arms:
arm 1: 420 mg ibrutinib administered once daily as three hard gelatin capsules (140 mg each) with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) arm 2: Three hard gelatin placebo capsules administered once daily with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC)

Interventions: intervention 1: Ibrutinib intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules were to be administered orally with water once daily. For participants who required nasogastric tube (NGT) placement while on study, capsules may have been administered by opening the capsules, mixing with water, and flushing down the NGT. intervention 2: Capsules were to be administered orally with water once daily. For participants who required nasogastric tube (NGT) placement while on study, capsules may have been administered by opening the capsules, mixing with water, and flushing down the NGT.

Protocol document:
Prot_000.pdf: 
NCT04375397


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SCHEMA
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS
1
OBJECTIVES
6
1.1 STUDY DESIGN
6
1.2 PRIMARY OBJECTIVE
6
1.3 SECONDARY OBJECTIVES
6
2
BACKGROUND
7
2.1 STUDY DISEASE(S)
7
2.2 IND AGENT
7
2.3 RATIONALE
7
3
PARTICIPANT SELECTION
16
3.1 ELIGIBILITY CRITERIA
16
3.2 INCLUSION OF WOMEN AND MINORITIES
19
4
REGISTRATION
19
5
TREATMENT PLAN
19
5.1 TREATMENT CRITERIA
19
5.2 AGENT ADMINISTRATION
20
5.3 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES FOR SUBJECTS ON STUDY DRUG
21
5.4 MEDICATIONS TO BE USED WITH CAUTION
22
5.5 GUIDELINES FOR IBRUTINIB MANAGEMENT WITH SURGERIES OR PROCEDURES
24
5.6 DURATION OF THERAPY
25
5.7 DURATION OF FOLLOW UP
25
5.8 CRITERIA FOR TAKING A PARTICIPANT OFF STUDY
26
5.9 PROTOCOL DEVIATIONS
26
6
DOSING DELAYS/DOSE MODIFICATIONS
26
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
28
7.1 ADVERSE EVENT LIST FOR IBRUTINIB
31
7.2 EXPEDITED ADVERSE EVENT REPORTING
35
 
 
 
 


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8
PHARMACEUTICAL INFORMATION
36
8.1 IBRUTINIB
36
9
STUDY CALENDAR
38
10 COROLLARY STUDIES
40
11 DATA REPORTING/REGULATORY REQUIREMENTS
41
11.1 SOURCE DOCUMENTS AND CASE REPORT COMPLETION
41
11.2 DATA QUALITY ASSURANCE
41
11.3 DATA SAFETY MONITORING
41
12 STATISTICAL CONSIDERATIONS
42
12.1 STUDY DESIGN AND ENDPOINTS
42
12.2 SAMPLE SIZE JUSTIFICATION
44
12.3 INTERIM ANALYSIS
44
12.4 EFFICACY ANALYSIS
44
12.5 SAFETY ANALYSIS
45
12.6 SAMPLE SIZE, ACCRUAL RATE AND STUDY DURATION
45
13 ETHICS
45
13.1 INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
45
13.2 ETHICAL CONDUCT OF THE STUDY
45
13.3 SUBJECT CONFIDENTIALITY
45
14 COMPLETION OF THE STUDY
46
15 PUBLICATION PLAN
46
16 REFERENCES
46
LIST OF TABLES
TABLE 1.
SUMMARY OF PRO-INFLAMMATORY AND CHEMO-ATTRACTANT CYTOKINE PATTERNS
12
TABLE 2.
IBRUTINIB DOSE MODIFICATION GUIDANCE FOR CO-ADMINISTRATION WITH CYP3A
INHIBITORS
23
 
 
 
 


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TABLE 3.
DOSE DE-ESCALATION SCHEDULE FOR TOXICITY
27
TABLE 4.
DOSE MODIFICATION GUIDANCE FOR CHRONIC HEPATIC IMPAIRED SUBJECTS
28
LIST OF FIGURES
FIGURE 1.
A MODEL FOR THE IMMUNOPATHOGENESIS OF SARS BASED ON SARS-COV-1 MODEL
9
FIGURE 2.
SUMMARY OF THE MAIN MACROPHAGE POLARIZATION STATES OF ACTIVATED
MACROPHAGES
10
FIGURE 3.
PULMONARY FINDINGS FOR MICE TREATED WITH PHOSPHATE BUFFERED SALINE OR IBRUTINIB 
FOLLOWING LETHAL INTRANASAL CHALLENGE WITH MOUSE-ADAPTED H1N1 INFLUENZA
13
FIGURE 4.
SURVIVAL AND WEIGHT LOSS OF C57BL/6 MICE INFECTED INTRANASALLY WITH INFLUENZA A 
VIRUS
14
FIGURE 5.
INFLAMMATORY CELLS OBSERVED IN BAL FLUIDS AND CYTOKINE LEVELS FROM LUNG 
HOMOGENATES IN MICE TREATED WITH PHOSPHATE BUFFERED SALINE OR IBRUTINIB 
FOLLOWING LETHAL INTRANASAL CHALLENGE WITH MOUSE-ADAPTED H1N1 INFLUENZA
15
FIGURE 6.
ORDINAL SCALE FOR CLINICAL IMPROVEMENT
43
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
49
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
51
APPENDIX C.
INHIBITORS AND INDUCERS OF CYP3A
52
APPENDIX D.
GUIDANCE ON POSSIBLE DRUG INTERACTIONS FOR IBRUTINIB AND MEDICATIONS THAT MAY BE
IN USE TO TREAT COVID-19
53
APPENDIX E.
CHILD-PUGH SCORE FOR SUBJECTS WITH LIVER IMPAIRMENT
54
APPENDIX F.
PROTOCOL SUMMARY OF CHANGES
55
 
 
 
 


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1 OBJECTIVES
1.1
Study Design
There is currently no standard of care for hospitalized patients experiencing coronavirus disease 2019
(COVID-19) infections beyond supportive care.  Numerous studies examining various study interventions 
are underway.  Discovering/providing treatment options for patients with moderate or severe COVID-19 
infection is a high priority, particularly for those with respiratory distress.  Exaggerated cytokine 
response triggered by Alveolar Type II cells and resident macrophages in response to severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2) appears etiological for the pulmonary injury and 
respiratory failure associated with COVID-19 infection.  Ibrutinib blocks Toll-receptor signaling, and 
cytokines associated with SARS-CoV-2, including those found in Alveolar Type II (ACE2+) cells.  
Importantly, in a relevant experimental mouse model, ibrutinib protected mice subjected to lethal 
intranasal inoculums of mouse adapted H1N1 influenza and suppressed inflammatory cell recruitment 
and pathological cytokines that overlapped with many of those observed in SARS-CoV-2 infected 
patients.  Based on this, it is hypothesized that Ibrutinib may potentially provide protection against lung 
injury.  Ibrutinib is an oral agent approved by the United States (US) Food and Drug Administration 
(FDA), European Medicines Agency, and other global health authorities for the treatment of various B-
cell malignancies.  For those patients whose health care providers feel that they qualify to participate in 
this study, who meet inclusion/exclusion criteria and sign an associated consent form, they will be 
enrolled and randomized 1:1 in a randomized, placebo-controlled, double blinded study to receive 
either supportive care and placebo or supportive care and ibrutinib for up to 28 days.  For subjects 
randomized to receive ibrutinib, the dose of ibrutinib will be 420 mg a day.  Approximately 46 subjects 
will be enrolled in this study.  Participating clinical sites must have the capability of implementing 
appropriate infection control measures to prevent infection of study staff and others who share the 
clinical site space.
1.2
Primary Objective
The primary objective of this study will be:

To evaluate the proportion of subjects alive and without respiratory failure at Day 28
1.3 Secondary Objectives
The secondary objectives of this study will be:

To determine if the addition of ibrutinib to supportive care reduces necessity for hospitalization, 
length of need for supplemental oxygen, mechanical ventilation in hospitalized subjects who 
presented with COVID-19 related pulmonary distress requiring supplemental oxygen.
 
 
 


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
To assess the safety and tolerability of ibrutinib as an adjuvant therapy to supportive care in 
hospitalized subjects who presented with COVID-19 related pulmonary distress requiring 
supplemental oxygen.
2 BACKGROUND
2.1 Study Disease(s)
Subjects with confirmed COVID-19 infection by reverse transcriptase (RT)-polymerase chain reaction 
(PCR) from nasopharyngeal swabs, who requires hospitalization and has been on supplemental oxygen 
for a duration of ≤5 days for pulmonary distress related to COVID-19 infection are eligible for this study.
2.2 IND Agent
Ibrutinib is an irreversible inhibitor of Bruton's Tyrosine Kinase (BTK) that is approved by the US.  FDA for 
the treatment of adult subjects with:

Mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

Accelerated approval was granted for this indication based on overall response rate.  
Continued approval for this indication may be contingent upon verification and description 
of clinical benefit in a confirmatory trial.

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).

CLL/SLL with 17p deletion

Waldenström's macroglobulinemia (WM).

Marginal zone lymphoma (MZL) who require systemic therapy and have received at least 1 prior 
anti-CD20-based therapy.

Accelerated approval was granted for this indication based on overall response rate.  
Continued approval for this indication may be contingent upon verification and description 
of clinical benefit in a confirmatory trial.

Chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy.
2.3 Rationale
COVID-19 is an infectious disease caused by SARS-CoV-2.1  Pulmonary failure is the main cause of 
mortality related to COVID-19 infection.2,3  Up to 80% of patients who require hospitalization for COVID-
19 infection require supplemental oxygenation for an average of 13 days.4  Furthermore 30 - 40% of 
those hospitalized for pulmonary distress may require mechanical ventilation.2,5  Therapies that block 
COVID-19 related lung injury and improve pulmonary function are therefore urgently needed.
 
 
 


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SARS-CoV-2 binds via the ACE2 -receptor that is highly expressed on ACE2+ cells in the lung.6  ACE2+
cells constitute 5 - 15% of the lung epithelium.  While Alveolar Type I cells are highly adapted for gas 
exchange, ACE2+ cells have a specialized role in innate immune response.7  ACE2+ cells express Toll-like
receptors (TLRs) and can trigger inflammatory cytokines and chemo-attractants in response to viral and 
bacterial pathogens that recruit and activate other immune cells including macrophages and 
neutrophils.8-12  Highly relevant to coronavirus infection, expression of pro-inflammatory and chemo-
attractant cytokines interleukin (IL)1-B, IL6, interferon-inducible protein 10 (IP10/CXCL10), monocyte 
chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor alpha (TNF-a) were identified in the 
ACE2+ cells from autopsy tissue of SARS-CoV-1 infected patients, that appeared causally related to the 
acute lung injury and pathogenesis observed with SARS-CoV-1 (Figure 1).13  A similar profile of elevated 
cytokine levels of IL6, IL8, IP10/CXCL10 and MCP-1 was also reported in the plasma of SARS-CoV-1 
patients during the progressive and end stage of infection,14 a profile more consistent with M1 polarized 
macrophage response (Figure 2).15,16
 
 
 


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Figure 1.
A Model for the Immunopathogenesis of SARS Based on SARS-Cov-1 Model
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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Figure 2.
Summary of the Main Macrophage Polarization States of Activated 
Macrophages
SARS-CoV-1 shares 86% homology and has a similar pathogenetic mechanism to SARS-CoV-2.17,18  Similar 
to SARS-CoV-1 patients, SARS-Cov-2 patients that required intensive care showed elevated plasma levels 
of inflammatory cytokines and chemo-attractants such as IL2, IL6, IL7, IL10, granulocyte colony 
stimulating factor (G-CSF), IP-10/CXCL-10, MCP-1/CCL2, macrophage inflammatory protein (MIP)-
1a/CCL3, and TNF-a.19  The importance of inflammatory cytokines to lung injury in SARS-CoV-2 infected 
patients has been suggested by reports of benefit with IL6 and IL6-receptor blocking antibodies, and 
clinical trials to examine their use have been initiated (NCT04317092, NCT04306705, NCT04315298).
In previous studies, we and others showed an important role for the TEC family member BTK, and its 
upstream activator, hematopoietic cell kinase (HCK), a SRC family member in triggering TLR-mediated 
signaling.20-22  Both BTK and HCK can be triggered by MYD88, a TLR-adaptor protein that signals for all 
Toll receptors except TLR3 in response to viral and bacterial pathogens, including coronaviruses.23  ATII 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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cells express TLRs, as do alveolar macrophages that coordinate inflammatory responses with ATII cells.8-
12  As components of TLR/MYD88 signaling, BTK and HCK can drive inflammatory cytokine production 
through ERK1/2.24
In a transgenic mouse model, overexpression of activated HCK promoted extensive pulmonary 
inflammation and enhanced innate immune response characterized by extensive eosinophilic and 
mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, 
as well as marked epithelial mucus metaplasia in conducting airways.25  Lungs from these mice show 
areas of emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung 
function and respiratory distress, particularly in aging mice.25  Elevated levels of TNF-a were also 
identified in the bronchoalveolar lavage fluids of these mice following lipopolysaccharide (LPS)
challenge.  The pulmonary pathology findings from these mice show great overlap with those described 
in the lungs of patients with COVID-19 infection which showed serous and fibrin exudation with alveolar 
infiltration consisting majorly of macrophages and monocytes.  The blood vessels of alveolar septum 
were also congested, edematous and widened, with modest infiltration of monocytes and 
lymphocytes.26,27
Ibrutinib is a highly potent, covalent inhibitor of BTK (biochemical IC50 0.5 nM).  Ibrutinib is also a potent 
reversible inhibitor of HCK (IC50 49 nM).22,28  The IC50 levels for BTK and HCK are well within the 
pharmacologically attainable dosimetry of orally administered ibrutinib, although HCK inhibition has not 
yet been demonstrated in patients under ibrutinib therapy, possibly due to the rapid clearance.29  
Serially collected blood samples from patients with CLL, WM, and cGVHD on ibrutinib monotherapy 
showed marked reductions in pro-inflammatory and chemo-attractant cytokines that greatly overlapped 
with those reported elevated in the plasma of SARS-Cov-1 and SARS-COV-2 patients, and in ACE2+ cells 
from lung tissue of SARS-CoV-1 patients (Table 1).13,14,19,30-32  In the iLLUMINATE randomized study, CLL 
subjects treated with ibrutinib immediately prior to infusion with obinutuzumab also showed 
significantly decreased levels of inflammatory cytokines associated with infusion related reactions (a 
cytokine release syndrome).33
 
 
 




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Figure 3.
Pulmonary Findings for Mice Treated with Phosphate Buffered Saline or 
Ibrutinib Following Lethal Intranasal Challenge with Mouse-Adapted H1N1 
Influenza
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
   


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Mice treated with PBS also lost weight and died, whereas those treated with ibrutinib recovered their 
weight after a brief loss and all survived (Figure 4).34  Notably, mice treated with ibrutinib also showed 
decreased inflammatory cell infiltration as well as pro-inflammatory cytokines in lung tissues that 
included pro-inflammatory and chemo-attractant cytokines such as IL1β, IL6, KC/CXCL1, TNF-a, and 
MCP-1 observed in SARS-Cov-1 and SARS-CoV-2 patients (Figure 5).34
Figure 4.
Survival and Weight Loss of C57BL/6 Mice Infected Intranasally with 
Influenza A Virus
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   


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Figure 5.
Inflammatory Cells Observed in BAL Fluids and Cytokine Levels from Lung 
Homogenates in Mice Treated with Phosphate Buffered Saline or Ibrutinib 
Following Lethal Intranasal Challenge with Mouse-Adapted H1N1 Influenza
The above findings support the rationale that an exaggerated cytokine response triggered by Alveolar 
Type II cells and resident macrophages in response to SARS-CoV-2 is etiological for the pulmonary injury 
and respiratory failure associated with COVID-19 infection.  The importance of inflammatory cytokines 
to lung injury in SARS-CoV-2 infected patients has been suggested by reports of benefit with IL6 and IL6-
receptor blocking antibodies, and clinical trials to examine their use have been initiated (NCT04317092, 
NCT04306705, NCT04315298).  The ability to block inflammatory cytokine production to limit pulmonary 
injury has been observed in patients with severe COVID-19 infections who received treatment with the 
IL6 blocking antibody Tocilizumab.
Ibrutinib blocks Toll-receptor signaling, and cytokines associated with SARS-CoV-2, including those found 
in Alveolar Type II (ACE2+) cells.  Importantly, in a relevant experimental mouse model, ibrutinib 
protected mice subjected to lethal intranasal inoculums of mouse adapted H1N1 influenza and 
suppressed inflammatory cell recruitment and pathological cytokines that overlapped with many of 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 


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those observed in SARS-CoV-2 infected patients.  Ibrutinib may therefore protect against lung injury in 
patients with COVID-19 related pulmonary distress.
A case series of 6 patients being treated with ibrutinib for WM were recently published, which suggests 
that ibrutinib may protect against pulmonary injury in COVID-19 infected patients.35  Five of the 
6 patients were on the recommended dose of 420 mg/day, while the sixth patient was on a reduced 
dose of 140 mg/day due to arthralgias.  The 5 patients on ibrutinib at 420 mg/day did not experience 
dyspnea and did not require hospitalization. Their clinical course was marked by steady improvement, 
with resolution or near resolution of COVID-19 related symptoms.  The 1 patient on the reduced dose of 
140 mg/day experience progressive dyspnea and hypoxia resulting in hospitalization.  Ibrutinib dosing 
was held upon hospital admission due to findings of bilateral ground glass opacities and a pleural 
effusion on chest CT.  Hydroxychloroquine (HCQ) and azithromycin were administered, however 
azithromycin was discontinued on hospital Day 3 due to QRS complex tachyarrhythmia.  Hypoxia 
worsened and fever persisted during HCQ.  Ibrutinib was restarted at 140 mg/day and tocilizumab 
400 mg on hospital Day 5 with improvement in oxygenation and reduction in C-reactive protein (CRP).  
Intravenous immunoglobulin was administered on hospital Days 6 - 10, with worsening hypoxia and 
increased CRP noted on hospital Day 10, and which required mechanical ventilation.  Given the lack of 
hypoxia in the other COVID-19 infected WM patients on full dose ibrutinib, the dose of ibrutinib was 
increased from 140 mg/day to 420 mg/day on hospital Day 11 and 12.  On hospital Day 12, the patient 
had a rapid improvement in oxygenation followed by successful extubation and maintenance of oxygen 
saturation of 94 - 96% on 3 liters/min supplemental oxygen by nasal cannula.  The patient continued to 
improve, with oxygen saturation of 95% on room air and further decrease in CRP on Day 14, then was 
discharged home.  The authors suggest that ibrutinib may provide protection against lung injury and 
improve pulmonary function in hypoxic patients with COVID-19 due to the aforementioned modulation 
of inflammatory and chemo-attractants cytokines.
3 PARTICIPANT SELECTION
3.1 Eligibility Criteria
Inclusion Criteria
1. Age > 18 years
2. Willing and able to provide informed consent prior to study therapy, including by virtual 
consenting per hospital policy.
3. Subject requires hospitalization for COVID-19 infection 
4. Subject has Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection 
confirmed by RT-PCR test before study entry.
5. Subject requires supplemental oxygen for pulmonary distress related to COVID-19 infection, 
has been on supplemental oxygen for no more than 5 days, and on breathing room air has
oxygen saturation levels of 94% or less.
6. Subject has radiographic evidence of pulmonary infiltrates.
 
 
 
 


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7. Females of childbearing potential (FCBP) must use 1 reliable form of contraception or have 
complete abstinence from heterosexual intercourse during the following time periods related to 
this study:  1) while participating in the study; and 2) for at least 1 month after discontinuation 
of study drug.  FCBP must be referred to a qualified provider of contraceptive methods if 
needed.  FCBP must have a negative serum pregnancy test as of screening.
8. Men must agree to use a latex condom during treatment and for up to 3 months after the last 
dose of ibrutinib during sexual contact with a FCBP.
9. Adequate hematologic function defined as:

Absolute neutrophil count (ANC) > 750 cells/mm3 (0.75 × 109/L)

Platelet count > 50,000 cells/mm3 (50 × 109/L)

Absolute lymphocyte count (ALC) > 500 cells/mm3
10. Adequate hepatic and renal function defined as:

Estimated creatinine clearance (CrCl) ≥30 mL/min (Cockcroft-Gault).

Bilirubin < 2.0 × ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic 
origin).
11. Must be within 10 days of confirmed diagnosis of COVID-19.
Key Exclusion Criteria
1. Respiratory failure at time of screening as defined per protocol with any of these following 
therapies: 

Endotracheal intubation and mechanical ventilation

ECMO

High flow nasal cannula oxygen at flow rates ≥30 L/min and fraction of delivered oxygen 
≥0.5 (Subjects are eligible if utilizing oxygen delivered by high-flow nasal cannula at flow 
rates < 30 L/min or fraction of delivered oxygen < 0.5)

Non-invasive positive pressure ventilation
2. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
3. On a BTK-inhibitor, anti-IL6, anti-IL6R, or Janus kinase inhibitor (JAKi).
4. Has received rituximab within 180 days from study entry.
5. Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
6. Major surgery within 4 weeks of study entry.
7. Subjects in whom surgery is anticipated to be necessary within 72 hours.
8. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
 
 
 


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9. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) 
or hepatitis B virus (HBV).  Subjects who are positive for hepatitis B core antibody, hepatitis B 
surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction 
(PCR) result before enrollment.  Those who are PCR positive will be excluded.
10. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia 
or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional 
Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome 
within 6 months prior to randomization.
11. Asymptomatic arrythmias (e.g., NSVT, bradycardia HR less < 50, or AV block, or any other 
atrial or ventricular arrythmia) and or history of ejection fraction < 40% on an echo.
12. Subjects receiving a strong cytochrome P450 (CYP) 3A4 inhibitor with the exception of those 
receiving anti-fungal therapy/prophylaxis (Appendix C).
13. Subjects with chronic liver disease and hepatic impairment meeting Child Pugh class C
(Appendix E).  Note that clinical or laboratory changes attributed to acute liver dysfunction are 
not applicable to the evaluation of the Child-Pugh classification.
14. Female subjects who are pregnant, or breastfeeding, or planning to become pregnant while 
enrolled in this study or within 1 month of last dose of study drug.  Male subjects who plan to 
father a child while enrolled in this study or within 3 months after the last dose of study drug.
15. Unwilling or unable to participate in all required study evaluations and procedures.
16. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations).
17. Vaccinated with a live, attenuated vaccine within 4 weeks.
18. Uncontrolled hypertension (systolic blood pressure > 150 mm Hg).
19. History of interstitial lung disease.
20. Subjects on therapeutic anticoagulation at baseline.
21. Subject has history of malignancies, except:

Malignancy treated with curative intent and with no evidence of active disease present for 
more than 1 year prior to Screening and felt to be at low risk for recurrence by treating 
physician.

Subjects managed with localized radiation or hormonal therapy.

Adequately treated non-melanoma skin cancer or lentigo maligna without current evidence 
of disease.

Adequately treated cervical carcinoma in situ without current evidence of disease.
22. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3.0 × ULN, and total 
bilirubin > 2.0 × ULN.
23. International normalized ratio (INR) ≥ 1.5 × ULN attributable to coagulation disorders.
 
 
 


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24. Subject is co-enrolled in another interventional trial.
3.2 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4 REGISTRATION
Participants will be registered and randomly assigned to their treatment arm as per procedures outlined 
in a separate document.
5 TREATMENT PLAN
Subjects will be enrolled and randomized 1:1 in a randomized, placebo-controlled, double blinded study 
to receive either supportive care and placebo or supportive care and ibrutinib for up to 28 days.  For 
subjects randomized to receive ibrutinib, the dose of ibrutinib will be 420 mg a day.  Approximately 
46 subjects will be enrolled in this study.  Treatment for subjects on ibrutinib may be stopped at the 
discretion of the treating physician after 14 days if the subject is clinically stable and has been off 
supplemental oxygen for > 48 hours.
Nasogastric tube administration of ibrutinib is permitted for subjects unable to take ibrutinib/placebo
orally (see Pharmacy Manual for guidance).  Dose de-escalation for toxicity is permitted (see Section 6).  
Subjects may receive any supportive care treatments and/or interventions, however, infection 
prophylaxis-particularly for subjects receiving steroids, and dose modifications for cytochrome P450 
(CYP) 3A inhibitors may be necessary (see Table 2 in Section 5.4 and Appendix C). See also Table 4 for 
administration of ibrutinib to subjects with chronic hepatic impairment.  Drug guidance for dose 
modifications of ibrutinib related to agents that may be in use to treat COVID-19 infection are also 
provided in Appendix D.  If subject is on chloroquine or hydroxychloroquine frequent electrocardiogram 
(EKG) or telemetry monitoring should be performed to monitor QT interval changes for subjects on 
ibrutinib/placebo.
Administration of ibrutinib/placebo therapy and dosing should be recorded in the subject's medical 
record.  A diary will be provided for discharged subjects to record daily dosing as outpatients.
5.1 Treatment Criteria
Treatment should be withheld for adverse events (AE) as outlined below:

Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or 
antidiarrheal therapy) related to ibrutinib.

Grade 4 or unmanageable nonhematologic Grade 3 toxicities related to ibrutinib

Neutrophil count ≤ 500/μL
 
 
 
 


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
In subjects without baseline thrombocytopenia:

Platelet count ≤50,000/μL in the presence of bleeding

Platelet count ≤25,000 μL without bleeding
For AEs that are felt to be related to worsening COVID-19 infection, the investigator may continue 
ibrutinib, however, in subjects with hepatic or cardiac dysfunction, bleeding, or multiple infections 
related to COVID-19 infection, the risks of continuing ibrutinib may outweigh the potential benefit of 
continuing treatment with ibrutinib.
5.2 Agent Administration
Ibrutinib or placebo will be administered orally once daily.  Three capsules (each 140 mg) of ibrutinib or 
placebo are to be taken around the same time each day with a glass of water.  The capsules should be 
swallowed intact and subjects should not attempt to open capsules or dissolve them in water.  For 
subjects who require nasogastric tube (NGT) placement while on study, capsules may be administered 
by opening the capsules, mixing with water, and flushing down the NGT (see Pharmacy Manual for 
details).  Though the use of strong CYP3A inhibitors/inducers (see Appendix C), and grapefruit and 
Seville oranges should be avoided for the duration of treatment, treatment with antifungal prophylaxis 
(e.g., voriconazole, posaconazole) is permitted; however, dose reductions are necessary (see 
Section 5.4).  See also Table 4 for administration of study drug to subjects with chronic hepatic 
impairment.  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.
Subjects will be treated for up to 28 days.  Treatment may be stopped at the discretion of the treating 
physician after 14 days if the subject is clinically stable and has been off supplemental oxygen for 
> 48 hours.  The dose of 420 mg/day of ibrutinib is the dose approved by the FDA for the treatment of 
subjects with CLL, WM, and cGVHD.  Subjects with these disorders receive ibrutinib until disease 
progression or prohibitive side effects which cannot be managed with dose reduction.  The dose chosen 
reflects daily dosing associated with reduced inflammatory and chemo-attractant cytokines observed in 
CLL, WM, and cGVHD subjects that are elevated in subjects with SARS-CoV-1 and SARS-CoV-2 infections 
and may be responsible for pulmonary injury (see Section 2.3).
Dose reductions for toxicity will be permitted (see Section 6).
For hospitalized subjects, study drug will be administered by nursing staff.  For subjects discharged from 
the hospital, study drug will be self-administered, and participants will be instructed to write in a diary 
daily, documenting that the drug was taken and AEs experienced.  Subjects should be instructed to take 
the study drug with a glass of water at approximately the same time each day.  Subjects taking study 
drug at home will be instructed on how to complete the diary by study staff prior to discharge.  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.  The missed dose will not be made up and must be returned at the next scheduled visit.  
The subject will be instructed to document missed drug doses in the study diary.  Furthermore, they will 
 
 
 


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be instructed to call their provider, the site or principal investigator if vomiting occurs or they have 
recurrence of their COVID-19 symptoms or any other AEs consistent with the product label.  If the pills 
are vomited, this should be noted on the subject diary, but a replacement dose should not be taken that 
day.  All dosages prescribed and dispensed to the subject, and all dose changes during the study should 
be recorded.  Diaries will be collected at the end of the treatment period.  In the event of circumstances 
that prevent a discharged subject from returning to clinic, a tele-health visit is permitted.  Study staff will 
collect or coordinate with subject in the event of a tele-health visit for the return of any unused drug 
and the study diary.  Unused drug will be counted and returned to the pharmacy to be destroyed.  A 
prescription for dispensing study drug for at home use, as detailed above, will be filled by the study 
pharmacy.  Medication labels will comply with US legal requirements and be printed in English.  The 
storage conditions for study drug will be described on the medication label.  Study drug will be provided 
by Pharmacyclics LLC/AbbVie Inc.  Ibrutinib or placebo is formulated as capsules for oral administration 
and will be available for this study in 140 mg and 70 mg capsules.
Overdose
Any dose of study drug in excess of that specified in this protocol is considered to be an overdose.  Signs 
and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a 
Serious Adverse Event in the appropriate time frame and documented as clinical sequelae to an 
overdose.  There is no specific experience in the management of ibrutinib overdose in subjects.  There 
are limited data on the effects of ibrutinib overdose.  No maximum tolerated dose (MTD) was reached in 
the Phase 1 study in which subjects received up to 12.5 mg/kg/day (1,400 mg/day).  In a separate study 
1 healthy subject who received a dose of 1,680 mg experienced reversible Grade 4 hepatic enzyme 
increases (AST and ALT).  Refer to the IB for additional details about this case.  There is no specific 
antidote to ibrutinib.  Subjects who ingest more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment.
5.3 General Concomitant Medication and Supportive Care Guidelines 
for Subjects on Study Drug
Supportive care medications and intervention for COVID-19 infection, including use of a ventilator 
support as clinically indicated is permitted at the treating physician's discretion.  Drug guidance for dose 
modifications of study drug related to agents that may be in use to treat COVID-19 infection are also 
provided in Appendix D.
Careful monitoring for signs and symptoms of bleeding are indicated, consistent with the safety profile 
of ibrutinib.  Anti-emetics are permitted if clinically indicated.  All concomitant medications during the 
treatment period should be recorded.  The following restrictions apply during the entire duration of the 
study:

If steroids are necessary, strongly consider treatment with an appropriate anti-fungal 
prophylaxis agent (e.g., voriconazole/posaconazole).  Consider the addition of anti-bacterial 
prophylaxis as clinically necessary.

Concomitant use of hydroxychloroquine or chloroquine should be avoided if possible.
 
 
 
 


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
Growth factors (i.e., G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) and 
transfusion support is permitted.  

Concomitant use of anti-platelet agents and anticoagulants should be avoided (if possible) due 
to the anti-platelet effects of ibrutinib, however their use may be clinically necessary.

The use of deep vein thrombosis prophylaxis is permitted.  Participants receiving anti-platelet 
agents in conjunction with study drug should be observed closely for any signs of bleeding or 
bruising, and study drug should be withheld in the event of any Grade 2 or higher bleeding 
events until  ≤Grade 1.  Participants with any grade central nervous system bleeding should 
have treatment discontinued.  

Subjects requiring the initiation of therapeutic anticoagulation therapy (e.g., atrial fibrillation), 
consider the risks and benefits of continuing study drug treatment.  If therapeutic 
anticoagulation is clinically indicated, treatment with study drug should be held and not be 
restarted until the subject is clinically stable and has no signs of bleeding.  Subjects should be 
observed closely for signs and symptoms of bleeding.  No dose reduction is required when study 
drug is restarted.

Supplements such as fish oils and vitamin E preparations should be avoided.

Use study drug with caution in subjects requiring other anticoagulants or medications that 
inhibit platelet function.

Subjects with a history of hepatitis B and C viral infection and baseline negative PCR that 
develop elevations in liver function tests should be evaluated for viral reactivation.

Subjects cannot co-enroll in other interventional trials. Other interventions are acceptable, 
including remdesivir, and open-label compassionate use of therapies, such as convalescent 
plasma.
5.4 Medications to be Used with Caution
5.4.1
CYP3A Enzyme Inhibitors/Inducers
Ibrutinib is primarily metabolized by CYP3A4.  Concomitant use of ibrutinib and drugs that strongly or 
moderately inhibit CYP3A can increase ibrutinib exposure, and strong CYP3A inhibitors should be 
avoided.  Avoid grapefruit and Seville oranges during study drug administration as these contain 
moderate inhibitors of CYP3A.  Dose adjustment of study drug due to concomitant use of CYP3A 
inhibitors should follow Table 2 as applicable.
 
 
 


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Table 2.
Ibrutinib Dose Modification Guidance for Co-Administration with CYP3A 
Inhibitors
Co-administered Drug
Recommended Ibrutinib or Placebo Dose for the Duration of the 
Inhibitor Usea
Mild CYP3A inhibitors
420 mg once daily.  No dose adjustment required.
Moderate CYP3A inhibitors 
280 mg once daily.
Voriconazole 200 mg twice daily
Posaconazole suspension 100 mg once 
daily, 100 mg twice daily, or 200 mg 
twice daily
140 mg once daily.
Posaconazole at higher dosesb
70 mg once daily.
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 
7 days or less), interrupt ibrutinib.
If the benefit outweighs the risk and long-term dosing is required 
(more than 7 days), reduce ibrutinib dose to 140 mg once daily for the 
duration of the inhibitor use.
CYP3A = cytochrome P450 isoform 3A; IV = intravenous
a.
Monitor for adverse reactions 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 C.  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/.
This website is continually revised and should be checked frequently for updates.
5.4.2
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp) nor other major 
transporters, except organic cation transporter 2 (OCT2).  The dihydrodiol metabolite and other 
metabolites are P-gp substrates.  Ibrutinib is a mild inhibitor of P-gp and breast cancer resistance protein 
(BCRP).  Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates.  
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a therapeutic 
dose.  There is no clinical data available.  To minimize a potential interaction in the GI tract, narrow 
therapeutic range P-gp substrates such as digoxin or methotrexate, should be taken at least 6 hours 
before or after ibrutinib.  Ibrutinib may also inhibit BCRP systemically and increase the exposure of drugs 
that undergo BCRP-mediated hepatic efflux, such as rosuvastatin.
 
 
 
 


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Antiplatelet Agents and Anticoagulants 
Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet 
function.  In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen induced platelet 
aggregation were observed.  Supplements such as fish oil and vitamin E preparations should be avoided 
during treatment with ibrutinib.  Bleeding events of any grade, including bruising and petechiae, 
occurred in subjects treated with ibrutinib.  See below for guidance on management of subjects to 
reduce risk of bleeding while on ibrutinib and requiring surgeries or procedures.  Subjects with 
congenital bleeding diathesis have not been studied.
5.5 Guidelines for Ibrutinib Management with Surgeries or Procedures
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following guidance 
should be considered in the perioperative period for subjects on study drug who require surgical 
intervention or an invasive procedure.
5.5.1
Minor Surgical Procedures
For minor procedures (e.g., central venous catheter, arterial line placement) that are urgently needed 
and could result in bleeding, immediately stop study drug and consider transfusion with platelets just 
prior to procedure.  Study drug should be held for 24 hours after procedure.  If there is ongoing bleeding 
after the procedure, additional platelet transfusions can be administered and ibrutinib held to 24 hours 
after bleeding stops.  No drug hold or platelet transfusions are needed for routine venipunctures or 
peripheral intravenous line placement.
For subjects requiring endotracheal intubation, study drug should be temporarily stopped for 24 hours 
following intubation.  If there is evidence of bleeding at the time of the endotracheal intubation, a 
platelet transfusion should be given as soon as possible.  If there is no evidence of bleeding during 
intubation, study drug may be resumed after 24 hours.
For subjects who require endotracheal intubation after enrollment on the trial, study drug may be 
continued if, in the opinion of the investigator, the subject appears to be benefiting from treatment and 
the risk of continuing therapy outweighs the risks associated with ibrutinib (e.g., bleeding).
5.5.2
Elective Major Surgical Procedures
For any elective surgery or invasive procedure requiring sutures or staples for closure, study drug should 
be held at least 3 - 7 days prior to the intervention (except for emergency procedures) and should be 
held at least 3 - 7 days after the procedure and restarted at the discretion of the treating physician when 
the surgical site is reasonably healed without serosanguineous drainage or the need for drainage tubes.  
For less than 7 days hold prior to the procedure, consider a transfusion of platelets just prior to the 
procedure to decrease risk of bleeding.
5.5.3
Emergency Major Surgery Procedures
For emergency procedures that could result in bleeding, and require sutures or staples for closure, 
subject unblinding will be permitted.  For subjects on ibrutinib arm, transfusion with platelets prior to 
 
 
 


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the procedure should be given and study drug held after the procedure for at least 3 days after the 
surgical procedure.  Consider also additional platelet transfusions peri- and post-operatively to reduce 
bleeding risk or active bleeding.
5.6 Duration of Therapy
Duration of therapy will depend on individual response, evidence of pulmonary disease progression and 
tolerance.  In the absence of treatment delays due to AEs, treatment may continue until 1 of the 
following criteria applies:

Intercurrent illness that in the medical judgment of the treating physician prevents further 
administration of treatment.

Unacceptable AEs.

Subject demonstrates an inability or unwillingness to comply with the oral medication regimen 
and/or documentation requirements.

Subject decides to withdraw from the protocol therapy.

General or specific changes in the participant's condition, including the development of atrial 
fibrillation that render the participant unacceptable for further treatment with study drug in the 
judgment of the treating physician.

Study drug should be stopped in subjects experiencing Grade 4 toxicity, and not resumed.  
These subjects should be followed through to toxicity resolution to at least Grade 2 or less and 
study completion.

Treatment for subjects on ibrutinib may be stopped at the discretion of the treating physician 
after 14 days if the subject is clinically stable and has been off supplemental oxygen for 
> 48 hours.

For all subjects discontinuing from study treatment, the reason for discontinuation should be 
recorded in the medical record.
Subjects will be removed from the protocol therapy when any of these criteria apply.  The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the 
medical record.  Alternative care options will be discussed with the participant.
5.7 Duration of Follow Up
Participants will be followed for 8 weeks following start of therapy or until death, whichever occurs first.  
Subjects experiencing grade 4 toxicities at least possibly related to study drug will be followed until 
toxicity resolution to at least Grade 2 or less.  Participants removed from protocol therapy for 
unacceptable AEs will be followed until resolution or stabilization of the AE.
 
 
 


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5.8 Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Pregnancy

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the electronic case report form (eCRF) In addition, subjects who are lost to follow-up or 
withdraw consent must be reported to AbbVie immediately so they can potentially be replaced.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified), the investigator is responsible for notifying independent 
ethics committee (IEC)/independent review board (IRB), regulatory authorities (as applicable), and 
AbbVie.
6 DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made using above.  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
dose delays and dose modifications.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
website:  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
antidiarrheals, etc.).  All AEs experienced by subjects that at least may be possibly related to ibrutinib 
will be collected from the time of the first dose of study treatment, through the end of therapy should 
be documented in the medical record.  If subjects continue to experience ibrutinib toxicity at the end of 
treatment, they may be contacted for additional assessments until the toxicity has resolved or is 
deemed irreversible.  Dose de-escalations for toxicity will be performed per Table 3.
Dosing will be held for any of the following conditions:

Grade 4 ANC (< 500/μL).  Discontinue study drug.  Neutrophil growth factors may be used for 
ANC recovery.

Grade 3 Platelets (< 50,000/μL) in the presence of clinically significant bleeding events; or  
 
 
 


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
Grade 4 Platelets (< 25,000/μL).  Discontinue study drug.  Platelet transfusions may be used for 
platelet recovery.

Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic and/or
antidiarrheal therapy); discontinue study drug for grade 4 nausea, vomiting or diarrhea.

Any other grade 4 toxicities and any unmanageable non-hematologic Grade 3 or higher 
toxicities.  Discontinue study drug.

For Grade 3 atrial fibrillation, consider the risks and benefits of restarting and continuing study 
drug.  If clinically indicated, the use of non-warfarin or vitamin k antagonist anticoagulants or 
antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation.  
Discontinue study drug for Grade 4 atrial fibrillation.
For subjects experiencing treatment emergent Grade 3 toxicities (e.g., ALT or AST > 5 × ULN) related to 
study drug, hold study drug.  Treatment may be restarted if toxicity resolves to baseline at the next 
lowest dose level per Table 3.
Table 3.
Dose De-Escalation Schedule for Toxicity
Dose Level
Study Drug
Level 1 – Starting Dose
420 mg/day (Days 1 - 28)
Level 2
280 mg/day
Level 3
140 mg/day
Level 4
Discontinue
For AEs that are felt to be related to worsening COVID-19 infection, the investigator may continue study 
drug, however, in subjects with worsening hepatic or cardiac dysfunction, bleeding, or multiple 
infections related to COVID-19 infection, study drug should be discontinued.
Any subject developing the following laboratory abnormalities should permanently discontinue study 
treatment:

ALT or AST > 8 × ULN

ALT or AST > 5 × ULN for more than 2 weeks

ALT or AST > 3 × ULN and (total bilirubin ≥2 × ULN or INR > 1.5)

ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right

Upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
For subjects with mild chronic liver impairment (Child-Pugh Class A), the recommended dose is 140 mg 
daily.  For subjects with moderate chronic liver impairment (Child-Pugh Class B), the recommended dose 
is 70 mg daily.  Monitor subjects for signs of ibrutinib toxicity.  It is not recommended to administer 
ibrutinib to subjects with severe hepatic impairment.  Subjects with clinically significant chronic hepatic 
 
 
 
 


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impairment at the time of Screening (Child- Pugh Class C) are excluded from study participation.  
Concomitant use of strong CYP inhibitors is not permitted in subjects with chronic hepatic impairment.  
Refer to Appendix E for Child-Pugh classification.  Please refer to Table 4 for dose modifications due to 
chronic hepatic impairment.
Table 4.
Dose Modification Guidance for Chronic Hepatic Impaired Subjects
Child Pugh Class A
(Mild hepatic impairment)*
Child Pugh Class B
(Moderate hepatic impairment)
Child Pugh Class C
(Severe hepatic 
impairment)
Ongoing at time 
of enrollment 
Develops during 
study 
Ongoing at time 
of enrollment 
Develops during 
study 
Develops during 
study 
Ibrutinib 
Dose 
(daily) 
140 mg 
1. Hold study drug 
until 
improvement 
to baseline.
2 Restart dose at
140 mg
3. Discontinue for 
recurrence
70 mg
1. Hold study 
drug until 
improvement 
to baseline.
2. Restart dose 
at 70 mg
3. Discontinue
for 
recurrence
Discontinue study 
drug
*
In the event that additional reduction is needed, ibrutinib should be held for non-hepatic toxicity until resolution.
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from study drug, necessitate therapeutic medical intervention, meets protocol-specific criteria
(Section 5.1 and Section 6), and/or if the investigator considers them to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
 
 
 
 




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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, study procedure-related serious and nonserious AEs will be collected from the time the subject 
signs the study-specific informed consent.
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an IMP related to any dose 
administered that result in death, are life-threatening, require inpatient 
hospitalization or prolongation of existing hospitalization, result in persistent or 
significant disability or incapacity, or are a congenital anomaly or birth defect.
SUSAR
A suspected SAR:  refers to individual SAE case reports from clinical trials where 
a causal relationship between the SAE and the IMP was suspected by either the 
sponsor or the investigator, is not listed is the applicable Reference Safety 
Information, and meets 1 of the following serious criteria:  results in death, is 
life-threatening, requires hospitalization or prolongation of an existing 
hospitalization, results in persistent or significant disability or incapacity, or is a 
congenital anomaly or birth defect.  All individually reported SARs are 
considered suspected.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the NCI CTCAE Version 5.0.
The investigator will use the following definitions to assess the relationship of the AE to the use of the 
study drug (ibrutinib/matching placebo):
 
 
 


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Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.8).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners will be collected from the 
date of the first dose through 90 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
7.1 Adverse Event List for Ibrutinib
7.1.1
Risks
Bleeding-related events
There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and without 
thrombocytopenia.  These include primarily minor hemorrhagic events such as contusion, epistaxis, and 
petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, intracranial 
hemorrhage and hematuria.  Use of ibrutinib in subjects requiring other anticoagulants or medications 
that inhibit platelet function may increase the risk of bleeding.  In an in vitro platelet function study, 
inhibitory effects of ibrutinib on collagen induced platelet aggregation were observed.  A higher risk for 
major bleeding was observed with anticoagulant than with antiplatelet agents.  Consider the risks and 
benefits of anticoagulant or antiplatelet therapy when co-administered with ibrutinib.  Monitor for signs 
and symptoms of bleeding.  Supplements such as fish oil and vitamin E preparations should be avoided.  
Subjects with congenital bleeding diathesis have not been studied.  See Section 5.4 for guidance on 
concomitant use of anticoagulants, antiplatelet therapy and/or supplements.  See Section 5.5 for 
guidance on ibrutinib management with surgeries or procedures.
 
 
 


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Cardiac Arrhythmias
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal events, 
have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, 
hypertension, acute infections, and a previous history of cardiac arrhythmia.  Periodically monitor 
subjects clinically for cardiac arrhythmia.  Subjects who develop arrhythmic symptoms (e.g., palpitations, 
lightheadedness, syncope, chest discomfort or new onset of dyspnea) should be evaluated clinically, and 
if indicated, have an EKG performed.  For cardiac arrhythmias which persist, consider the risks and 
benefits of ibrutinib treatment and follow the protocol dose modification guidelines.
Hypertension
Hypertension has occurred in subjects treated with ibrutinib.  Regularly monitor blood pressure in 
subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout treatment 
with ibrutinib as appropriate.
Cerebrovascular Accidents
Although causality has not been established, cases of cerebrovascular accident, transient ischemic 
attack, and ischemic stroke including fatalities have been reported with the use of ibrutinib in the post-
marketing setting, with and without concomitant atrial fibrillation and/or hypertension.  Regular 
monitoring and appropriate treatment of conditions that can contribute to the occurrence of these 
events is recommended.
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) have been 
reported in subjects treated with ibrutinib.
Diarrhea
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting, and 
constipation.  These events are rarely severe and are generally managed with supportive therapies 
including antidiarrheals and antiemetics.  Subjects should be monitored carefully for gastrointestinal AEs 
and cautioned to maintain fluid intake to avoid dehydration.  Medical evaluation should be made to rule 
out other etiologies such as Clostridium difficile or other infectious agents.  Should symptoms be severe 
or prolonged, follow the protocol dose modification guidelines (see Section 6).
Infections
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated with 
ibrutinib therapy.  Some of these infections have been associated with hospitalization and death.  
Consider prophylaxis according to standard of care in subjects who are at increased risk for 
opportunistic infections.  Although causality has not been established, cases of progressive multifocal 
leukoencephalopathy and hepatitis B reactivation have occurred in subjects treated with ibrutinib.  
Subjects should be monitored for signs and symptoms (fever, chills, weakness, confusion, vomiting and 
jaundice) and appropriate therapy should be instituted as indicated.
 
 
 


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Non-Melanoma Skin Cancer
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib.  Monitor subjects for the 
appearance of non-melanoma skin cancer.
Rash
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash occurred at a 
higher rate in the ibrutinib arm than in the control arm.  Most rashes were mild to moderate in severity.  
Isolated cases of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) 
have been reported in subjects treated with ibrutinib.  Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS.  Subjects receiving ibrutinib should be observed closely 
for rashes and treated symptomatically, including interruption of the suspected agent as appropriate.  In 
addition, hypersensitivity-related events including erythema, urticaria, and angioedema have been 
reported.
Interstitial Lung Disease (ILD)
Cases of interstitial lung disease (ILD) have been rarely reported in subjects treated with ibrutinib.  It 
may be difficult to separate from those of COVID-19.  Monitor subjects for pulmonary symptoms 
indicative of ILD, and if suspected to be ibrutinib related, discontinue therapy.  If symptoms develop, 
interrupt ibrutinib and manage ILD appropriately.  If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines.
Pregnancy
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur in a female study subject, consent to provide follow-up information 
regarding the outcome of the pregnancy and the health of the infant until 30 days old will be requested.  
A female subject must immediately inform their treating physician if she becomes pregnant from the 
time of consent to 30 days after the last dose of ibrutinib.  A male subject must immediately inform the 
treating physician if his partner becomes pregnant from the time of consent to 90 days after the last 
dose of ibrutinib.  Any female subjects receiving study drug(s) who become pregnant must immediately 
discontinue ibrutinib.  The Investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus.  Although pregnancy itself is not regarded as an AE, the 
outcome will need to be documented.  Any pregnancy occurring in a subject or subject's partner from 
the time of consent to 30 days (or 90 days for male partners) after the last dose of study drug must be 
reported.  Any occurrence of pregnancy must be reported to AbbVie Pharmacovigilance, or designee, 
per SAE reporting timelines.  All pregnancies will be followed for outcome, which is defined as elective 
termination of the pregnancy, miscarriage, or delivery of the fetus.  Pregnancies with an outcome of live 
birth, the newborn infant will be followed until 30 days old by completing will need to be reported to 
AbbVie Pharmacovigilance per SAE reporting timelines.  Any congenital anomaly/birth defect noted in 
the infant must be reported as a serious adverse event.
 
 
 


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Other Malignancies
All new malignant tumors including solid tumors, skin malignancies and hematologic malignancies will 
be reported for the duration of study treatment and during any protocol specified follow-up periods 
including post-progression follow-up for overall survival.  If observed, enter data in the corresponding 
eCRF.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting 
for the Investigational Medicinal Product (IMP) in accordance with Directive 2001/20/EC.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local guidelines and the 
Investigator Brochure will serve as the Reference Safety Information (RSI).  The RSI in effect at the start 
of a DSUR reporting period serves as the RSI during the reporting period.  For follow-up reports, the RSI 
in place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to assess 
expectedness.
8 PHARMACEUTICAL INFORMATION
8.1 Ibrutinib
8.1.1
Description
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1- piperidinyl]-2-
propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis).  Ibrutinib exhibited 18% 
to 23% oral bioavailability in rats and 7% to 11% oral bioavailability in dogs.  The mean terminal half-life 
of ibrutinib after oral administration ranged from 1.7 to 3.1 hours in mice, 1 to 4.7 hours in rats, and 
3.3 to 6.4 hours in dogs.  Preliminary results suggest a 1.5- to 2.5-hour half-life of ibrutinib in humans.  
The effects of renal and/or hepatic impairment on drug clearance are not known at this time.  In vitro 
studies have indicated that ibrutinib is metabolized extensively by CYP3A4.
8.1.2
Form
Ibrutinib is a white to off-white crystalline solid.  Ibrutinib has a single chiral center and is the 
R-enantiomer.  Ibrutinib product is manufactured for Pharmacyclics LLC by a contract manufacturer.  
Ibrutinib PO Hard Gelatin Capsule is an oral formulation containing micronized ibrutinib and the
following compendial excipients:  microcrystalline cellulose (NF); croscarmellose sodium (NF); sodium 
lauryl sulfate (NF);  magnesium stearate (NF).  The 140 mg strength contains 140 mg of the active 
ingredient, ibrutinib, adjusted for water content and purity in a size 0, gray, hard gelatin capsule.  The 70 
mg strength contains 70 mg of the active ingredient, ibrutinib, adjusted for water content and purity in a 
size 2, yellow, hard gelatin capsule.  Capsules are packaged in high-density polyethylene (HDPE) bottles
with an induction seal and a child resistant screw top cap.  Each bottle is distributed by Pharmacyclics 
LLC/AbbVie Inc.  The number of capsules per bottle is indicated on the label.  The HDPE bottles are 
labeled with the appropriate information and intended for distribution to participants.  Empty HDPE 
bottles will not be supplied by Pharmacyclics LLC/AbbVie Inc.
8.1.3
Storage and Stability
The recommended storage condition for ibrutinib PO Hard Gelatin Capsule is at 15°C to 25°C [59° F to 
77° F] with excursions permitted to 30°C (86°F).  Under these conditions, the drug product is expected to 
remain within specifications for at least 36 months.  Temperatures lower than 15°C or greater than 30°C 
must be reported to Pharmacyclics/AbbVie for evaluation of impact on product quality.
 
 
 


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8.1.4
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic 
agent in a self-contained and protective environment.
If a drug shipment arrives damaged, or if there are any other drug complaints, a product complaint must 
be reported.  A product complaint is any complaint related to the biologic or drug component of the 
product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event. Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
8.1.5
Availability
Ibrutinib will be supplied free-of-charge from Pharmacyclics LLC/AbbVie Inc for this study.
8.1.6
Administration
Ibrutinib should be self-administered daily by the participant or qualified hospital staff and should be 
taken at approximately the same time each day.  Ibrutinib is intended to be administered orally once 
daily with 8 ounces (approximately 240 mL) of water (avoid grapefruit juice and Seville orange juice 
products due to CYP450 3A4 inhibition).  The capsules should be swallowed intact and participants 
should not attempt to open capsules or dissolve them in water.
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.  The missed dose will not be made up and must be returned to the site at the next 
scheduled visit.  If the pills are vomited this should be noted on the diary, but a replacement dose 
should not be taken that day.  A study diary will be used to aid with study drug administration 
compliance for subjects taking drug in a non-hospital setting.
8.1.
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful record 
of the inventory and disposition of the study drug.  Each site will be responsible for maintaining drug 
accountability records and lot numbers during the study.
8.1.8
Destruction and Return
Unused ibrutinib capsules will be returned by the participant, collected and counted at each study visit 
and will be returned to pharmacy for destruction.  Unused supplies of ibrutinib will be destroyed 
according to institutional policies.
 
 
 


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9 STUDY CALENDAR
See study calendar below for screening and follow-up assessments.
Baseline
(Screening)
Days 1 – 281, 4
Day 28
(± 3 days)
Follow-up Visit
(Day 58 ± 7 days)
Informed Consent
X
Demographics
X
Current and complete
medical history (including 
days of symptom onset to 
study start, alcohol and 
tobacco history)
X
Concurrent medications 
(including supplements)
X
X
X4
X4
Physical exam including vitals
X
Daily while in hospital
X4
X4
Clinical status on 8-Point 
Scale
X
Daily8
X4,8
X4,8
O2 saturation and 
documentation of 
supplemental O2, and 
mechanical/cardiopulmonary 
support (if any)
X
Daily while in hospital
X
As clinically 
indicated4
Arterial blood gas
As clinically 
indicated
As clinically indicated
As clinically 
indicated
As clinically 
indicated
CBC with differential
(including INR at baseline)
X
Every 7 days or more 
often, if clinically 
indicated
X
As clinically 
indicated4
Serum Chemistries, BUN, Cr
X
Every 7 days or more 
often if clinically 
indicated
X
As clinically 
indicated4
C-reactive protein, ferritin
X
X (Day 3 ± 1 day, 
Day 10 ± 1 day)
Corollary Studies per 
Section 10
X2
X2
(Day 3 ± 1 day and 
Day 10 ± 1 day)
X2
X2
EKG
X5
X5
X5
As clinically 
indicated
 
 
 
 


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Baseline
(Screening)
Days 1 – 281, 4
Day 28
(± 3 days)
Follow-up Visit
(Day 58 ± 7 days)
SARS-CoV-2 viral testing by 
RT-PCR by nasopharyngeal 
swab
X
X6
B-HCG7
X
Radiological Evaluation 
X3
As clinically indicated
X3
As clinically 
indicated
Survival status
X
X
X4
X4
Adverse Events Related or 
Possibly Related to Ibrutinib
X
X4
X4
Reason for early study 
discontinuation (if applicable)
noted in medical record
X
X
Ibrutinib or placebo (once 
daily)
X
X
Review subject diary (if 
applicable)
X
X
B-HCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; CBC = complete blood count; Cr = creatinine; 
CT = computed tomography; EKG = electrocardiogram; INR = international normalized ratio; NGT = nasogastric tube; 
RT-PCR = reverse transcriptase polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2
1.
Treatment for subjects may be stopped at the discretion of the treating physician after 14 days if the subject is clinically 
stable and has been off supplemental oxygen for > 48 hours or treatment may be discontinued for reasons outlined in 
Section 5.8.  In either case, Day 28 procedures (below) should be performed in the event of hospital discharge, applicable 
procedures for the Treatment Period should continue until Day 28 (either in hospital or via subject diary), and procedures 
under Day 28 should still be performed on Day 28 (± 3 days), regardless of when the subject stops receiving study drug.
2.
Unless subject is unstable or blood draw is not possible.  See corollary studies in Section 10 for research blood collection.
3.
Chest x-ray and/or CT scan to be used to meet the criteria as determined by the PI. A similar modality of study may be 
used for follow-up unless medical resources are limited.
4.
A tele-health visit with coordinated diary collection and/or return of ibrutinib is permitted prior to Day 28, at Day 28, and 
at Day 58 if circumstances prevent a clinic visit.  Lab draws and other assessments that may be clinically indicated will be 
performed through outpatient laboratory or radiology services, or other accessible facilities determined by the treating 
physician or study team unless it is not medically safe.
5.
EKG assessments will be performed for all subjects at baseline, and daily thereafter for the first 3 days, on Day 7, and 
weekly thereafter while subjects are hospitalized and on study drug.  Serial EKGs are not needed for subjects on 
continuous telemetry during the time they are on telemetry.  EKGs should also be performed as clinically indicated.
6.
Quantitative assessments are preferred, and same nostril as that used at baseline should ideally be used for testing should 
be used unless medically not possible (i.e., due to NGT tube insertion).
7.
Required for female subjects of child bearing potential.
8.
Clinical status on an 8-point ordinal scale (Figure 6) should be recorded taking into account limitations on activities and 
required supportive care (oxygen or ventilation) in hospital and on diary if discharged.
 
 
 
 


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10 COROLLARY STUDIES
Serial evaluations of inflammatory and chemo-attractant cytokines, IgM and IgG antibody titers to SARS-
CoV-2 will be performed as exploratory studies.  These studies will help inform if a clinically meaningful 
biomarker(s) for response can be identified, and to evaluate if ibrutinib as a BTK-inhibitor impacts 
humoral response to SARS-CoV-2.
Additional information on the collection, handling/processing, disposition, and measurement methods 
will be provided in the central lab manual/separate document.
Sampling may not be possible for all collection times in those subjects who are medically unstable or 
inaccessible or if hospital resources preclude collection.  An allowance of ± 1 day is permitted for sample 
collection for Days 3, 10 due to medical reasons.  An allowance of ± 3 days is permitted for Day 28, and 
58 blood collections in the event of medical reasons or scheduling conflicts.
Cytokine Studies (Study Wide)
A magnetic multiplex enzyme-linked immunosorbent assays will be used for inflammatory and chemo-
attractant cytokine assessments that may include but not limited to: GMCSF, IL1B, IL2, IL6, IL7, IL8, IL10, 
IP10/CXCL10, MCP-1/CCL2, MIP-1A/CCL3, MIP1B/CCL4, INFγ, IL12p40 and TNF-a (as per studies cited in 
Table 1) will be performed on samples from subjects on supportive care plus placebo or supportive care 
plus ibrutinib.
Signaling Studies (Study Wide)
NanoString transcriptome analysis for innate and adaptive immune signaling to investigate immune cell 
types including T and B-cell subtypes and monocytes will be carried out on subject whole blood.
Serology for SARS-CoV-2 IgM and IgG antibody response (Study Wide)
The kinetics of SARS-CoV-2 IgM and IgG antibody response have not been reported.  Both IgM and IgG 
antibody responses were documented in patients with SARS-CoV-1 infection, with positivity noted 
1 week after infection and peak IgM titers at 3 weeks, and a sustained IgG antibody response after 
Week 3 that peaked at Week 12.36 Serial evaluations of IgM and IgG antibody titers will be performed 
by a central laboratory. Any remainder sample material not used in the above studies will be banked for 
future studies of other response biomarkers.
Statistical Plan for Corollary Studies
All efficacy endpoints will be assessed using corollary study data to identify potential predictors of 
change in the disease course.  These analyses are exploratory in nature and no alpha adjustment will be 
made to address multiplicity.  Mean cytokine and antibody titer changes from baseline between the 
ibrutinib treated and untreated controls will be analyzed using blocking model designs to account for 
known confounding factors such as age and gender.
 
 
 


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Handling of Samples
Collection tubes for corollary studies will be sourced from the Treon Laboratory at the Dana Farber 
Cancer Institute.  For corollary studies supply and replacement contact 
 (Treon 
Laboratory) at
 or call 
.
For cytokine, NanoString, and serology studies, study sites will process locally until end of study or as 
directed by study sponsor.  Sites will utilize sample shipping kit and instructions provided by the sponsor 
to batch ship samples to central laboratory for testing.  Please refer to the central laboratory manual for 
additional information.
11
DATA REPORTING/REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 (Adverse 
Events:  List and Reporting Requirements).
11.1 Source Documents and Case Report Completion
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
11.2 Data Quality Assurance
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11.3 Data Safety Monitoring
An independent data monitoring committee (DMC) will review and monitor toxicity and accrual data 
from the study on an ongoing basis.  The safety and interim efficacy of the study will be monitored by 
the DMC as outlined in a separate DMC charter.  An early safety evaluation will occur by the DMC 
following the enrollment of 3 - 6 subjects with at least 7 days of follow up and will continue in regular 
frequency approximately every 3 - 4 weeks until all subjects reach Day 28 or prematurely discontinue 
from study.
 
 
 
 


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12
STATISTICAL CONSIDERATIONS
12.1 Study Design and Endpoints
A statistical analysis plan (SAP) will be prepared and finalized prior to interim database lock.  This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.  Any deviations in the planned analysis as stated in the 
protocol will be delineated in the SAP.  Any deviations from the SAP will be reported in the clinical study 
report (CSR).  
Subjects will be randomized 1:1 to ibrutinib + supportive care vs.  placebo + supportive care, stratified 
by prescription for remdesivir.  As no standard for treatment of COVID-19 in pulmonary distress 
currently exists and new treatment options are urgently needed, this study will be exploratory in nature.
Primary Endpoint:  The primary endpoint will be the proportion of subjects alive and without respiratory 
failure at Study Day 28.
Secondary endpoints will include:

Change in the World Health Organization (WHO)-8 point ordinal scale from baseline between 
the experimental and control arms at Study Day 14 (Figure 6)

Median reduction in days spent on supplemental oxygen, with time on supplemental oxygen 
imputed to the maximum number of days on study drug (28) for all points following the death of 
a subject,

All-cause mortality at Study Days (7, 14, 21, and 28),

Proportion of subjects experiencing respiratory failure or death on Study Days (7, 14, 21, and 28)

Mechanical ventilation-free survival

Days on mechanical ventilation

Duration of hospitalization

Time to discharge

PaO2:FiO2 and/or oxygenation index, and

Safety and tolerability of ibrutinib as an adjuvant therapy to standard of care as assessed by 
treatment emergent adverse events (TEAEs), serious adverse events (SAEs), related AEs, TEAEs 
by grade, and abnormal laboratory findings.  Type, frequency, seriousness and relatedness of 
TEAEs will be analyzed according to the Medical Dictionary for Regulatory Activities (MedDRA).  
Laboratory abnormalities will be analyzed according to NCI CTCAE v5.0.
 
 
 


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Respiratory failure is defined by clinical diagnosis of respiratory failure and initiation of 1 of the 
following therapies:
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),
4.
Noninvasive positive pressure ventilation,
5.
Clinical diagnosis of respiratory failure with initiation of none of these measures only when 
clinical decision-making driven is driven solely by resource limitation (these events must be 
formally collected as data and flagged, for purposes of sensitivity analyses).
These study endpoints are in alignment with other ongoing studies in COVID-19; in particular, many 
studies use a similar ordinal scale assessment (NCT04292899; NCT04315298) as in the first secondary 
endpoint.
Figure 6.
Ordinal Scale for Clinical Improvement
ECMO = extracorporeal membrane oxygenation; RRT = renal replacement therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2 Sample Size Justification
Forty-six subjects will be randomized at an allocation of 1:1 to supportive care plus placebo or 
supportive care plus ibrutinib, stratified by prescription for remdesivir.  Baseline is assessed at the time 
of randomization, which based on the acute nature of study subjects is likely to be on the same day as 
initiation of study drug.  The proportion of subjects alive, without respiratory failure at 28 days of 
control arm is assumed to be 60% and the experimental arm is assumed to 90%.  Forty-six subjects total 
are required to achieve ≥80% power with 1-sided alpha = 0.1.  Replacement may be implemented for 
subjects that withdraw consent or are lost to follow up prior to Day 28.
12.3 Interim Analysis
One interim analysis using the gamma family spending function with a conservative boundary 
(parameter = –4) for futility (non-binding) will be conducted after 18 subjects are randomized and 
treated/followed for at least 28 days.  The DMC will review and evaluate efficacy and safety results 
while the sponsor remains blinded.
In addition, an analysis to estimate the overall proportion and number of subjects alive and without 
respiratory failure will be conducted in a blinded fashion when approximately 70% of the planned 
subjects in the FAS population (i.e., 32 subjects) have completed the Day 28 Visit or died.  The objective 
of this analysis to re-estimate sample size if needed.  If the final sample size is increased > 20% from the 
initial sample size (i.e., final sample size > 56 subjects), then an additional interim analysis may be 
conducted after 46 subjects have completed the Day 28 visit or discontinued from the study.  The Lan-
Demets alpha spending function based on O'Brien-Fleming boundary for superiority assessment and the 
gamma family spending function with a conservative boundary (parameter = –4) for non-binding futility 
assessment will be utilized at this interim analysis.  The DMC will review and evaluate efficacy and safety 
results while the sponsor remains blinded.
12.4 Efficacy Analysis
All efficacy analyses will be performed using the Full Analysis Set (FAS) which will include all subjects 
who are randomized and received at least one dose of study drug. Subjects will be grouped according to
treatment as randomized. In addition, a supplemental analysis of the primary and secondary efficacy 
endpoints will be performed for the modified FAS which will include all randomized and dosed subjects 
who have assessment through Day 28 or die before Day 28.  All details of analysis methods will be 
described in the statistical analysis plan.
The primary analysis will occur after all subjects have completed the Day 28 Visit or prematurely 
discontinued study.  The data for the primary analysis will be locked after data cleaning.  Data after the 
Day 28 Visit will be added to a new version of the database which will be cleaned and locked at the end 
of the study.  The sponsor will be unblinded at the primary analysis.
 
 
 


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12.5 Safety Analysis
Safety data will be generated from the Safety Population which consists of all subjects receiving at least 
1 dose of study drug (ibrutinib or placebo).  Subjects are assigned to a treatment group based on the 
treatment actually received, regardless of the treatment randomized.
Detailed tabulations of safety data (AEs, clinical laboratory tests and other safety endpoints) will be 
summarized by treatment arm for the safety population.
12.6 Sample Size, Accrual Rate and Study Duration
Subjects will be randomized 1:1 in a placebo-controlled, double blinded study to receive either 
supportive care and placebo or supportive care and ibrutinib for up to 28 days.  For subjects randomized 
to receive ibrutinib, the dose of ibrutinib will be 420 mg a day.  Approximately 46 subjects will be 
enrolled in this study.  Subjects that withdraw consent or are lost to follow up from the study before 
Day 28 may be replaced.  Enrollment is anticipated to be complete within 3 - 6 months of activation.  
The study is expected to be complete within 6 - 9 months after activation.
13
ETHICS
13.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
13.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  
13.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
 
 
 


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14
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
15
PUBLICATION PLAN
Time to presentation or publication is expected within 6 - 9 months after study activation.  Any formal 
presentation or publication of data from this trial may be published after review and comment by 
Pharmacyclics LLC/AbbVie Inc prior to any outside submission.  Pharmacyclics LLC/AbbVie Inc must
receive copies of any intended communication in advance of publication (3 days for presentational 
materials, abstracts, manuscripts).  These requirements acknowledge Pharmacyclics LLC/AbbVie's 
responsibility to provide peer input regarding the scientific content and conclusions of such publications 
or presentations.  The principal investigator shall have the final authority to determine the scope and 
content of resulting publications, provided such authority shall be exercised with reasonable regard for 
proprietary interests and not permit disclosure of confidential or proprietary information that belongs to 
Pharmacyclics LLC/AbbVie Inc.
16
REFERENCES
1.
Guan WJ, et al.  Clinical characteristics of coronavirus disease 2019 in China.  NEJM 2020; Feb 
28.  doi:  10.1056/NEJMoa2002032.
2.
Wang D, Hu B, Hu C, et al.  Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel 
Coronavirus-Infected Pneumonia in Wuhan, China.  JAMA. 2020;323:1061-69.
3.
Bhatraju PK, et al.  Covid-19 in critically ill patients in the Seattle region-case series.  NEJM 2020.  
DOI:  10.1056/NEJMoa2004500.
4.
Cao B, et al.  A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19.  NEJM 
2020.
5.
Wu C, et al.  Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in 
Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.  JAMA 2020; Published 
online March 13, 2020.  doi:10.1001/jamainternmed.2020.0994.
6.
Hoffman M, et al.  SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a 
Clinically Proven Protease Inhibitor.  Cell 2020.  Mar 4.  pii:  S0092-8674(20)30229-4.
7.
Fujino N, et al.  isolation of alveolar epithelial type II progenitor cells from adult human lungs.  
Lab Invest.  2010; 91:363-78.
8.
Pechkovsky D, et al.  CCR2 and CXCR3 chemokines are differentially expressed and regulated in 
human alveolar epithelial cells type II.  Resp.  Res.  2005;6:75.
9.
Wang J, et al.  Differentiated human alveolar type II cells secrete antiviral IL-29 in response to 
influenza A infection.  J Immunology. 2009;182:1296-304.
10. Thorley AJ, et al.  Innate immune responses to bacterial ligands in the peripheral human lung-
role of alveolar epithelial TLR expression and signaling.  PLOS ONE.  2011;6:e21827.
 
 
 


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STUDY M20-310 (PCYC-1150-IM)  |  Version 3.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
11. Chuquimia O, et al.  Alveolar epithelial cells are critical in protection of the respiratory tract by 
secretion of factors able to modulate the activity of pulmonary macrophages and directly 
control bacterial growth.  Infection and Immunity. 2013;81:381-89.
12. Werner JL, Steele C.  Innate receptors and cellular defense against pulmonary infections.  J. 
Immunology.  193:3842-50.
13. He L, et al.  Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected 
ACE2+ cells in SARS patients:  relation to acute lung injury and pathogenesis of SARS.  J.  
Pathology. 2006;210:288-97.
14. Jiang Y, et al.  Characterization of cytokine/chemokine profiles of severe acute respiratory 
syndrome.  Am J Respir Care Med. 2005;171:850-57.
15. Ley K.  M1 means Kill; M2 means Heal.  J. Immunology. 2017;199:2191-93.
16. Atri C, et al.  Role of human macrophage polarization in inflammation during infectious diseases.  
Int J Mol.  Sci.  2018;19:1801.
17. Chan JF, et al.  Genomic characterization of the 2019 novel human-pathogenic coronavirus 
isolated from a patient with atypical pneumonia after visiting Wuhan.  Emerg Microbes Infect.  
2020;9:221-36.
18. Heurich A, et al.  TMPSSR2 and ADAM17 cleave ACE2 differentially and only proteolysis by 
TMPSSR2 augments entry driven by the severe acute respiratory syndrome coronavirus spike 
protein.  J Virology. 2014;88:1293-307.
19. Huang C, et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, 
China.  Lancet. 2020;395:565-74.
20. Jeffries CA, et al.  Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding 
protein that participates in nuclear factor kappaB activation by Toll-like receptor 4.  J Biol.  
Chem.  2003;278:26258-64.
21. Yang G, et al.  A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by 
activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.  Blood. 
2013;122:1222-32.
22. Yang G, et al.  HCK is a survival determinant transactivated by mutated MYD88, and a direct 
target of ibrutinib.  Blood. 2016;127:3237-52.
23. Wang Y, Liu L.  The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus 
Functions as a Novel Cytosolic Pathogen-Associated Molecular Pattern To Promote Beta 
Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism.  mBio.  
2016;7(1):e01872-15.  doi:  10.1128/mBio.01872-15.
24. Chen JG, et al.  BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-
mutated cells by a paracrine mechanism.  Blood. 2018;131:2047-59.
25. Ernst M, et al. Constitutive activation of the SRC family kinase HCK results in spontaneous 
pulmonary inflammation and an enhanced innate immune response.  J Exp Med.  
2002;196:589-604.
 
 
 


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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
26. Tian S, et al.  Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) 
Pneumonia in Two Patients With Lung Cancer.  J Thoracic Oncology. 2020;Feb 28.  pii:  S1556-
0864(20)30132-5.
27. Yao XH, et al.  A pathological report of three COVID-19 cases by minimally invasive autopsies.  
Zhonghua Bing Li Xue Za Zhi.  2020 Mar 15;49(0):E009.
28. Available from:  https://lincs.hms.harvard.edu/db/datasets/20222/results?page=1
29. Byrd JC, et al.  Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.  N Engl J 
Med. 2013;369:32-42.
30. Niemann CU, et al.  Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–
Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II 
Study.  Clin Cancer Res.  2015;22:1572-82.
31. Vos JM, et al. CXCL13 levels are elevated in patients with Waldenström macroglobulinemia, and 
are predictive of major response to ibrutinib.  Haematologica. 2017;102:e455.
32. Miklos D, et al.  Ibrutinib for chronic graft-versus-host disease after failure of prior therapy.  
Blood. 2017;130:2243-50.
33. Greil R, et al.  Ibrutinib decreases obinutuzumab induced secretion of cytokines associated with 
infusion related reactions in patients with CLL:  Analysis from the ILLUMINATE study.  Proc.  
ICML 2019 (Hematological Oncology 37(2):210-12.
34. Florence JM, et al.  Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza 
induced acute lung injury.  Am J Physiol.  Lung Cell Mol.  Physiol.  2018;315:L52-58.
35. Treon S, Castillo J, Skarbink A, et al.  The BTK-inhibitor ibrutinib may protect against pulmonary 
injury in COVID-19 infected patients.  Blood 2020:  e-pub ahead of print 2020/01/17; doi:  
https://doi.org/10.1182/blood.2020006288.
36. Li G, Chen X, Xu A.  Profile of specific antibodies to the SARS-Associated coronavirus.  N Engl J
Med.  2003;349(5):508-9.
 
 
 


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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ACE2+
Alveolar Type II
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BCRP
breast cancer resistance protein
BTK
Bruton's Tyrosine Kinase
cGVHD
chronic graft versus host disease
CLL
chronic lymphocytic leukemia
COVID-19
Coronavirus disease 2019
CrCl
creatinine clearance
CRP
c-reactive protein
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DMC
Data Monitoring Committee
eCRF
electronic case report form
EDC 
electronic data capture
EKG
electrocardiogram
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
HCK
hematopoietic cell kinase
HCQ
hydroxychloroquine
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL
interleukin
 
 
 


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ILD
interstitial lung disease
IMP
Investigational Medicinal Product
IP10/CXCL10
interferon-inducible protein 10
IRB
Institutional Review Board
LPS
lipopolysaccharide
MCL
mantle cell lymphoma
MCP-1
monocyte chemoattractant protein-1
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
MZL
marginal zone lymphoma
NCI
National Cancer Institute
NGT
nasogastric tube
PBS
phosphate-buffered saline
PCR
polymerase chain reaction
P-gp
P-glycoprotein
RT
reverse transcriptase
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus-2
SLL
small lymphocytic leukemia
SUSAR
suspected unexpected serious adverse reaction
TA MD
Therapeutic Area Medical Director
TLR
Toll-like receptors
TNF-a
tumor necrosis factor alpha
ULN
upper limit of normal
US
United States
WHO
World Health Organization
WM
Waldenström's macroglobulinemia
 
 
 


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-310 (PCYC-1150-IM):  ibrutiNib in SARS CoV-2 induced Pulmonary Injury and Respiratory 
failure (iNSPIRE)
Protocol Date:  06 July 2020
Clinical research studies sponsored by AbbVie are subject to the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 
 
 


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APPENDIX C. INHIBITORS AND INDUCERS OF CYP3A
NOTE:  Itraconazole and ketoconazole can be replaced with voriconazole for study subjects.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 




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APPENDIX E. CHILD-PUGH SCORE FOR SUBJECTS WITH LIVER 
IMPAIRMENT
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
< 34 (< 2)
34 - 50 (2 - 3)
> 50 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 - 35 (2.8 - 3.5)
< 28 (< 2.8)
PT/INR
< 1.7
1.71 - 2.30
> 2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I - II (or suppressed 
with medication)
Grade III - IV 
(or refractory)
INR = international normalized ratio; PT = prothrombin time
Points
Class
5 - 6
A
7 - 9
B
10 - 15
C
Source: 
1.
Child CG, Turcotte JG.  Surgery and portal hypertension.  In Child CG.  The liver and portal 
hypertension.  Philadelphia:Saunders.  1964;50-64.
2.
Pugh RN, Murray-Lyon IM, Dawson L, et al.  Transection of the oesophagus for bleeding 
oesophageal varices.  The British journal of surgery. 1973;60:646-9.
 
 
 
 


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APPENDIX F. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 2.0
03 May 2020
Version 1.0
22 April 2020
The purpose of this Version is to make the following updates:

Increased number of potential study sites
Rationale:  To ensure that the study can be fully enrolled in a timely manner.

Revised eligibility criteria to allow subjects to be on oxygen therapy for up to 5 days, removed 
the 6 L limit on oxygen therapy, and clarified restrictions on concurrent malignancy.
Rationale:  To reduce burden around timing of enrollment to allow more subjects access to 
therapy.

Removed recommendation for subjects to avoid corticosteroid use.
Rationale: Based on recent publications and updates to standard of care for the treatment of 
COVID-19.

Adjusted resolution criteria for bleeding events
Rationale: Many low-grade bleeding events (e.g., petechiae, echymoses) are not expected to 
completely resolve immediately and pose little risk to subjects.

Revisions to ibrutinib stability description.
Rationale: Correction of error.

Updated details regarding the planned and potential interim analyses.
Rationale:  To allow for a potential additional interim analysis to be conducted in case of a 
relatively large increase in the final sample size.  A group sequential design is specified to 
provide strong control of the type 1 error rate at this potential analysis.

Updated drug interaction guidance for compounds that may be used to treat COVID-19.
Rationale: To align with evolving treatment standards for COVID-19.

Made minor clarifications to the study calendar.
Rationale:  To address questions from study sites.
In addition, minor clerical errors were corrected and edits for consistency within the document were 
made.
 
 
 

SAP_001.pdf: 
Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
1
Statistical Analysis Plan for Study M20-310 
(PCYC-1150-IM)
ibrutiNib in SARS CoV-2 induced Pulmonary Injury 
and Respiratory failure (iNSPIRE)
Date:  20 April 2021
Version 3.0
NCT04375397


Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
2
Table of Contents
1.0
Introduction .............................................................................4
2.0
Study Design and Objectives..................................................4
2.1
Objectives and Hypotheses........................................................................4
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................6
2.4
Sample Size Determination........................................................................6
3.0
Endpoints..................................................................................7
3.1
Primary Endpoint(s)...................................................................................7
3.2
Secondary Endpoint(s)...............................................................................8
3.3
Other Efficacy Endpoint(s)........................................................................8
3.4
Safety Endpoint(s) .....................................................................................8
3.5
Additional Endpoint(s)...............................................................................9
4.0
Analysis Populations ...............................................................9
5.0
Subject Disposition................................................................10
6.0
Study Drug Duration, Compliance and Dose 
Intensity..................................................................................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................11
7.1
Demographics and Baseline Characteristics............................................11
7.2
Medical History .......................................................................................13
7.3
Prior and Concomitant Medications ........................................................13
8.0
Efficacy Analyses...................................................................13
8.1
General Considerations............................................................................13
8.2
Handling of Missing Data........................................................................14
8.3
Primary Efficacy Endpoint and Analyses ................................................17
8.3.1
Primary Efficacy Endpoint ......................................................................17
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint ................18
8.3.3
Primary Efficacy Analysis .......................................................................18
8.3.4
Additional Analyses of the Primary Efficacy Endpoint...........................18
8.4
Secondary Efficacy Analyses...................................................................19
8.5
Efficacy Subgroup Analyses....................................................................23


Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
3
9.0
Safety Analyses ......................................................................24
9.1
General Considerations............................................................................24
9.2
Adverse Events ........................................................................................24
9.2.1
Treatment-Emergent Adverse Events ......................................................24
9.2.2
Adverse Event Overview .........................................................................25
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................25
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation or Dose Reduction................................................26
9.2.5
Other Safety Observations .......................................................................26
9.3
Analysis of Laboratory Data....................................................................26
9.4
Analysis of Vital Signs ............................................................................28
9.5
Other Safety Analyses..............................................................................28
10.0
Interim Analyses....................................................................29
10.1
Data Monitoring Committee....................................................................31
11.0
Overall Type-I Error Control ..............................................32
12.0
Version History......................................................................33
13.0
References...............................................................................33
List of Tables
Table 1.
SAP Version History Summary...............................................................33
List of Figures
Figure 1.
Study Schematic.........................................................................................5
List of Appendices
Appendix A.
Definitions of Other Safety Observations................................................35
Appendix B.
Definitions of Toxicity Grades 1, 2, 3 and 4 for Laboratory Values .......36
Appendix C.
Ordinal Scale for Clinical Improvement..................................................37


Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
4
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Ibrutinib 
Study M20-310 titled "ibrutiNib in SARS CoV-2 induced Pulmonary Injury and 
Respiratory failure (iNSPIRE)."
Study M20-310 examines the efficacy, safety, and tolerability of ibrutinib as an adjuvant 
therapy to supportive care in hospitalized subjects who presented with coronavirus 
disease 2019 (COVID-19) related pulmonary distress requiring supplemental oxygen.  
The exploratory analyses of inflammatory and chemo-attractant cytokines, IgM and IgG 
antibody titers to SARS-CoV-2 will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The primary objective of this study will be:  
●
To evaluate the proportion of subjects alive and without respiratory failure 
through Day 28 in hospitalized subjects who present with COVID-19 related 
pulmonary distress requiring supplemental oxygen.
The secondary objectives of this study will be:
●
To determine if the addition of ibrutinib to supportive care reduces necessity 
for hospitalization, length of need for supplemental oxygen, or mechanical 
ventilation in hospitalized subjects who present with COVID-19 related 
pulmonary distress requiring supplemental oxygen.


Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
5
●
To assess the safety and tolerability of ibrutinib as an adjuvant therapy to 
supportive care in hospitalized subjects who present with COVID-19 related 
pulmonary distress requiring supplemental oxygen.
2.2
Study Design Overview
M20-310 is a multi-center, phase 2, double-blind, placebo-controlled study where 
approximately 46 subjects will be enrolled and randomized with 1:1 ratio to receive either 
supportive care and placebo or supportive care and ibrutinib for up to 28 days, with 
possible replacement for subjects who withdraw consent or are lost to follow up before 
Day 28.  All subjects will be followed to Day 58 with diary and telehealth visits permitted 
after discharge from hospital.  
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
*
Treatment may be stopped at the discretion of the treating physician after 14 days if the patient is clinically stable, 
with negative COVID-19 viral nasopharyngeal swab by RT-PCR and has been off supplemental oxygen for 
> 48 hours.


Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
6
2.3
Treatment Assignment and Blinding
Subjects meeting eligibility criteria will be randomized to ibrutinib + supportive care vs. 
placebo + supportive care in a 1:1 ratio.  Randomization will be stratified by prescription 
for remdesivir at baseline.
All subjects will be assigned a unique identification number at the initial screening visit.  
For subjects who rescreen, they should retain the same identification number at the initial 
screening visit. 
An unblinded AbbVie Central Randomization Person (ACRP) will perform the role of the 
traditional IRT system by collaborating with the unblinded pharmacists at sites to assign a 
unique randomization number and the associated treatment (ibrutinib or placebo for 
ibrutinib) to subjects at baseline based on the computer generated randomization 
schedules generated by the statistics department at AbbVie.  Subjects that withdraw 
consent or are lost to follow up from the study before Day 28 may be replaced.  All 
randomized subjects who received at least 1 dose of study drug will be included in the 
Full Analysis Set.
The investigator, study site personnel (other than the unblinded pharmacist) and the 
subjects will remain blinded to each subject's treatment throughout the study.  The 
sponsor will remain blinded until the primary analysis, i.e., after all subjects have 
completed the Day 28 Visit or prematurely discontinue the study.
Should a subject withdraw consent during study treatment or is lost to follow up during 
study treatment, the site will notify the ACRP immediately to allow for possible 
replacement.
2.4
Sample Size Determination
Forty-six subjects will be randomized at an allocation of 1:1 to supportive care or 
supportive care plus ibrutinib, stratified by prescription for remdesivir.  The power 
calculations are based on the proportion of subjects alive, without respiratory failure at 


Ibrutinib
M20-310 – Statistical Analysis Plan
Version 3.0 – 20 April 2021
7
28 days in the control arm and in the experimental arm.  This sample size will provide at 
least 80% power to detect the difference between a placebo response rate of 60% and an 
active response rate of 90% at 1-sided significance level of 0.1, based on a chi-square test.  
The response rate in the control arm is based on the previously reported clinical outcomes 
among patients with COVID-19 during hospitalization.1  No dropout rate is accounted for 
since subjects that withdraw consent or are lost to follow up from the study before Day 28 
may be replaced.  
A blinded sample size re-estimation (BSSR) will be conducted when approximately 70% 
of the planned subjects (i.e., 32 subjects) have completed the Day 28 visit to assess if the 
sample size estimation assumption holds.  If the overall observed response rate is closer to 
0.5, sample size increase may be needed.  Detailed methodology for the BSSR is 
described in Section 11.0.  
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint will be the proportion of subjects alive and without respiratory 
failure through Study Day 28, where respiratory failure is defined as a clinical diagnosis 
of respiratory failure AND initiation of one of the following therapies:
●
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),
●
non-invasive positive pressure ventilation,
●
clinical diagnosis of respiratory failure with initiation of none of these measures 
only when clinical decision-making is driven solely by resource limitation.


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3.2
Secondary Endpoint(s)
The secondary endpoints include the following:
●
Change in the World Health Organization (WHO)-8 point ordinal scale from 
baseline between the experimental and control arms at Study Day 14 
●
Median reduction in days spent on supplemental oxygen
●
All-cause mortality by Study Days 7, 14, 21, and 28
●
Proportion of subjects experiencing respiratory failure or death by Study 
Days 7, 14, 21, and 28
●
Mechanical ventilation-free survival
●
Days on mechanical ventilation
●
Duration of hospitalization
●
Time to discharge
●
PaO2:FiO2 and/or oxygenation index
3.3
Other Efficacy Endpoint(s)
There are no additional efficacy endpoints for this study. 
3.4
Safety Endpoint(s)
To assess the safety and tolerability of ibrutinib as an adjuvant therapy to standard of care, 
the following endpoints will be included in the safety analyses: 
●
Treatment-emergent adverse events 
●
Serious adverse events 
●
Adverse events leading to study drug discontinuation
●
Other Safety Observations as defined in Section 9.2.5
●
Clinical laboratory tests
●
12-lead electrocardiogram (ECG)


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3.5
Additional Endpoint(s)
The exploratory analyses of inflammatory and chemo-attractant cytokines, IgM and IgG 
antibody titers to SARS-CoV-2 will not be covered in this SAP.
4.0
Analysis Populations
The following population sets will be used for the analyses.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose 
of study drug.  The FAS will be used for all baseline demographics and disease 
characteristics and efficacy analyses.  Subjects will be included in the analysis according 
to the treatment groups to which they are randomized.
Modified FAS
The modified FAS includes all randomized and dosed subjects who have assessment of 
the primary endpoint through Day 28 or die before Day 28.  A supplementary analysis of 
the primary endpoint as well as the first 3 secondary endpoints (i.e., change in WHO-8 
point ordinal scale from baseline, median reduction in days spent on supplemental 
oxygen, and all-cause mortality) will be performed on the modified FAS population.
Safety Population
Safety analyses will be performed using the Safety Population which consists of all 
subjects who received at least 1 dose of study drug.  Subjects will be included in the 
analysis according to the study drug that they actually received.  If a subject takes more 
than 1 treatment, the subject will be grouped in the treatment group for which they 
received the most doses.  Note for the interim analysis, subjects will be grouped according 
to treatment as randomized since treatment information will not be available until study 
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5.0
Subject Disposition
The total number of subjects who were screened, randomized, and treated will be 
summarized.  Reasons for exclusion, including screen failure, will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects randomized in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who prematurely discontinued study drug;
●
Subjects who completed protocol-specified treatment of 28 days;
●
Subjects who prematurely discontinued the study;
●
Subjects who completed the study; 
●
Subjects in each analysis population.
The number and percentage of subjects who discontinued study drug by reason (all 
reasons and primary reason, including discontinuation due to being clinically stable and 
off of supplemental oxygen for > 48 hours after Day 14) will be summarized overall and 
by treatment group for the FAS.  Similar summaries will be provided for discontinuations 
from the study.
6.0
Study Drug Duration, Compliance and Dose 
Intensity
For the Safety Population, duration of treatment will be summarized for each treatment 
group.  Duration of treatment is defined for each subject as last dose date minus first dose 
date + 1 day.  Duration of treatment will be summarized using the number of subjects 
treated, mean, standard deviation, median, minimum and maximum.  In addition, the 
number and percentage of subjects in each treatment duration interval (≤ 14 days, 
> 14 days) will be summarized.
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●
Subjects with reported study drug temporary interruptions by reason as 
captured on the eCRF;
●
Subjects with reported study drug dose reduction by reason as captured on the 
eCRF.
Treatment compliance is defined as the number of tablets actually taken divided by the 
number of tablets that should have been taken.  
Compliance will be calculated for each subject and summarized by treatment group with 
the number of subjects treated, mean, median, SD, minimum, and maximum.  Percent 
compliance will be summarized.
Dose intensity is defined for each subject as average daily dose/intended daily dose (i.e., 
420 mg), where the average daily dose is defined as the total cumulative dose received 
(mg) divided by duration of treatment in days.  Dose intensity will be summarized using 
the number of subjects treated, mean, standard deviation, median, minimum and 
maximum.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS overall and by treatment group.  
Categorical variables will be summarized with the number and percentage of subjects; 
percentages will be calculated based on the number of non-missing observations.  
Continuous variables will be summarized with descriptive statistics (number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum).
7.1
Demographics and Baseline Characteristics
The following demographic and characteristics parameters will be summarized. 


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Subject Demographics
●
Sex (male, female)
●
Age (years)
●
Race (White, Black, American Indian/Alaska Native, Native Hawaiian or Other 
Pacific Islander, Asian, Multi, Other)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Body weight (kg) at baseline
●
Height (cm) at baseline
●
BMI (kg/m2) at baseline
Disease Characteristics
●
Stratification factor of prescription for remdesivir (yes, no)
●
WHO-8 ordinal scale at baseline (4, 5)
●
WHO-8 ordinal scale at screening (4)
●
For cirrhotic subjects only: Child-Pugh classification at baseline (not done, A, 
B)
●
SARS-CoV-2 RNA detection at baseline (negative, positive, indeterminate)
●
PaO2:FiO2 at baseline (continuous; <100 mmHg, ≥100 mmHg and <200
mmHg, ≥200 mmHg and <300 mmHg, ≥300 mmHg)
●
Supplemental oxygen use at baseline (yes, no) 
●
For subjects on supplemental oxygen only: interface of supplemental oxygen, 
fraction of oxygen and flow rate (L/min)
●
Non-invasive positive pressure ventilation use at baseline (yes, no)
●
COVID-19 symptom onset duration prior to baseline (continuous; ≤ median, 
> median; ≤ 10 days, > 10 days)
●
COVID-19 diagnosis duration prior to baseline
●
Tobacco user (current, former, never, unknown)
●
Alcohol status (current, former, never, unknown)


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7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug, 
or any medication that started on or after the date of the first dose of study drug but not 
after the date of the last dose of study drug.  The number and percentage of subjects 
taking medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted for the FAS unless otherwise specified.  All 
efficacy tests will be 2-sided at an alpha level of 0.2.
The Primary Analysis will be performed after all ongoing subjects have completed the 
Day 28 visit or have prematurely discontinued from study and the database has been 
locked.  


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"Baseline" refers to the last non-missing observation on or before the first day of study 
drug administration.
8.2
Handling of Missing Data
Missing data could occur due to various reasons, including missed assessments, early 
dropout from the study, etc. In general, if a subject takes a BTK inhibitor besides the 
study drug, then all data after the start of that BTK inhibitor will be set to missing.  
Handling of missing data will be described for the different types of efficacy endpoints as 
follows.
Primary Endpoint of Being Alive and Without Respiratory Failure
If a subject is missing daily records on the Supplemental Oxygen or Invasive Ventilation -
Mechanical/Cardiopulmonary Support eCRFs before Day 28, but has an WHO-8 point 
ordinal score recorded to fill in those days then it will be used to record respiratory failure 
or not (i.e., an ordinal score of 4 or below indicates no respiratory failure or death on the 
same day). 
After the above, subjects with no record of death or respiratory failure and one of the 
following events will be analyzed as follows:
●
If a subject has missing responses on days after being discharged from hospital 
prior to Day 28 as indicated on the Hospitalization eCRF without any 
re-hospitalization record, the subject will be categorized as a success. 
●
If a subject has missing responses on days after completing study drug with a 
reason of "clinically stable and off of supplemental oxygen for > 48 hours after 
Day 14" as indicated on the study drug completion eCRF without any 
re-hospitalization record, the subject will be categorized as a success.
●
If a subject takes a BTK inhibitor besides the study drug (and does not meet 
either condition in the previous 2 bullets), then all data after the start of that 
BTK inhibitor will be set to missing.


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If a subject has missing responses of death or respiratory failure for ≤ 2 consecutive days 
and is a success for both the preceding response and succeeding response, the missing 
responses on the day(s) will be imputed as a success. 
If a subject has missing responses for > 2 successive days or monotone missing data 
before Day 28 without WHO-8 point ordinal score to fill in those days, the missing 
responses will be handled with multiple imputation method with fully conditional 
specification (FCS) approach to generate 30 datasets using the logistic regression method.  
The imputation model will include treatment, stratification factor of prescription for 
remdesivir, and duration of symptoms before Day 1 (continuous).  The random seed for 
PROC MI will be the SAS numerical form of the first subject randomization date in the 
study.  In case of non-convergence, the random seed will be updated by adding 100000 at 
each attempt until convergence of model occurs.  If the model will not converge due to 
data sparsity issue, then stratification factor will be removed from the imputation model.  
Using the Miettinen and Nurminen (MN) method2 for the difference in the response rates 
between treatment groups adjusting for the stratification factor of prescription for 
remdesivir, the imputed endpoints will be analyzed using each of the 30 datasets.  PROC 
MIANALYZE will be used to generate the final inferences of the risk difference between 
treatment groups. 
WHO Ordinal Scale
The secondary endpoint of change in the WHO-8 point ordinal scale from baseline 
between treatment groups at Day 14 will be determined based on subjects' clinical status 
as indicated on the Ordinal Scale for Clinical Improvement eCRF at both Day 1 and the 
Day 14 visit.  Subjects without records of ordinal scale on Day 1 will be excluded from 
analysis. 
If a subject takes a BTK inhibitor besides the study drug, then all data after the start of 
that BTK inhibitor will be set to missing.


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Subjects with no record of ordinal scale at the Day 14 visit due to the following events 
and without oxygen therapy recorded to fill in the days will be analyzed as follows:
●
If a subject has been discharged from hospital without record of re-
hospitalization or death before the Day 14 visit, then the missing ordinal score 
for the Day 14 visit will be imputed to the minimum of 2 or their last non-
missing score before the Day 14 visit window.
●
If a subject died before reaching the Day 14 visit, then the missing ordinal score 
for the Day 14 visit will be imputed as 8.
Similar imputation will be performed for subjects with no records of ordinal scale at the 
Day 7 visit and Day 28 visit.
Days on Supplemental Oxygen, Mechanical Ventilation and of Hospitalization
For the analysis of the days spent on supplemental oxygen, days on mechanical 
ventilation, or duration of hospitalization, the number of days will be imputed to the 
maximum number of days on study drug (28) following the death of a subject or if data is 
missing (e.g., due to starting another BTK inhibitor during the time period).
If a subject prematurely discontinued from study without the date of the subject being off 
the supplemental oxygen then the subject's premature discontinuation date will be used for 
the duration calculation.  Similarly, if a subject prematurely discontinued from study 
without the date of the subject being off mechanical ventilation, or if a subject 
prematurely discontinued from study without a discharge date, then the subject's 
premature discontinuation date will be used for the duration calculation.
All-Cause Mortality
All deaths through Day 28 will count in all-cause mortality, even deaths after starting 
another BTK inhibitor.


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PaO2:FiO2 and oxygenation index
For continuous endpoints of PaO2:FiO2 or oxygenation index, missing data will be 
handled using a Mixed-Effect Model Repeated Measurement (MMRM) model.
●
The MMRM will be conducted using a mixed model including observed 
measurements at Study Days 7, 14, 21 and 28.  The mixed model includes the 
categorical fixed effects of treatment, visit and treatment-by-visit interaction, 
stratification factor for prescription of remdesivir, and the continuous fixed 
covariate of Baseline measurement.  An unstructured variance covariance 
matrix (UN) will be used.  If the model cannot converge, an appropriate 
covariance structure matrix (e.g., autoregressive (1) or compound symmetry) 
will be used.  The parameter estimations are based on the method of restrictive 
maximum likelihood (REML).  The fixed effects will be used to report 
model-based means at corresponding visits.
8.3
Primary Efficacy Endpoint and Analyses
8.3.1
Primary Efficacy Endpoint
The primary endpoint will be the proportion of subjects alive and without respiratory 
failure through Study Day 28, where respiratory failure is defined as a clinical diagnosis 
of respiratory failure AND initiation of one of the following therapies:
●
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),
●
non-invasive positive pressure ventilation,
●
clinical diagnosis of respiratory failure with initiation of none of these measures 
only when clinical decision-making is driven solely by resource limitation.


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For the primary efficacy endpoint, a subject will be defined as a failure if the subject died 
or had a clinical diagnosis of respiratory failure with initiation of any of the 5 therapies as 
indicated on the "Invasive ventilation – Mechanical/Cardiopulmonary support" and/or 
"Supplemental Oxygen" eCRFs on any single day from Day 1 through Day 28.  If the 
subject had no clinical diagnosis of respiratory failure (or had a clinical diagnosis of 
respiratory failure without fulfilling any of the bullets above) and was alive from Day 1 
through Day 28, the subject will be defined as a success.  The days of the clinical 
diagnosis and respiratory therapies need not coincide.
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint
The handling of missing data for the primary efficacy endpoint is described in Section 8.2.
8.3.3
Primary Efficacy Analysis
The number and percentage of subjects alive and without respiratory failure will be 
summarized by treatment arm, within each stratum and across strata.  The difference in 
response rates between the experimental arm and the control arm will be analyzed using 
the Miettinen–Nurminen (MN) method adjusting for the stratification factor of 
prescription for remdesivir.  MN test p-value for testing the rate difference = 0 at 
two-sided alpha = 0.2 and associated 80% and 95% MN confidence intervals for the rate 
difference will be reported. 
If there is a stratum for a treatment arm that has 0 subjects in any cell in the contingency 
table, the MN test will be performed by combining the strata or the Cochran-Mantel-
Haenszel (CMH) test will be used if needed.
8.3.4
Additional Analyses of the Primary Efficacy Endpoint
A supplementary analysis of the primary endpoint will be performed on the FAS 
population excluding subjects who developed respiratory failure before the first dose of 
study drug administration.


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In addition, a supplementary analysis of the primary endpoint as well as the first 3 
secondary endpoints (i.e., change in WHO-8 point ordinal scale from baseline, median 
reduction in days spent on supplemental oxygen, and all-cause mortality) will be 
performed on the modified FAS population.  A supplementary analysis of the primary 
endpoint will be performed on the modified FAS populations using the MN method as 
described above for the primary analysis.
8.4
Secondary Efficacy Analyses
The following secondary efficacy endpoints will be analyzed by treatment group within 
each stratum and across strata.
●
Change in the World Health Organization (WHO)-8 point ordinal scale from 
baseline between the experimental and control arms at Study Day 14 
●
Median reduction in days spent on supplemental oxygen
●
All-cause mortality by Study Days 7, 14, 21, and 28
●
Proportion of subjects experiencing respiratory failure or death by Study 
Days 7, 14, 21, and 28
●
Mechanical ventilation-free survival
●
Days on mechanical ventilation
●
Duration of hospitalization
●
Time to discharge
●
PaO2:FiO2 and/or oxygenation index
To evaluate the odds of clinical status improvement as determined by the WHO-8 point 
ordinal scale (Appendix C) from baseline at the Day 14 visit between treatment groups, a 
proportional odds model will be conducted using the ordinal score change from baseline 
to the Day 14 visit as the dependent variable, with treatment as the main effect, and the 
stratification factor of prescription for remdesivir and baseline ordinal score as covariates.  
If model does not converge, the baseline ordinal score and the stratification factor will be 
removed one at a time to check if the model will converge.  If quasi-complete separation 
issue occurs, then the separated ordinal levels may be combined as appropriate.  The point 


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estimate for the odds ratio between experimental arm and control arm and the associated 
80% and 95% Wald confidence intervals will be provided, as well as the p-value for 
testing the odds ratio = 1 from the Wald chi-square test.  A p-value from the score test for 
the proportionality assumption will also be provided.  If the score test fails to satisfy the 
proportionality assumption, then a multinomial logistic regression model may be used.
Similar analyses will be used to analyze the odds of clinical status improvement as 
determined by the WHO-8 point ordinal scale from baseline to Day 7 visit and Day 28 
visit between treatment groups.
In addition, proportional odds models will be used to analyze the WHO ordinal scale 
scores at Day 7 visit, Day 14 visit and Day 28 visit, respectively.
The stacked bar plots will be provided both for proportion of subjects in each score of the 
ordinal scale and each category of change from baseline in ordinal scale score by 
treatment arm at the Day 7 visit, Day 14 visit and Day 28 visit.
A supplementary analysis of the change of WHO-8 point ordinal scale from baseline at 
the Day 14 visit will be performed by using the WHO-8 point ordinal scale at screening as 
baseline for all subjects.
In addition, the number and proportion of subjects with at least 2 points of clinical 
improvement as indicated by the WHO ordinal scale from baseline to the Day 14 visit will 
be summarized by treatment arm, within each stratum and across strata.  The MN test 
p-value for testing the rate difference = 0 at two-sided alpha = 0.2 and associated 80% and 
95% MN CIs for the rate difference across strata will also be presented.  The 80% and 
95% MN CIs for the rate difference within each stratum will also be presented.  If there is 
a stratum for a treatment arm that has 0 subjects in any cell in the contingency table, the 
MN test will be performed by combining the strata or the CMH test will be used if 
needed.  A supplementary analysis of the proportion of subjects with at least 3 points of 
clinical improvement as indicated by the WHO ordinal scale from baseline to the Day 14 
visit will also be performed using the same procedures.


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For the analysis of median reduction in days spent on supplemental oxygen, mechanical 
ventilation or duration of hospitalization, the duration in number of days are defined as 
follows:
●
Days spent on supplemental oxygen = the date of the subject being off the 
supplemental oxygen – date of initiation of supplemental oxygen + 1 day. 
●
Days spent on mechanical ventilation = the date of the subject being off 
mechanical ventilation – date of initiation of mechanical ventilation + 1 day. 
●
Duration of hospitalization = the hospitalization discharge date –hospitalization 
admission date + 1 day. 
If a subject received more than 1 period of supplemental oxygen therapy during the study 
or switched from supplemental oxygen to a more intensive therapy, then the days spent on 
supplemental oxygen will be calculated as the sum of all the periods where the subject is 
on supplemental oxygen or a more intensive therapy through Day 28.  Similar calculation 
will be applied to the number of days on mechanical ventilation or duration of 
hospitalization through Day 28.  If the date of the first initiation of supplemental oxygen 
is before Baseline Day 1, then the days spent on supplemental oxygen will be calculated 
from Baseline Day 1 to the date of the subject being off the supplemental oxygen.  Similar 
calculation will be applied to duration of hospitalization through Day 28.
Descriptive statistics will be presented for days spent on supplemental oxygen through 
Day 28.  Median days spent on supplemental oxygen will be compared between treatment 
groups using Van Elteren's test3 with the stratification factor of prescription for 
remdesivir.  Similar analysis will be performed on the number of days on mechanical 
ventilation and duration in number of days of hospitalization.
Number and percentage of subjects with all-cause mortality by Day 7, Day 14, Day 21, 
and Day 28 will be summarized by treatment group, within each stratum and across strata.  
The MN test p-value for testing the rate difference = 0 at two-sided alpha = 0.2 and 
associated 80% and 95% MN CIs for the rate difference across strata will be reported, and 
80% and 95% MN CI for the rate difference within each stratum will be presented.  If 


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there is a stratum for a treatment arm that has 0 subjects in any cell in the contingency 
table, the MN test will be performed by combining the strata or CMH test will be used if 
needed.  Similar analysis will be performed on the number and percentage of subjects 
experiencing respiratory failure by Day 7, Day 14, Day 21, and Day 28.  
Mechanical ventilation-free survival is defined as the number of days from Baseline 
Day 1 to the date when a subject initiated mechanical ventilation or died, whichever 
occurred first, during the 28 days post baseline.  If the specified event does not occur by 
Day 28, subjects will be censored.  Specifically, a subject without any post-baseline 
assessment record will be censored at Baseline Day 1, a subject who prematurely 
discontinued from study without a record of death or start of mechanical ventilation will 
be censored at the earlier timepoint of the date of study discontinuation or Day 28, an on-
going subject in the study without a record of death or start of mechanical ventilation will 
be censored at the earlier timepoint of the date of the last evidence that the subject is not 
on mechanical ventilation or Day 28. 
Time to discharge from hospital is defined as the number of days from Baseline Day 1 to 
the date of the last evidence that a subject is last discharged from hospital, during the 28 
days post baseline.  If the specified event does not occur by Day 28, subjects will be 
censored.  Specifically, a subject without any postbaseline assessment record will be 
censored at Baseline Day 1, a subject who died will have time to discharge from hospital 
censored at Day 28, a subject who prematurely discontinued from study without a record 
of hospitalization discharge will be censored at the earlier timepoint of the date of study 
discontinuation or Day 28, an on-going subject in the study without a record of 
hospitalization discharge will be censored at the earlier timepoint of the date of the last 
evidence that the subject is hospitalized or Day 28.
For the analysis of mechanical ventilation-free survival and time to discharge from 
hospital, respectively, the distribution of time to event will be estimated by treatment 
group using Kaplan-Meier methodology and compared between the experimental arm and 
the control arm using the log-rank test stratified by prescription for remdesivir and p-value 
presented.  If there is no event in one of the strata, then the unstratified log-rank test will 


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be performed.  Median event onset time will be calculated and the 80% and 95% 
confidence intervals will be constructed separately by treatment group.
The restricted mean survival time for the mechanical ventilation-free survival and time to 
discharge, respectively, will be analyzed by comparing the areas under the survival 
functions between treatment groups.  Mean and standard error for the areas under the 
survival functions will be provided for each treatment group.  The p-value and the 80% 
and 95% confidence intervals from the between-group-comparison will also be provided.
For the analysis PaO2:FiO2 and oxygenation index, descriptive statistics (number of 
observations, mean, median, standard deviation, median, minimum and maximum) will be 
presented for the observed values of PaO2:FiO2 and oxygenation index at Study Days 7, 
14, 21 and 28, respectively. 
Mean difference in the PaO2:FiO2 values between treatment groups at Study Days 7, 14, 
21 and 28 will be compared using a MMRM model as described in Section 8.3.2.  Point 
estimates and 80% and 95% CIs for the mean difference in the PaO2:FiO2 between 
treatment groups will be provided.  A similar MMRM model will be performed to analyze 
the oxygenation index.
8.5
Efficacy Subgroup Analyses
Subgroup analysis of the primary efficacy endpoint will be performed by baseline 
age (18 to < 40 yr, 40 to < 65 yr, ≥65 yr), race, ethnicity, sex, COVID-19 symptom onset 
duration (≤ median, > median), baseline ordinal score (4, 5), and use of dexamethasone as 
well as other emerging treatment(s) for COVID-19, if applicable. 
The number and percentage of subjects alive and without respiratory failure and for the 
difference in response rates between treatment group will be presented for each subgroup.  
Any subgroup levels with fewer than 10 subjects will be combined with other levels as 
appropriate for analyses.  The 2-sided 80% and 95% confidence intervals of the difference 
in response rates using MN method will be produced if there are at least 10 subjects in 


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either of the treatment groups of the subgroup.  For any subgroup, if there are 0 subjects 
within a stratum in any treatment group, the unstratified MN method will be used.
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Population.  Safety summaries will be 
presented by treatment group.  For the safety analysis, subjects are assigned to a treatment 
group based on the treatment actually received, regardless of the treatment randomized.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest toxicity grade and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAEs) are defined as any AE with the onset date that is after 
the first dose of study drug and no more than 30 days after the last dose of study drug.  
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  All treatment-emergent AEs will be summarized overall, as well as 
by primary MedDRA SOC and Preferred Term.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.


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In addition, a listing of subjects experiencing AE related to study drug according to the 
investigator prior to first dose of study drug or post 30 days after the last dose of study 
drug will be provided.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to study drug according to the investigator
●
Any TEAE of grade 3 or higher
●
Any serious TEAE
●
Any TEAE leading to discontinuation of study drug
●
Any TEAE leading to study drug dose reduction
●
Any TEAE leading to death
●
AEs identified as Other Safety Observations as specified in Appendix A
●
All deaths
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum toxicity grade and SOC and PT; 
and by subject number and SOC and PT.  Specific adverse events will be counted once for 
each subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest toxicity grade and level 
of relationship to investigational product will be reported.
In addition, all TEAEs will be summarized by PT and sorted by decreasing frequency for 
the experimental arm.


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9.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation or Dose Reduction
SAEs (including deaths) and AEs leading to study drug discontinuation or dose reduction 
will be summarized by SOC and PT and in listing format.
9.2.5
Other Safety Observations
The following Other Safety Observations will be identified per Standardized MedDRA 
Queries (SMQs), SOC and/or PT search.  Detailed information about the search criteria 
are provided in Appendix A.
●
Hemorrhagic events and major hemorrhage 
●
Cytopenic AEs
●
Infections
●
Atrial fibrillation
●
Cardiac arrhythmia (including ventricular tachyarrhythmias)
●
Hepatic disorders
●
Interstitial lung disease
●
Hypertension 
●
Ischemic stroke
Number and percentage of subjects experiencing at least one treatment-emergent AE 
identified as Other Safety Observations will be summarized and presented by SOC and 
PT.  Tabular listings of Other Safety Observations also will be provided.
9.3
Analysis of Laboratory Data
Laboratory measurements of total bilirubin, AST, ALT, albumin, glucose, creatinine, 
sodium, potassium, calcium, CPK, GGT, alkaline phosphatase, hemoglobin, platelets, 
WBC, neutrophils, lymphocytes, and INR will be summarized. 
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 


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minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between treatment groups (experimental arm 
vs. control arm).
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
shift table from baseline to the minimum and maximum value during treatment will be 
created. Similar shift table(s) will be provided to summarize shifts from baseline to the 
final post-baseline value.
The number and percentage of subjects with a maximum of at least CTC Grade 3 during 
treatment for the laboratory parameters as defined in Appendix B will be summarized.  
The post-baseline value must be in a toxicity grade that is more extreme than the toxicity 
grade corresponding to the baseline value in order to be counted.  A listing of all relevant 
laboratory parameters will be provided for each subject who had an increase to Grade 3 or 
higher will be provided.
The following criteria will be used to assess for potential hepatotoxicity.
●
ALT > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
AST > 3 × ULN, > 5 × ULN, > 10 × ULN, > 20 × ULN
●
TBL > 1.5 x ULN, > 2 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN
●
ALT > 3 × ULN and TBL > 1.5 × ULN
●
ALT > 3 × ULN and TBL > 2 × ULN
●
Alkaline phosphatase > 1.5 × ULN


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The number and percentage of subjects with laboratory values meeting the above criteria 
during treatment will be summarized.  Listing of ALT, AST, total bilirubin, and alkaline 
phosphatase values will be provided for each subject who met one or more of the criteria 
defined above.
An Evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot of the maximum 
post-baseline ALT value (as a multiple of the ULN) vs. the maximum post-baseline total 
bilirubin value (as a multiple of the ULN) during treatment, not necessarily concurrent, 
will also be utilized to assess for potential hepatotoxicity.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, body 
temperature, respiratory rate and oxygen saturation will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  The change from baseline mean, standard error, and 95% 
confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups (experimental arm vs. control 
arm).
Potentially clinically significant vital sign abnormalities will be assessed by the 
investigators and reported as adverse events.
9.5
Other Safety Analyses 
The number and percentage of subjects in following types of mechanical ventilation at the 
Day 1, Day 7, Day 14, Day 21 and Day 28 visits will be summarized by treatment group.
●
endotracheal 
●
transtracheal


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ECG findings will be summarized by treatment group at baseline and the Day 7, Day 14, 
Day 21 and Day 28 visit.  Summaries will include n (%) of patients in the following 
categories:
●
Normal
●
Abnormal – Not Clinically Significant
●
Abnormal – Clinically Significant
●
Unable To Evaluate
●
Missing
10.0
Interim Analyses
An interim analysis will occur when 18 subjects have been randomized and 
treated/followed until availability of the primary endpoint.  A database snapshot will be 
performed for this analysis.  Efficacy assessment will be performed using the FAS and 
will include a futility analysis of the primary endpoint. 
The primary analysis for this study will take place after all subjects have completed the 
Day 28 visit or discontinue from study prior to Day 28, appropriate data cleaning has been 
performed and the database has been locked for analysis.
In order to ensure the sample size estimation assumption holds for the study, a blinded 
sample size re-estimation (BSSR) will be conducted when approximately 70% of the 
planned subjects (i.e., 32 subjects) have completed the Day 28 visit or have data available 
for the primary endpoint.  The objective of analysis is to re-estimate sample size increase 
if needed.  A study database snapshot will be performed for this analysis.  The BSSR 
analysis will be performed by the AbbVie study statistician on the blinded efficacy data.  
Only the overall response rate across the treatment groups is used in the BSSR.  
Therefore, the Type-I error will not be inflated, and no multiplicity adjustment is needed 
for the BSSR.


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Detailed Methodology for BSSR
With an initial sample size of   = 46 subjects, the study is powered at > 80% if the ratio 
of the response rate for the primary endpoint in the experimental arm to the control arm is 
1.5 with the overall response rate of 75% across arms.  
For a test of statistical superiority, assuming a ratio of  = 	
∗
∗
⁄
, and ∗is the overall 
proportion of successes across treatment groups, the sample size  is determined by:4
 =
[ 2∗(1 −∗) + ∗(1 −∗) + 	
∗(1 −	
∗)]
(	
∗−∗)
where  and  are the critical z-scores to control the Type-I and Type-II errors at  and 
, respectively.
In order to incorporate a cap on the sample size (i.e.,  = 2 ∗  = 92), the final 
recalculated sample size will be
 ! = min(max (  , ),  )
Based on the formula above, the final recalculated sample size will always be greater than 
or equal to the initial sample size of 46 evaluable subjects and less than or equal to the 
limit of 92 evaluable subjects. 
If the final sample size is increased <= 20% from  (i.e., final sample size <= 56 
subjects), then the primary analysis will occur after all subjects per the increased sample 
size have completed the Day 28 visit or discontinued from study prior to Day 28.  At that 
point, the Sponsor will be unblinded. 
If the final sample size is increased > 20% from  (i.e., final sample size > 56 subjects),
then an additional interim analysis will be performed when 46 subjects have completed 
the Day 28 or discontinued from the study prior to Day 28 where the study team will 
remain blinded and a DMC will be utilized to review efficacy results (also see 
Section 10.1 and Section 11.0). 


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Interim Database Lock
An interim lock will be performed for the primary analysis when all subjects have 
completed the Day 28 visit (including those who discontinue from study prior to Day 28).  
Data for the primary analysis will be locked after data cleaning.  Data after the Day 28 
visit will be added to a new version of the database which will be cleaned and locked at 
the end of the study.
If an interim analysis based on 46 subjects' available data for the primary endpoint is to be 
conducted, an interim database lock will be performed after appropriate data cleaning 
before this interim analysis will be conducted for DMC review.
10.1
Data Monitoring Committee  
An external data monitoring committee (DMC) composed of multiple clinicians and 
1 statistician who are independent of AbbVie and with relevant expertise in their field will 
review and monitor unblinded toxicity and accrual data from Study M20-310 on an 
ongoing basis.  The safety and interim efficacy of the study will be monitored by the 
DMC as outlined below.
An early safety evaluation will occur by the DMC following the enrollment of 
approximately 3-6 subjects with at least 7 days of treatment/follow up and will continue in 
regular frequency approximately every 3 – 4 weeks or when an additional 4-5 subjects 
have been enrolled (and have at least 7 days of follow-up) since the last DMC meeting, 
whichever is longer, (or ad-hoc as needed) during study drug treatment until all subjects 
reach Day 28 or prematurely discontinue from study.  
In addition, an interim efficacy assessment will be conducted for DMC review after 
18 subjects have been randomized and treated/followed until availability of the primary 
endpoint.  Efficacy assessment will be performed using the FAS and will include primary 
endpoint and all secondary efficacy endpoints, and a non-binding futility analysis of the 
primary endpoint (also see Section 11.0).


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An additional interim efficacy analysis may be conducted (see Section 10.0 for the 
triggering condition) for DMC review after 46 subjects have been randomized and 
treated/followed until availability of the primary endpoint.  Efficacy assessment will be 
performed using the FAS and will include primary endpoint and all secondary efficacy 
endpoints.  A superiority analysis and a futility analysis of the primary endpoint will also 
be conducted (also see Section 11.0).
The primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study and to monitor the efficacy profile of the accumulating data and 
provide recommendations to AbbVie on whether to continue, modify, or terminate the 
study.  A separate DMC charter describes the roles and responsibilities of the DMC 
members, frequency of data reviews, relevant data to be assessed, and general operations.
11.0
Overall Type-I Error Control
A group sequential design5 will be used to provide strong control of the type 1 error rate at 
one-sided alpha of 0.1 across the interim analysi(e)s and the primary analysis comparing 
the experimental arm to the control arm with respect to the primary endpoint.  
Specifically, for the first interim efficacy analysis conducted for DMC review based on 
18 subjects' availability data for the primary endpoint, a futility boundary using the 
gamma family spending function with a conservative boundary (gamma=-4) will be used 
for futility analysis.  Since no superiority analysis is to be performed, no alpha will be 
spent at this interim and thus no Type I error inflation is associated with this interim 
analysis.
If a second interim analysis based on 46 subjects' availability data for the primary 
endpoint is to be conducted (see Section 10.0 for the triggering condition), the Lan-
DeMets alpha spending function based on O'Brien-Fleming boundary will be used to 
decide a pre-specified weight of alpha allocation for the superiority analysis of the 
primary endpoint at this interim.  A futility analysis using the gamma family spending 


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function with a conservative boundary (gamma=-4) will also be performed on the primary 
endpoint at this interim.
12.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
08 July 2020
Original version
2.0
17 August 2020
!
Updates were made to add additional efficacy analysis of 
both the WHO ordinal scale at Day 7, 14 and 28 visits 
and the change from baseline in scale at each of the visits.
!
Added analysis of the areas under the survival functions 
for the mechanical ventilation-free survival and time to 
discharge.
!
Added 95% confidence intervals to all efficacy analysis 
and clarified p-values to be based on 2-sided tests at an 
alpha level of 0.2.
3.0
20 April 2021
!
Updated the DMC meeting frequency based on subject 
enrollment to ensure sufficient new data are available for 
each review.  
!
Added additional analysis of the primary endpoint and the 
secondary endpoint of WHO-8 point ordinal scale from 
baseline.
!
Updated handling of missing data for WHO-8 point 
ordinal scale to incorporate measurements following 
hospital discharge in imputation.
!
Added Ordinal Scale for Clinical Improvement as 
Appendix C
13.0
References
1.
Richardson S, Hirsch JS, Narasimhan M, et al.  Presenting Characteristics, 
Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 
in the New York City Area.  JAMA.  2020;323(20):2052-9.
2.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 
1985;4(2):213-26.


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3.
Van Elteren PH. On the combination of independent two-sample tests of 
Wilcoxon.  Bull Int Stat Inst.  1960;37:351-61.
4.
Proschan MA.  Two-stage sample size re-estimation based on a nuisance 
parameter:  a review.  J Biopharm Stat.  2005;15(4):559-74.
5.
Jennison C, Turnbull BW.  Group Sequential Methods with Applications to 
Clinical Trials.  New York:  Chapman & Hall; 2000.


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Appendix A.
Definitions of Other Safety Observations
Other Safety Observations will be identified using the following search criteria:
Other Safety Observations
Search Criteria
Include in AE 
Overview 
(Y/N)
Hemorrhagic events and 
major hemorrhage
!
Hemorrhage SMQ excluding laboratory terms 
(SMQ 20000039 EXCL); narrow search
!
Sub-analysis of Hemorrhage (SMQ 20000039 
EXCL) limited to hemorrhagic events of grade 
3+, serious hemorrhagic events, or CNS 
hemorrhage of any grade
Y
Cytopenic AEs
PTs of "Neutropenia" (PT 10029354), "Febrile 
neutropenia" (PT 10016288), "Thrombocytopenia"
(PT 10043554), and "Anaemia" (PT 10002034)
Y
Infections (including viral 
reactivation)
!
SOC of "Infections and Infestations" (SOC 
10021881) 
!
Sub-analysis of Opportunistic infections (SMQ 
20000235)
Y
Atrial fibrillation
PT of "Atrial fibrillation" (PT 10003658)
Y
Cardiac arrhythmia 
(including ventricular 
tachyarrhythmias)
!
Cardiac arrhythmias (SMQ 20000049) excluding 
PT of "Atrial fibrillation"
!
Ventricular tachyarrhythmias (SMQ 20000058); 
narrow search
Y
Hepatic disorders
SOC of "Hepatobiliary Disorders" (SOC 10019805)
Y
Interstitial lung diseases 
(ILD)
ILD (SMQ 20000042); narrow search
Y
Hypertension
Hypertension (SMQ 20000147); narrow search
Y
Ischaemic stroke
Ischaemic central nervous system vascular 
conditions (SMQ 20000063); narrow search
Y


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Appendix B.
Definitions of Toxicity Grades 1, 2, 3 and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
ALT/SGPT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
AST/SGOT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Alkaline 
Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 – 20 × ULN
> 20 × ULN
Total 
Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 10 × ULN
> 10 × ULN
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
CPK
>ULN - 2.5 × ULN
>2.5 - 5 × ULN
>5 - 10 × ULN
>10 × ULN
GGT
>ULN - 2.5 × ULN
>2.5 - 5 × ULN
>5 - 20 × ULN
>20 × ULN
Hemoglobin
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
Neutrophils
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelets
< LLN – 75.0 × 
109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 
109/L
< 25.0 × 109/L
Lymphocytes
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
WBC
<LLN - 3.0 × 109/L
<3.0 - 2.0 × 109/L
<2.0 - 1.0 × 109/L
<1.0 × 109/L
INR
>1 - 1.5 × ULN
>1.5 - 2.5 × ULN
>2.5 × ULN
--
Note:
Definitions based on NCI-CTCAE Version 4.03.


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Appendix C.
Ordinal Scale for Clinical Improvement
Note:
World Health Organization (WHO)-8 point ordinal scale