Clinical trial NCT04356690
Conditions: COVID-19
Keywords: Etoposide hemophagocytic lymphohistiocytosis (HLH) cytokine storm
Sponsor: Boston Medical Center
Start date: 2020-05-08; Completion date: 2022-07-01
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, open-label phase II study designed to evaluate the safety and efficacy of etoposide in patients with the 2019 novel coronavirus (COVID-19) infection. Randomization will be performed with a 3:1 allocation ratio. Treatment will be comprised of etoposide administered intravenously at a dose of 150 mg/m2 on Days 1 and 4 in patients with COVID-19 infection meeting eligibility criteria. Subsequent doses of etoposide will be allowed if the investigator and treating physician believe the patient had clinical benefit from etoposide therapy but subsequently has evidence of recurrent clinical deterioration. Subjects randomized to control will receive standard of care treatment. No placebo will be used.

Detailed description:
The rationale for the use of etoposide to treat the cytokine storm in COVID-19 is the high mortality associated with the hyperinflammatory response to the virus, which is similar to that seen in other secondary types of Hemophagocytic lymphohistiocytosis. Autopsy studies of Acute respiratory distress syndrome (ARDS) in COVID patients show a high number of cytolytic T cells in the lungs of such patients. Early autopsy results of COVID patients at Boston Medical Center demonstrate significant hemophagocytosis in lymph nodes and spleen. Comparable studies in the related coronavirus infection severe acute respiratory syndrome (SARS) have demonstrated hemophagocytosis, a hallmark of HLH.15 By targeting the T cells and monocytes driving the cytokine storm in patients with the more severe forms of COVID infection, we hope to alleviate the progression of lung and multi-organ dysfunction characteristic of patients who die from this illness.

Arms: arm 1: Participants that are on ventilation Etoposide 150 mg/m2 daily days 1 and 4 arm 2: Standard of care therapy in participants that are on ventilation
Interventions: intervention 1: Etoposide
Intervention descriptions: intervention 1: Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4.

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
This document is confidential and the property of Boston University School of Medicine. 
No part of it may be transmitted, reproduced, published, or used by other persons without 
prior written authorization from the study sponsor. 
A Phase II Single-Center, Randomized, Open-Label, Safety and Efficacy 
Study of Etoposide in Patients with COVID-19 Infection 
 
 
Simple Title:  Etoposide in COVID-19 patients 
 
IRB #: H-40102 
 
NCT #: NCT04356690 
 
Statistical Analysis Plan pages 15-16 
 
Principal Investigator: 
J. Mark Sloan, MD 
Section of Hematology and Oncology 
 
Boston Medical Center 
 
One Boston Medical Center Place / FGH-1  
Boston, MA  02118 
 
617-638-2367  
Mark.Sloan@bmc.org 
 
Co-Investigators: 
Praveen Govender, MD 
Meredith Halpin, MD 
Adam Lerner, MD 
Manish Sagar, MD 
Shayna Sarosiek, MD 
Bhavesh Shah RPH, BCOP 
 
Medical Monitor:  
Peter Everett, MD 
 
Statistician:  
Janice Weinberg, ScD 
 
Agent:  Etoposide 
 
IND #:  149640  
 
Protocol Version # 2 
Amendment 1 
 
Original version:  18 May 2020 


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TABLE OF CONTENTS  
 
1.  INTRODUCTION...................................................................................................................5 
1.1. Cytokine Storm in COVID-19 and Hemophagocytic Lymphohistiocytosis ................5 
1.2. Etoposide Background and Proposed Mechanism of Action .......................................6 
1.3. Rationale for Clinical Study ............................................................................................6 
1.4. Rationale for Etoposide Dose Selection ..........................................................................8 
 
2. STUDY PLAN ..........................................................................................................................8 
2.1. Study design ......................................................................................................................8 
2.2. Number of sites .................................................................................................................9 
2.3. Number of patients ...........................................................................................................9 
2.4. Primary objective ..............................................................................................................9 
2.5. Secondary objectives ........................................................................................................9 
 
3. PARTICIPANT SELECTION ...............................................................................................9 
3.1. Screening, Recruitment, and Consenting .......................................................................9 
3.2. Inclusion Criteria ............................................................................................................10 
3.3. Exclusion Criteria ...........................................................................................................10 
 
4. INVESTIGATIONAL PLAN ...............................................................................................11 
4.1. Overall Design .................................................................................................................11 
4.2. Patient Cohorts ...............................................................................................................11 
4.3. Randomization ................................................................................................................12 
4.4. Schema .............................................................................................................................12 
4.5. Criteria for removal from protocol treatment .............................................................12 
 
5. ETOPOSIDE FORMULATION AND ADMINISTRATION ...........................................12 
5.1.  Etoposide Chemistry, Mechanism of Action, and Formulation ................................12 
5.2.  Etoposide Availability ....................................................................................................13 
5.3.  Etoposide Administration .............................................................................................13 
5.4.  Etoposide Expected Toxicities and Management........................................................13 
5.5.  Etoposide Dose Modifications .......................................................................................14 
5.6. Etoposide Drug Interactions ..........................................................................................14 
 
6. STUDY PROCEDURES & CALENDAR ...........................................................................15 
 
7. STATISTICAL CONSIDERATIONS .................................................................................15 
7.1. Sample Size Considerations ...........................................................................................15 
7.2. Statistical Analysis ..........................................................................................................16 
 
8. MEASUREMENT OF EFFECT ..........................................................................................16 
8.1.  Definitions .......................................................................................................................16 
8.2.  Response Definitions ......................................................................................................17 
 


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9. ADVERSE EVENTS AND UNANTICIPATED EVENTS ................................................17 
9.1. Adverse Event (AE) Definition ......................................................................................17 
9.2. Serious Adverse Event (SAE) Definition ......................................................................18 
9.3. Unanticipated Problem (UP) Definition .......................................................................18 
9.4. Interim Analysis ..............................................................................................................19 
9.5. Stopping Rules ................................................................................................................19 
 
10. DATA MANGEMENT ..........................................................................................................19 
10.1  Analyses and Reporting ................................................................................................19 
10.2  Data Safety Monitoring ................................................................................................20 
10.3  Study Monitoring and Auditing ..................................................................................20 
 
11. REGULATORY CONSIDERATIONS ...............................................................................21 
11.1  Protocol Amendments ..................................................................................................21 
11.2  Protocol Deviations .......................................................................................................21 
11.3  Institutional Review Board/Ethics Committee Approval .........................................21 
11.4  Study Records Requirements.......................................................................................21 
 
12. REFERENCES .......................................................................................................................22 
 
 
 


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1. BACKGROUND 
 
1.1 Cytokine Storm in COVID-19 and Hemophagocytic Lymphohistiocytosis (HLH) 
 
Evidence is accumulating that patients with severe COVID-19 infection have a cytokine storm 
syndrome.  Cytokine changes similar to secondary hemophagocytic lymphohistiocytosis (HLH) 
have been seen in COVID-19 and are associated with disease severity.  The cytokines known to 
be elevated in HLH and COVID-19 are interleukin (IL)-2, IL-7, granulocyte colony stimulating 
factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage 
inflammatory protein 1-α, and tumor necrosis factor-α.1 A recent retrospective, multicenter study 
of 150 confirmed COVID-19 cases in Wuhan, China, demonstrated predictors of mortality which 
included elevated ferritin (mean 1297.6 ng/mL in non-survivors v. 614.0 ng/mL in survivors; 
p<0.001) and IL-6 (mean 11.4 ng/mL in non-survivors v. 6.8 in survivors; p<0.0001).2 This 
suggests that mortality in COVID-19 may be partially driven by virally associated 
hyperinflammation with resulting increase in markers of inflammation.  Cytokine modulation 
with monoclonal antibodies such as tocilizumab (anti-IL-6) and anakinra (anti-IL-1) are being 
studied elsewhere in phase III trials and are being given on an ad hoc basis at Boston Medical 
Center.  The safety and efficacy of these medications in COVID is unproven.  The Infectious 
Disease Society of America (IDSA) recommends against treatment with biologic outside the 
context of a clinical trial.  Treatment with etoposide will impact the cells elaborating multiple 
cytokines and may provide more robust reduction in inflammation.  Etoposide has an established 
and predictable safety profile; its potential efficacy is supported by previous studies in HLH3,4.  
 
Hemophagocytic lymphohistiocytosis is a rare disorder of excessive immune activation with 
both laboratory and clinical evidence of severe inflammation.  The etiologies of this syndrome 
include genetic mutations of cytotoxic function (familial HLH), as well as secondary causes such 
as infections, malignancy, or metabolic conditions (acquired HLH).  HLH is well described in 
the pediatric population, but has also been described and studied in adult populations.  
Hypercytokinemia mediates the clinical and laboratory presentation.  Familial HLH typically 
presents in early childhood and is caused by mutations in genes important for NK and T-cell 
cytotoxic function.5 Secondary HLH is the phenotype that occurs in both children and adults in 
the absence of a known genetic cause.  A retrospective study from the Mayo Clinic of 62 patients 
with secondary HLH revealed the cause to be a malignancy (52%), infection (34%), autoimmune 
disorder (8%), or unknown cause (6%).  The most common malignancy observed was T cell 
lymphoma (59%) and the most common infection was Epstein Barr Virus (EBV) (26%).6   
 
HLH is diagnosed by a constellation of signs, symptoms, and laboratory abnormalities.  
Multiorgan dysfunction and critical illness are common.  In 2004, The Histiocyte Society 
proposed an updated set of criteria to aid in identification of patients with HLH for clinical trials, 
which include molecular testing consistent with HLH or 5 of 8 of the following criteria: fever, 
splenomegaly, cytopenias affecting ≥2 lineages, hypertriglyceridemia and/or 
hypofibrinogenemia, hemophagocytosis (in bone marrow, spleen, or lymph node), 
hyperferritinemia, impaired NK cell function, and elevated soluble CD25 (sCD25) (ie, sIL2R).7  
Other common findings include transaminitis, coagulopathy, hyponatremia, edema, rash, 
hypoalbuminemia, elevated lactate dehydrogenase (LDH), C-reactive protein, and d-dimer, and 
neurologic symptoms ranging from focal deficits to altered mental status.8 Elevated ferritin 


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occurs in the vast majority of patients with HLH but is nonspecific. The published criteria use a 
ferritin cutoff value of ≥500 µg/L when diagnosing HLH. This is based on the HLH-94 study 
that showed a sensitivity of 84% at this level. Subsequent studies have demonstrated that a 
higher threshold of ≥10,000 µg/L has a 90% sensitivity and 96% specificity for HLH.9 The 
diagnosis of secondary HLH can be challenging to make because the symptoms and laboratory 
features may overlap with other severe illnesses such as sepsis and hematologic malignancy, 
including disorders which are known to trigger HLH.  Fardet et al created and validated the 
HScore, which includes 9 weighted variables based on a retrospective cohort of 312 patients.10  
Some patients with cytokine storm from COVID-19 seen at Boston Medical Center meet formal 
HLH criteria, although bone marrow biopsies to confirm hemophagocytosis have not been 
routinely performed to make this assessment.   Autopsies done on COVID patients at Boston 
Medical Center show evidence of hemophagocytosis in the lymph nodes and spleen, thereby 
suggesting that the true incidence of HLH in COVID patients is higher than pre-mortem 
estimates. 
 
 
1.2 Etoposide Background and Proposed Mechanism of Action 
 
Etoposide has been used to successfully treat HLH. It inhibits topoisomerase II, which leads to 
double stranded DNA breaks.  In a murine model of HLH, etoposide selectively depleted 
activated T cells leading to suppression of inflammatory cytokines and improved survival.11 Of 
note in this same study, dexamethasone had minimal benefit, despite the fact that dexamethasone 
is included in many clinical HLH regimens with the goal of further suppression of 
hypercytokinemia and inflammation.  Etoposide may be more effective than cytokine-specific 
therapies because it eliminates the cells that are elaborating the cytokines, rather than targeting a 
specific cytokine in the evolving cytokine storm. 
 
There are no prospective trials for treatment of HLH in adults, and treatment is largely based on 
the HLH-94 study, a large prospective pediatric study in patients less than 16 years old without 
history of immunosuppression or malignancy.  In that study, the investigators used a regimen 
that included an 8 week induction with dexamethasone and etoposide.3 Response to treatment 
was determined by clinical and laboratory evidence of resolution, including fever curve, trend of 
sIL2R, LFTs, fibrinogen and ferritin level.  Timely diagnosis and early administration of therapy 
has been demonstrated to improve survival. In a retrospective multicenter study of 162 patients 
with HLH looking at predictors of mortality, use of etoposide was associated with better 
survival.4  
 
Etoposide is an already FDA approved drug that is comparably inexpensive and currently 
available.  Etoposide has an established safety profile and its use is supported by previous studies 
in HLH3,4.  We propose a Phase II study of etoposide for the treatment of cytokine storm in 
severe COVID-19 infection.    
 
1.3 Rationale for Etoposide Clinical Study 
 
The cytokine storm related to COVID-19 appears to be similar to the hyperinflammation seen in 
other virally triggered secondary HLH.  Others have postulated that the combination of 
topoisomerase I and topoisomerase II inhibitors could potentially be an effective treatment to 


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protect COVID 19 patients from cytokine storms.12  We posit that the cytokine storm seen in 
COVID-19 infection resembles secondary HLH seen as a result of other viral infections, 
resulting in an aberrant and overly exuberant cytokine response which is deleterious and leads to 
multiorgan dysfunction.   
The rationale for the use of etoposide to treat the cytokine storm in COVID-19 is the high 
mortality associated with the hyperinflammatory response to the virus, which is similar to that 
seen in secondary types of HLH.  Early use of etoposide has been shown to improve survival in 
secondary HLH.13  Autopsy studies of ARDS in COVID patients show a high number of 
cytolytic T cells in the lungs of such patients.14 Early autopsy results of COVID patients at BMC 
demonstrate significant hemophagocytosis in lymph nodes and spleen.  Comparable studies in 
the related coronavirus infection SARS have demonstrated hemophagocytosis, a hallmark of 
HLH.15  By targeting the T cells and monocytes driving the cytokine storm in patients with the 
more severe forms of COVID infection, we hope to alleviate the progression of lung and multi-
organ dysfunction characteristic of patients who die from this illness.  
Potential concerns about the use of etoposide and dexamethasone for COVID-19 infected 
patients include decreased immune response and pathogen clearance.  Studies in humans and 
animals indicate that corticosteroid immunosuppression (both inhaled and systemic) impairs 
induction of anti-viral type-I interferon responses to a range of respiratory viruses.16 Opinions on 
the use of steroids in COVID-19 are mixed, and based on limited data.  A retrospective cohort 
study of 201 patients with confirmed COVID-19 pneumonia in Wuhan China, suggested that risk 
factors associated with the development of ARDS and progression from ARDS to death included 
older age, and neutrophilia, as well as organ and coagulation dysfunction (eg, higher lactate 
dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] 
and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). 
Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 
0.38; 95% CI, 0.20-0.72).17 The CDC cautions interpretation of this data given its observational 
by nature, and patients with MERS-CoV or influenza who were given corticosteroids were more 
likely to have prolonged viral replication, receive mechanical ventilation, and have higher 
mortality.18 Given the data in MERS and influenza, and the lack of randomized data 
demonstrating benefit of corticosteroids, others caution against the use of steroids in COVID 19 
patients.19   For these reasons in the study proposed here, we do not plan to use corticosteroids as 
part of the treatment protocol. 
Another potential concern is that decrease in cytotoxic T cell and humoral immune response with 
the administration of cytotoxic chemotherapy.  Prolonged etoposide therapy has been shown to 
reduce cytotoxic T cell activity, macrophage/monocyte number and function, and humoral 
responses in animal models, some of which initiate low dose daily etoposide prior to a viral 
challenge.20,21  In HLH, etoposide has been argued to be effective as a result of its ability to 
ablate activated T cells.11 In the study proposed here, etoposide will be used well after patients 
have developed an established COVID infection and we plan to use a very limited dose and 
schedule of this drug so as to minimize the likelihood of arresting the production of neutralizing 
antibodies to COVID-19, but still allow ablation of cytolytic T cells that are leading to cytokine 
activation. To our knowledge, no studies have examined the immunologic effect of brief 
etoposide therapy relatively late in a human viral infection. Etoposide is used in the treatment of 


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HLH associated with Epstein Barr Virus (EBV) infection without known worsening of viral 
infection.  In studies of hematologic malignancy patients who were inoculated with a varicella 
zoster vaccine, then underwent high dose chemotherapy followed by autologous stem cell 
transplant, neutralizing antibody production was detected despite this myeloablative regimen.22 
1.4 Rationale for Dose Selection 
 
In this trial, patients will be treated with a markedly abbreviated course of the dosing regimen 
used in the current standard adult HLH protocol. In the standard HLH regimen, etoposide is 
given at 150 mg/m2 twice a week for two weeks, followed by weekly therapy, in combination 
with dexamethasone. In this trial, patients will receive the standard initial two doses of etoposide 
in the first week (150 mg/m2 IV x 2) on day 1 and 4 of treatment. Further etoposide therapy will 
not be given unless the assessment of the patient’s subsequent course is that they improved after 
etoposide treatment but then had recurrent clinical deterioration, at which point further etoposide 
therapy would be allowed (according to the HLH-94 protocol)3 after discussion with the 
investigator. 
 
The rationale for such an abbreviated course of etoposide is three fold. First, the immune 
hyperactivation in COVID infections may differ from that of patients with classic secondary 
HLH and may require only a relatively brief period of pharmacologic down-regulation. Second, 
the development of neutralizing antibodies to COVID are likely to be an important aspect of 
recovery from this illness and prolonged treatment with etoposide could theoretically blunt such 
a response. Third, prolonged etoposide therapy will induce more significant myelosuppression in 
a group of patients who will be susceptible to bacterial super-infection. The proposed two doses 
of IV etoposide is not expected to cause deep or prolonged myelosuppression. 
 
2. STUDY PLAN 
 
2.1 Study Design 
 
This is a randomized, open-label phase II study designed to evaluate the safety and efficacy of 
etoposide in patients with COVID-19 infection.  Treatment will be comprised of etoposide 
administered intravenously at a dose of 150 mg/m2 on Days 1 and 4 in patients with COVID-19 
infection meeting eligibility criteria. Subsequent doses of etoposide will be allowed if the 
investigator and treating physician believe the patient had clinical benefit from etoposide therapy 
but subsequently has evidence of recurrent clinical deterioration. 
 
Two cohorts of patients will be treated with etoposide. Cohort 1 will be patients who require 
intubation due to their severe COVID-19 related respiratory illness.  Cohort 2 will be COVID-19 
patients who have progressive pulmonary dysfunction and evidence of severe inflammation but 
who are not yet intubated. Although prior treatment for COVID with anti-cytokine therapy will 
not exclude a patient from enrollment on this trial, a “washout” period of at least 3 half-lives will 
be required prior to initiation of etoposide therapy.  Enrollment will begin with cohort 1, 
following which a decision will be made to open cohort 2 or not, as outlined further in this 
document. 
 


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2.2 Number of sites   
 
One (Boston Medical Center, 820 Harrison Ave, FGH-2, Boston, MA 02118) 
 
2.3 Number of patients  
 
• 32 patients in each cohort with 3:1 allocation ratio (24 etoposide and 8 control per cohort) 
• 64 patients total  
 
2.4 Primary Objective 
 
• Improvement in pulmonary status by two-categories on 8 point ordinal scale of 
respiratory function (See Section 8.2) 
 
2.5 Secondary Objectives 
 
• Overall Survival at 30 days is a key secondary endpoint.  
• Improvement in inflammatory markers associated with cytokine storm (Ferritin, C-
Reactive Protein (CRP), d-dimer, white blood cell count) 
• Cumulative incidence of grade 3 and 4 adverse events during hospitalization 
• Cumulative incidence of serious adverse events during hospitalization 
• Duration of hospitalization 
• Duration of ventilation 
• Ventilator free days (reintubations or death within 28 days will result in zero ascribed 
time off ventilator prior to reintubation) 
• Improvement in oxygenation or paO2/FIO2 ratio 
 
3.  PARTICIPANT SELECTION 
 
3.1  Screening, Recruitment, and Consenting 
 
The investigators will recruit participants from within Boston Medical Center on the inpatient 
setting.  It will be standard for COVID-19 positive patients to be screened to determine if they 
may be eligible for any available clinical trials. A screening consent is not obtained, as the pre-
screening review is conducted prior to contacting the patient to discuss the trial.  At that time no 
data will be collected by the study team. The medical records are reviewed to determine if a 
patient may or may not be potentially eligible for a clinical trial.  
 
If the patient is potentially eligible, the inpatient nurse, treating physician or trial representative 
will inform the patient or the patient’s legally authorized representative (LAR) of the availability 
of a clinical trial.  No research procedures are performed until after written consent is obtained.  
 
If the patient agrees to discuss and receive information about the study, a copy of the IRB-
approved Informed Consent Form will be provided to the patient by a member of the patient’s 
clinical care team to avoid using additional personal protective equipment (PPE). In the event the 


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patient is too ill to make medical decisions, the patient’s LAR will be asked to review the informed 
consent form, which may be sent electronically.   
 
The inpatient provider will contact the research nurse and provide the phone number of the patient 
or the LAR.  The research nurse and/or investigator will call the patient or the LAR and will 
remotely conduct the consent discussion, reviewing all elements of consent and emphasizing the 
voluntary nature of research participation. Additional family members or friends may join the call 
at the subject’s request.  Once all questions have been asked and answered to the patient’s/LAR’s 
satisfaction, the research nurse will offer to end the call so the patient/LAR can be given the 
opportunity to review the consent form and discuss with family members (remotely) and/or other 
physicians.  The patient/LAR will have as long to decide as possible within the confines of the 
clinical urgency.  Once the patient/LAR is satisfied that all questions have been answered, if 
he/she wishes to participate, he/she will contact the research nurse or the research nurse will reach 
out to the patient/LAR again if requested by the patient/LAR.  The study team will have arranged 
for a witness to join the telephone call at this point, and consent will be obtained remotely, with 
the patient or LAR directing the witness to sign on their behalf.  The informed consent will also 
be documented in the medical record.   
 
The study team member conducting the consent discussion and the witness will both sign and 
date the consent form external to the patient’s room.  The signed consent form will be filed in the 
research records.  The patient will keep the unsigned copy. 
 
Potential participants who are non-English speaking will be consented using the Short Form (if 
IRB approved).  A hospital interpreter, or an interpreter on the phone line, will be used throughout 
the consent process and throughout their participation in the study.  The interpreter will sign as 
an impartial witness. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process will be recorded in the subject’s source documents.  
 
3.2  Inclusion Criteria (applicable for patients enrolled for treatment or data collection) 
 
• 
Age 18 years or older 
• 
Confirmed COVID-19 infection 
• 
Evidence of cytokine storm defined as: 
o Peak ferritin > 10,000 ng/mL OR 
o Peak ferritin > 500 ng/mL and one or more of the following at any time 
during hospital admission: 
▪ Lactate dehydrogenase > 500 U/L, d-dimer >1000 ng/mL, C-
reactive protein > 100 mg/L, or WBC > 15 k/uL 
• 
Cohort 1: Intubated status as a result of COVID infection-associated respiratory illness 
 
• 
Cohort 2 (if activated): Evidence of progressive respiratory failure (requiring >4 L/min of 
supplemental oxygen to maintain SaO2 greater than 92%) without intubation  
 
 


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3.3 
 Exclusion Criteria 
• 
Pregnancy or breastfeeding 
• 
History of severe hypersensitivity to etoposide products 
• 
Absolute neutrophil count (ANC) < 1000 cells/mm3 
• 
Platelet count <50,000/mm3 
• 
Bilirubin > 3.0 mg/dL 
• 
Aspartate OR alanine aminotransferase > 5.0 x ULN 
• 
Creatinine Clearance < 15 mL/min (calculated by Cockcroft and Gault formula) 
• 
Requiring continuous renal replacement therapy 
• 
Requiring > 1  vasopressor medications 
• 
Requiring extrcorporeal membrane oxygenation (ECMO) 
• 
Other active, life-threatening infections 
• 
Anti-cytokine treatment (including anakinra or IL6 antibodies eg tocilizumab, sarilumab) 
administration within three half-lives of the medication used 
• 
Hydroxychloroquine, colchicine, azithromycin, doxycycline—if administered for COVID 
infection—must be discontinued for at least 24 hrs prior to randomization.  
• 
Has a history or current evidence of any condition, therapy or laboratory abnormality that 
might confound the results of the study, interfere with subject participation, or is not in 
the best interest of the patient to participate, in the opinion of the investigator. 
• 
Inability to consent and no legally authorized representative 
• 
Poorly controlled HIV infection (CD4 count <100 cells/mm3) 
 
4. INVESTIGATIONAL PLAN 
 
4.1  Overall Design 
 
Open-label, randomized Phase II study of etoposide administered intravenously at a dose of 150 
mg/m2 once daily on Days 1 and 4 for a total of two doses to inpatient patients with moderate 
and severe COVID-19 who have consented to treatment on this clinical trial.  Dose reductions 
will be performed as outlined in Section 5.   
 
This study includes a screening period, a treatment period, and a follow-up period for adverse 
events that will include the remainder of hospitalization, with additional assessments at days 30 
and 60 as outlined in the study calendar (Section 6).  After obtaining informed consent, the 
patients randomized to etoposide will begin treatment with the study drug.  Subjects randomized 
to control will receive standard of care treatment.  No placebo will be used.  Subjects will be 
monitored for adverse events and to evaluate study outcomes.  Patients removed from the study 
due to any unacceptable adverse events will also be followed until time of death or hospital 
discharge.   
 
For patients randomized to standard of care, day 1 will be considered day of randomization.   
These patients will be followed to record the outcome of all primary and secondary objectives 
until time of death or hospital discharge, whichever occurs earlier. 
 
 


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4.2 Patient cohorts 
 
This protocol has two patient cohorts, including cohort 1) severe COVID-19 infection and cohort 
2) moderate COVID-19 infection (as defined in the inclusion criteria).  
 
Upon protocol activation, cohort 1 will open to accrual.  We will randomize and enroll 10 
patients and then perform interim safety analysis prior to further enrollment or opening of cohort 
2.  See Section 7.2 for statistical design and section 9.5 for stopping rules.  
 
Following treatment with two doses of etoposide (Day 1 and Day 4) in the first 10 participants in   
cohort 1, safety data including adverse events and patient outcomes will be submitted to the 
COVID Research Committee for review.  At that time, the committee will determine whether 
they feel that enrollment may be expanded to include cohort 2.  If necessary, the COVID 
Research Committee may ask for safety data to be presented after treating the full 32 patients on 
cohort 1 prior to opening cohort 2.  Only after permitted by the COVID Research Committee 
will 32 patients on cohort 2 be enrolled and treated.  The COVID Research committee is not 
tasked with medical monitoring, pharmacovigilance or applying stopping rules for this study.     
 
4.3 Randomization 
 
Randomization will be performed using a 3:1 allocation ratio using a block size of 4 separately in 
each cohort. 
 
4.4  Schema 
 
Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4. 
If the treating clinicians feel that the patient initially benefited from etoposide but then has 
evidence of relapse of cytokine storm, the patient may continue on the standard HLH-94 
etoposide schedule of day 8, 11, 18, 25 after discussion with one of the study investigators (prior 
to day 8 dosing).   
 
4.5 Criteria for removal from protocol treatment 
 
• Completion of study (either death or completion of day 60 survival assessment) 
• Unacceptable toxicity 
• Participant withdrawal for any reason 
 
5. DRUG FORMULATION AND ADMINISTRATION 
 
5.1 Etoposide Chemistry, Mechanism of Action, and Formulation 
 
Chemistry:  Etoposide is a semi-synthetic podophyllotoxin derivative from the plant 
podophyllum peltatum, and has antineoplastic properties in experimental animals and in man.   
 
Mechanism of action:  The epipodophyllotoxins exert specific spindle poison activity with 
metaphase arrest, but in contrast to the vinca-alkaloids, have an additional activity of inhibiting 


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cells from entering mitosis.  Suppression of tritiated thymidine, uridine, and leucine 
incorporation in human cells in tissue culture suggests effects against DNA, RNA and protein 
synthesis.   
 
Formulation: 100mg of VP-16 is supplied as 5ml or 10ml solution in sterile multiple dose vials 
for injection.  The pH of the yellow clear solution is 3-4.  Each ml contains 20mg VP-16, 2mg 
citric acid, 30mg of benzyl alcohol, 80mg polysorbate 80/tween 80, 650mg polyethylene glycol 
300, and 30.5% (v/v) alcohol. VP-16 must be diluted prior to use with either 5% Dextrose 
Injection, USP, or 0.9% sodium chloride injection, USP.  The time before precipitation occurs 
depends on concentration, however when at a concentration of 0.2mg/ml it is stable for 96 hours 
at room temperature and at 0.4mg/ml it is stable for 48 hours.   Concentrations over 0.5mg/ml is 
stable for at least 24 hours at room temperature.   
  
5.2  Etoposide Availability 
 
Etoposide is commercially available.  
 
5.3  Etoposide Administration  
 
Etoposide 150 mg/m2 will be administered over 60 minutes intravenously on Days 1 and 4.  
Admixed in NS-500ml.  
 
If the treating clinicians feel that the patient initially benefited from etoposide but then has 
evidence of relapse of cytokine storm, the patient may continue on the standard HLH etoposide 
schedule of day 8, 11, 18, 25 after discussion with one of the study investigators.   
 
5.4  Etoposide Expected Toxicities and Management 
Reversible myelotoxicity has been uniformly observed to be the major toxicity for VP-16 and to 
represent the only clinically significant side effect.  Following a single IV injection, peak 
myelotoxicity occurs at seven to nine days.  Following daily injections for five to seven days, 
myelotoxicity is maximal between 12-16 days from the initiation of therapy.  Bone marrow 
suppression is mainly manifested as granulocytopenia, with thrombocytopenia and anemia 
occurring to a lesser extent.  Gastrointestinal toxicities including transient modest nausea, 
vomiting, and diarrhea, are common.  Other reactions could include aftertaste, rash, 
pigmentation, pruritis, abdominal pain, constipation, and dysphagia.  Occasional alopecia is 
reported.  VP-16 does not produce phlebitis or nephrotoxicity.  Rarely anaphylactic-like 
reactions have been reported, as well as, hypotension.  The drug is to be infused over 60 minutes 
in this study to decrease the potential for hypotension, and the blood pressure and pulse will be 
monitored during the infusion.  Occasionally, chills, fever, peripheral neurotoxicity, stomatitis, 
hepatotoxicity, transient cortical blindness and radiation recall dermatitis may be a result of VP-
16 administration.  Stomatitis is usually associated with high dose regimens containing 
etoposide.  The occurrence of acute leukemia has been reported rarely in patients treated with 
VP-16 in association with other antineoplastic agents.  Etoposide can cause fetal harm when 
administered to a pregnant women.  It has been shown to be teratogenic in mice and rats.  In 
females of reproductive potential, etoposide may cause infertility and result in amenorrhea. 
Premature menopause can occur with etoposide. Recovery of menses and ovulation is related to 


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age at treatment. Males In male patients, etoposide may result in oligospermia, azoospermia, and 
permanent loss of fertility. Sperm counts have been reported to return to normal levels in some 
men, and in some cases, have occurred several years after the end of therapy Secondary 
leukemias associated with etoposide have been reported.  Women of childbearing potential will 
be advised to avoid becoming pregnant for at least 6 months after the final dose of 
etoposide.  Males with female partners of reproductive potential will be advised to use effective 
contraception for 4 months after the final etoposide dose.  
 Safety of etoposide for use by nursing women has not been established.  
 
5.5  Etoposide Dose Modifications 
 
Etoposide dosing in Hepatic and Renal Insufficiency 
T. Bili 1.5 – 3.0 mg/dL 
50% dose reduction 
T. Bili  > 3.0 mg/dL 
Omit dose 
AST > 2.5 x ULN 
50% dose reduction 
Albumin < 3.0 g/dL                     
30% dose reduction 
Creatinine Clearance 15-50 mL/min* 
25% dose reduction 
Creatinine Clearance <15 mL/min 
Omit dose 
Abs Neutrophil Count <500/uL 
Hold until ANC > 500/uL 
*calculated by Cockcroft Gault equation 
 
5.6 Etoposide Drug Interactions 
 
Patients receiving concomitant medications with known interactions with etoposide, as 
mentioned below, will be monitored closely for adverse events.  
• Cisplatin: Co-administration of cisplatin may increase exposure to etoposide.  
• Highly protein-bound drugs:  Phenylbutazone, sodium salicylate, and aspirin displaced 
protein-bound etoposide in vitro.  
• Select antiepileptic medications:  Co-administration with antiepileptic medications 
including phenytoin, phenobarbital, carbamazepine, and valproic acid may increase 
etoposide clearance.  
• Etoposide may be a substrate of the P-glycoprotein (P-gp) transporter system based upon 
in vitro studies 
 
Co-administration of etoposide with warfarin may result in elevated international normalized 
ratio (INR). If patients taking warfarin the INR will be monitored at least twice weekly. 
 
 
 


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6. STUDY PROCEDURES & CALENDAR 
REQUIRED STUDIES 
Screening  
Day 1, Day 4 and 
Day 7Σ# 
Prior to 
discharge 
 
Day 30* 
PHYSICAL 
 
 
 
 
History & Physical Exam 
X 
X 
X 
X 
Height, Weight, Body Mass Index, and Body Surface Area 
X 
 
 
 
Vital Signs 
X 
X 
X 
X 
Toxicity Notation 
X 
X 
X 
X 
Respiratory Status on 8 point scale^ 
X 
X 
X 
X 
HISTORY 
 
 
 
 
Concomitant medicines (including COVID therapies, ie 
hydroxychloroquine, tocilizumab, anakinra) with date of 
initiation 
X 
 
 
 
Smoking status 
X 
 
 
 
Comorbidities 
X 
 
 
Symptoms, including date of symptom onset 
X 
 
 
LABORATORY 
 
 
Beta HCG (for women of childbearing potential) 
X 
 
 
 
CBC with Differential+ 
X 
X 
X 
X 
Comprehensive metabolic panel+ 
X 
X 
X 
X 
Lactate Dehydrogenase 
X 
X 
X 
X 
D-dimer 
X 
X 
X 
X 
Ferritin 
X 
X 
X 
X 
C-reactive protein 
X 
X 
X 
X 
PaO2/FIO2 (P/F) ratio (cohort 2 only) 
X 
X 
X 
X 
INR (if on warfarin) Ω 
X 
 
 
 
ADDITIONAL TESTING 
 
 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
# For subjects randomized to treatment, the data for Day 1 and Day 4 will be collected prior to the etoposide dose (within 24 hours). 
*Information to be obtained as feasible, if patient has been discharged attempts will be made to obtain the information from the 
patient’s primary care provider.  If such results are not available, participant will be contacted by the research nurse to assess toxicities.  
^ Mortality assessment (included on the 8 point scale) will also be recorded at Day 14 and 60, in addition to Day 30 mentioned above  
+ CBC and comprehensive metabolic panel will be measured at least twice weekly during hospitalization.  These tests will also be 
obtained pre-dose 8, 11, 18, and 25 for those patients who require additional etoposide dosing as described above (Section 4.3 and 5.3) 
Ω INR to be repeated at least twice weekly for patients on warfarin 
Σ Day 1 of treatment for patients randomized to standard of care (SOC) will be considered the day of randomization 
 
 
7. 
STATISTICAL CONSIDERATIONS 
 
7.1  Sample Size Considerations 
 
This study will be performed with two cohorts 1) severe COVID-19 infection and 2) moderate 
COVID-19 infection (as defined in inclusion criteria).  
The effect of the intervention will be evaluated in each cohort separately.  A total of 32 patients 
will be enrolled in each cohort with a 3:1 allocation ratio (24 Etoposide and 8 control per cohort).  
Assuming a 30% response rate in the control group for the primary outcome of a 2 point 
improvement in respiratory status on an 8 point scale at Day 14, we can detect a 50% increase in 
response in the Etoposide group (80% response rate in the Etoposide group) with a 2-sided α of 
0.05 and 80% power.  While this study is not powered to detect a statistically significant 
difference in outcome, it will provide initial evidence of efficacy if improvement in response is 
observed.   


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7.2 Statistical Analysis 
 
Tabulations overall, and by treatment group, will be produced for appropriate demographic, 
baseline, efficacy, and safety parameters, with number and percentages reported for categorical 
variables and the mean, median, standard deviation, and range for continuous variables.   All 
analyses will be performed at an α=0.05 level using SAS v.4.  
 
Efficacy analyses will be performed in an intention-to-treat (ITT) population consisting of all 
patients randomized.  The difference in ordinal scale improvement rates between treatment 
arms will be calculated with a 95% confidence interval and formally compared using Fisher’s 
Exact Test .  For secondary analysis of the primary endpoint, logistic models individually 
adjusted for age, diabetes,  chronic lung disease/moderate or severe asthma, 
immunocompromise, liver disease, heart disease/hypertension, smoking and obesity (BMI > 
40), residence in long-term care facility, will also be examined with odds ratios and 95% 
confidence intervals reported.  
 
The analysis of secondary time to event endpoints including survival at 30 days, duration of 
hospitalization, duration of ventilation and ventilator free days, will be compared between 
treatment arms based on a log-rank test. The median will be estimated with a 95% CI for each 
treatment arm using the Kaplan-Meier method. Cox proportional Hazards models adjusted 
individually for age, diabetes,  chronic lung disease/moderate or severe asthma, 
immunocompromise, liver disease, heart disease/hypertension, smoking and obesity (BMI > 
40), residence in long-term care facility, will also be examined with odds ratios and 95% 
confidence intervals reported.. Changes in inflammatory markers and in oxygenation or 
paO2/FIO2 ratio, based on available recorded measurements, will be compared between 
treatment arms using a two sample t-test, or a Wilcoxon Rank Sum test, as appropriate.  
Incidence of grade 3 or 4 AEs and serious AEs will be compared using Fisher’s Exact test. 
 
Additional safety analyses will be based on the reported adverse events and other clinical 
information. Safety analyses will be performed in the all-treated (AT) population, consisting of 
all patients who took at least one dose of study treatment.  The safety and tolerability of 
Etoposide will be evaluated by means of drug-related AE reports, physical examinations, and 
laboratory safety evaluations and compared between groups using Fisher’s exact test.   The first 
10 patients allocated to the Etoposide group in the ventilated cohort will be evaluated for 
safety endpoints prior to initiating enrollment in the non-ventilated group. 
 
 
8. 
MEASUREMENT OF EFFECT 
 
8.1  Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment will 
be evaluable for toxicity from the time of their first treatment. 
 


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Evaluable for objective response: Only those participants who have received at least one 
dose of etoposide will be eligible for objective response.   
 
For purposes of data collection, day 1 of patients on the standard of care arm will be the 
day of randomization.   
 
8.2 Response Definitions 
 
8-Point Ordinal Scale: 
▪ 8 - Death; 
▪ 7 - Ventilation in addition to extracorporeal membrane oxygen (ECMO), 
continuous renal replacement therapy (CRRT), or need for vasopressors 
(dopamine ≥5 μg/kg/min OR epinephrine ≥0.1 μg/kg/min OR 
norepinephrine ≥0.1 μg/kg/min); 
▪ 6 - Intubation and mechanical ventilation; 
▪ 5 - Non-invasive mechanical ventilation (NIV) or high-flow oxygen; 
▪ 4 – Hospitalized, requiring oxygen by mask or nasal prongs; 
▪ 3 - Hospitalization without oxygen supplementation; 
▪ 2 – Discharged from hospital either to home with supplemental oxygen OR to 
inpatient rehabilitation/skilled nursing facility (+/- supplemental oxygen);  
▪ 1 – Discharged to home without supplemental oxygen 
 
When calculating Ventilator Free days, reintubations or re-hospitalizations or death 
occurring in the first 28 days should result in zero ascribed to time off the ventilator prior 
to reintubation 
 
When calculating days of hospitalization, re-hospitalization or death occurring in the first 
28 days should result in zero ascribed to time out of the hospital prior to readmission. 
 
When determining days of supplemental oxygen use and need for supplemental oxygen, 
the patient will only be considered to no longer need supplemental oxygen if a room air 
saturation is ≥ 90% after five minutes of rest.  
 
9. 
ADVERSE EVENTS AND UNANTICIPATED EVENTS 
 
9.1 Adverse Event Definition  
 
An adverse event is any untoward or unfavorable physical or psychological occurrence in a 
human subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease temporally associated with the subject’s participation 
in the research, whether or not considered related to the subject’s participation in the research. 
 
Toxicity will be scored using CTCAE Version 5.0 for toxicity and adverse event reporting. A 
copy of the CTCAE Version 5.0 can be downloaded from the CTEP homepage 
(HTTP://CTEP.INFO.NIH.GOV). All appropriate treatment areas will have access to a copy of 
the CTCAE Version 5.0. All adverse clinical experiences, whether observed by the investigator 


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or reported by the subject, must be recorded, with details about the duration and intensity of each 
episode, the action taken with respect to the test drug, and the subject’s outcome. The 
investigator must evaluate each adverse experience for its relationship to the test drug, its 
expectedness, and for its seriousness.  
 
The investigator must appraise all abnormal laboratory results for their clinical significance. If 
any abnormal laboratory result is considered clinically significant, the investigator must provide 
details about the action taken with respect to the test drug and about the subject’s outcome.  
 
9.2 Serious Adverse Event (SAE) Definition 
 
Serious Adverse Event:  According to the FDA’s Code of Federal Regulations Title 21 Part 
314.80, a SAE is any untoward medical occurrence that results in any of the following outcomes: 
• 
Death 
• 
A life-threatening event (an event that places the subject at immediate risk of death from the 
event as it occurred) 
• 
Inpatient hospitalization or prolongation of an existing hospitalization 
• 
A persistent or significant disability / incapacity 
• 
A congenital anomaly / birth defect 
• 
Important medical events based upon appropriate medical judgment that may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition of serious. 
 
Expectedness:  Unexpected events include any adverse drug experience that is not listed in the 
current package insert for the drug product (e.g., all previously unobserved or undocumented 
events).    
 
Relatedness:  Indicates that a determination has been made that an event had a reasonable 
possibility of being related to exposure to the product.  Examples of causality include not related, 
unlikely, possibly, probable, definitely related and unable to be determined. 
 
9.3  Unanticipated Problem (UP) Definition 
 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation in the research; AND 
• 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
Death due to progressive COVID infection will not be considered an unexpected event.   
 
Reporting of AEs, SAEs, and UPs to the IRB and FDA will take place according to institutional 
IRB and FDA policy (see Section 10).  AEs and SAEs will be reported from the first dose of 
study drug through hospital discharge. All SAEs should continue to be monitored until they are 


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resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).  
 
9.4 Interim Analysis 
 
Interim analysis will occur after 10 patients are enrolled into cohort 1.  Safety data including 
adverse events and patient outcomes will be presented to the medical monitor (and COVID 
research committee as detailed in section 4.2). If cohort 2 is activated, an interim analysis will 
also be performed after 10 patients have enrolled in that cohort.    
 
9.5 Stopping Rules 
 
Accrual in a cohort will continue after the interim analysis if  ≥ 1 of the treated patients in that 
cohort meets the primary endpoint of 2 point improvement in respiratory status on the 8 point 
scale at day 14.  If cohort 1 is stopped, enrollment in cohort 2 (if open) may still continue. 
 
10. DATA MANGEMENT 
 
10.1  Analyses and Reporting 
 
Data generated by the methods described in the protocol will be recorded in the subjects' medical 
records and/or study progress notes. The investigator will be the assessor of the primary 
endpoint. Data will be directly inputted into an electronic system.  Data will be analyzed and 
reported after study is completed or meaningful endpoints are reached. All subsequent data 
collected will be analyzed and reported in a follow-up clinical report.  
 
The index data for patients on treatment is the day 1 dose of etoposide.  For patients enrolled into 
the standard of care arm, day 1 will be the day of randomization.  
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, 
safety monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB and FDA in 
accordance with established policies: 
• Unanticipated Problems occurring at BMC/BU Medical Campus will be reported to the 
IRB within 7 days of the investigator learning of the event. 
• Unanticipated Problems occurring at BMC/BU Medical Campus will be reported to the 
FDA within 15 days of the investigator learning of the event. 
• Unexpected fatal or life-threatening suspected adverse events occurring at BMC/BU 
Medical Campus will be reported to the IRB within 7 days of the investigator learning of 
the event. 
• Reports from the designated medical monitor with recommended changes will be reported 
to the IRB within 7 days of the investigator receiving the report.  
• Adverse Events (including Serious Adverse Events) will be reported in summary at the 
time of continuing review, along with a statement that the pattern of adverse events, in 
total, does not suggest that the research places subjects or others at a greater risk of harm 
than was previously known. 


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• Reports from designated medical monitor with no recommended changes will be reported 
to the IRB at the time of continuing review.  
  
10.2  Data Safety Monitoring  
 
Toxicity and accrual monitoring will be performed on a routine basis by the study investigators. 
Subjects will undergo toxicity assessment and laboratory tests according to the study calendar in 
Section 7.  The clinical status and laboratory reports of the study participants will be assessed 
routinely by the co-investigators throughout the study. The investigators, Medical Monitor and 
data analyst will remain as broadly informed as possible regarding emerging evidence from related 
studies as well as from the conduct of this protocol. 
 
In addition, a Medical Monitor has been appointed to provide additional data safety monitoring. 
The Medical Monitor is a qualified clinician with relevant expertise, but no direct connection 
with the research, whose primary responsibility is to provide independent safety monitoring in a 
timely fashion. The PI will submit a report to the Medical Monitor which will include a list of all 
adverse events and serious adverse events (regardless of relatedness). In addition, any 
unanticipated problems involving risks to participants or others and participant deaths will be 
reported to the monitor as soon as possible and within 24 hours.  Additional data may be 
requested by the Medical Monitor, and interim statistical reports may be generated as deemed 
necessary and appropriate.  
 
The Medical Monitor is expected to provide a formal, unbiased written report evaluating 
individual and cumulative participant safety data. Although the PI is responsible for assigning 
causality and expectedness, the medical monitor will comment on whether or not he is in 
agreement.  As an outcome of each review, the Medical Monitor will make a recommendation as 
to the advisability of proceeding with study intervention, and to continue, modify, or terminate 
this trial.    
 
Medical Monitor reports will be submitted to the PI following each review which the PI will, in 
turn, submit to the IRB.  The study will not stop enrollment awaiting these reviews, though the 
Medical Monitor may recommend temporary or permanent cessation of enrollment based on 
their safety reviews. 
 
Additional monitoring will also be performed by the COVID Research Committee after 10 
patients have been randomized in cohort 1.  At that time, the committee will determine whether 
they feel that enrollment may be expanded to include cohort 2, or may request that data be 
presented again when all patients on cohort 1 have been treated.   
 
10.3  Study Monitoring and Auditing 
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations (CFR).  
 
Investigators must enter study data onto CRFs or other data collection system. The Investigator 
will permit study-related monitoring visits and audits by IRB/EC review, and regulatory 


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inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study 
took place, to source documents, to CRFs, and to all other study documents.  
 
 
11.  REGULATORY CONSIDERATIONS 
 
11.1  Protocol Amendments 
 
Any amendment to this protocol must be agreed to by the Principal Investigator. Written 
verification of IRB approval will be obtained before any amendment is implemented. 
 
11.2  Protocol Deviations 
 
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that subject. A decision will be made as soon as possible to determine 
whether or not the subject (for whom the deviation from protocol was effected) is to continue in 
the study. The subject’s medical records will completely describe the deviation from the protocol 
and state the reasons for such deviation. In addition, the Investigator will notify the IRB in 
writing of such deviation from protocol. Non-emergency minor deviations from the protocol will 
be permitted with approval of the Principal Investigator. 
 
11.3  Institutional Review Board/Ethics Committee Approval 
 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Good Clinical Practice Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Subjects and Part 56 Institutional Review Boards.  
 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study. The approval will be obtained prior to the 
initiation of the study.  
 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number.  
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval. The Investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk 
to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
 
 


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11.4  Study Records Requirements 
 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions certified 
after verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) be retained by 
the Investigator for as long as needed to comply with institutional policies, which generally 
requires records to be kept for 7 years after closure of the clinical trial. The Investigator agrees to 
adhere to the document/records retention procedures by signing the protocol. 
 
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