Clinical trial NCT04388683
Conditions: COVID-19
Keywords: COVID-19 Inhaled Nitric Oxide
Sponsor: Tufts Medical Center
Start date: 2020-05-12; Completion date: 2020-11-23
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a pilot randomized-controlled (2:1) open label investigation of inhaled NO to prevent progression to more advanced disease in 42 hospitalized patients with COVID-19, at risk for worsening, based on baseline systemic oxygenation and 2 or more of the major risk factors of age \> 60 years, type II DM, hypertension, and obesity.

Detailed description:
Primary Objective:

• To investigate the hypothesis that inhaled NO will reduce clinical worsening of hospitalized, high-risk patients with early COVID-19 to progressive systemic de-oxygenation, intubation, or death.

Secondary Objectives:

• To investigate the hypothesis that the beneficial effects of inhaled NO occur coincident with a decrease in systemic inflammation in COVID-19.

This is a pilot randomized-controlled (2:1) open label investigation of inhaled NO to prevent progression to more advanced disease in 42 hospitalized patients with COVID-19, at risk for worsening, based on baseline systemic oxygenation and 2 or more of the major risk factors of age \> 60 years, type II DM, hypertension, and obesity.

We will perform computerized block randomization (on day zero) with a 2:1 study drug-to-control ratio to receive either open label pulsed inhaled nitric oxide, in addition to standard of care, or standard of care alone. Randomization will be stratified by being in clinical severity stage 1 or stage 2. Randomization will occur in blocks of 6 subjects: 4 iNO and 2 standard of care. Subjects will receive iNO using the INO pulse device at a dose of 125 mcg/kg IBW/hr (equivalent to approximately 20 ppm)

The clinical disease severity will be assessed pre-randomization as the worse of 2 scores measured 2 hours apart. Patients eligible for randomization will be those with scores of 1 or 2 (below), and randomization will be stratified according to score (1 or 2). Study drug will begin within 1 hour of randomization. Beginning on the day following randomization ("day 1"), we will be calculate clinical score, daily, as the average of 3 assessments made within 2 hour windows.

The patient will be followed, and clinical stage determined daily, through discharge, death or 28 days post-randomization. Treatment will be given for up to 2 weeks unless patient deteriorates and requires escalation to high flow or intubation or improves and is no longer deemed to need therapy.

The following severity score 3 times daily, based on the level of oxygenation / ventilation support, where the treatment target is 92% \<= O2 saturation \< 96%

: Scale Title:7-Point Respiratory Severity Scale Scale Range: 0-6 Higher values = worse

Stage Oxygen support

0\. Not receiving O2 supplementation; AND room air O2 saturation ≥95%

1. Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94%
2. Supplemental nasal O2 \>2 and \<= 5 liters/min
3. Supplemental nasal O2 \>5 liters/min
4. HFNC or NIV with FiO2 \> 50%
5. Intubation, ECMO, or need to intubate with "Do not intubate" order
6. Death

Treatment effect will also be assessed, as a secondary endpoint, via an alternate severity scale, assigned daily from the data accrued, as above, through 14 days post-randomization or discharge.

Data from this pilot study will be used to plan future a larger randomized controlled outcome trial.

Arms: arm 1: Will receive study drug treatment. arm 2: Will receive standard of care.
Interventions: intervention 1: Nitric Oxide
Intervention descriptions: intervention 1: Subjects will receive iNO using the INO pulse device at a dose of 125 mcg/kg IBW/hr (equivalent to approximately 20 ppm). The clinical disease severity will be assessed pre-randomization as the worse of 2 scores measured 2 hours apart. Patients eligible for randomization will be those with scores of 1 or 2 (below), and randomization will be stratified according to score (1 or 2). Study drug will begin within 1 hour of randomization. Beginning on the day following randomization ("day 1"), we will be calculate clinical score, daily, as the average of 3 measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM.

Protocol documents:
Prot_SAP_000.pdf: 
 
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VERSION 7/27/20 
 
 
TEMPLATE PROTOCOL INSTRUCTIONS: 
• 
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STUDY TITLE:  
 
Prevention of COVID-19 Progression Through Early Administration of Inhaled Nitric Oxide. The NO-
COVID Study. 
 
 
STUDY SPONSOR: Marvin A. Konstam, MD 
 
PRINCIPAL INVESTIGATOR  
Name: Marvin A. Konstam, MD 
Department: CardioVascular Center 
Telephone Number: 617-636-6293; Mobile: 617-519-1226 
Email Address: mkonstam@tuftsmedicalcenter.org 
 
VERSION DATE: 7/27/20 
 
 
 


 
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Table of Contents – Click on the links below to go directly to the applicable section 
 
A. 
Study Schema .................................................................................................................................................3 
B. 
Introduction ....................................................................................................................................................4 
B.1 Background and Rationale ..............................................................................................................................4 
B.2 Risks to Subjects .............................................................................................................................................5 
B.3 Potential Benefits to Subjects ..........................................................................................................................5 
B.4 Alternatives .....................................................................................................................................................5 
C. 
Objectives .......................................................................................................................................................6 
D. 
Enrollment and Withdrawal............................................................................................................................6 
D.1 Inclusion Criteria .............................................................................................................................................6 
D.2 Exclusion Criteria ............................................................................................................................................6 
D.3 Withdrawal of Subjects ...................................................................................................................................7 
D.4 Recruitment and Retention ..............................................................................................................................7 
D.4.1 Local Recruitment Methods .....................................................................................................................7 
D.4.2 Study-Wide Recruitment Methods ...........................................................................................................7 
D.4.3 Payment ....................................................................................................................................................7 
D.4.4 Reimbursement ........................................................................................................................................7 
E. 
Costs to Subjects.............................................................................................................................................7 
F. 
Study Design ..................................................................................................................................................7 
F.1 Study Timelines ...............................................................................................................................................7 
F.2 Procedures ........................................................................................................................................................8 
F.3 Evaluations.....................................................................................................................................................10 
F.4 Collection and Storage of Human Biological Specimens (Tissue Banking) .................................................10 
G. 
Ethics and Protection of Human Subjects ....................................................................................................10 
G.1 Informed Consent Process .............................................................................................................................10 
G.2 Waiver or Alteration of Consent Process ......................................................................................................11 
G.3 International Research ...................................................................................................................................11 
G.4 Confidentiality...............................................................................................................................................11 
G.5 Screening Data Collection Form/Screening Log...........................................................................................12 
G.6 Provisions to Protect the Privacy Interests of Subjects .................................................................................12 
G.7 Provisions to Monitor the Study to Ensure the Safety of Subjects ...............................................................12 
G.8 Vulnerable Populations .................................................................................................................................13 
H. 
Adverse Event Monitoring ...........................................................................................................................13 
H.1 Definitions .....................................................................................................................................................13 
H.2 Reporting Procedures ....................................................................................................................................14 
H.3 Reportable New Information .........................................................................................................................15 
I. 
Statistical Considerations .............................................................................................................................15 
I.1 Study Endpoints ..............................................................................................................................................15 
I.2 Statistical Analysis..........................................................................................................................................16 
I.3 Number of Subjects ........................................................................................................................................16 
I.4 Data Management ...........................................................................................................................................16 
I.5 Randomization ................................................................................................................................................16 
J. 
Drugs or Devices ..........................................................................................................................................17 
K. 
Study Administration ....................................................................................................................................17 
K.1 Setting ...........................................................................................................................................................17 
K.2 Registration ...................................................................................................................................................17 
K.3 Resources Available ......................................................................................................................................17 
K.4 IRB Review ...................................................................................................................................................18 
K.5 Multi-Site Research .......................................................................................................................................18 
K.6 Community-Based Participatory Research ...................................................................................................18 
K.7 Sharing Results with Subjects .......................................................................................................................18 
L. 
References ....................................................................................................................................................18 
 


 
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A. Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline assessments: measurement of disease severity score 
(Table 1), assessment of dyspnea (dyspnea score), oxygen 
saturation, ABG, IL6, TNFa, fibrinogen and CRP, ferritin, D-
dimer; creatinine, BUN, eGFR; Pregnancy test. 
Screening hospitalized COVID-19 patients with comorbidities.  
Enroll total N= 42: Obtain informed consent. 
iNO 
28 patients 
Placebo 
(inhaled 
nitrogen) 
14 patients 
Block 
Randomization 
Follow up assessments of study endpoints and safety: disease 
severity score (Table 1).  
Assessment of dyspnea (dyspnea score) 6±2 hours after 
initiation of treatment/placebo and daily thereafter 
Blood measurements at specific timepoints: 
-24 hours: IL6, TNFa, fibrinogen*, CRP*, ferritin*, D-
dimer*, and methemoglobin  
-72 hours: IL6, TNFa, fibrinogen* CRP*, ferritin*, D-dimer* 
-1 week: methemoglobin, IL6, TNFa, fibrinogen* CRP*, 
ferritin*, D-dimer* 
- Daily vital signs*, creatinine*, BUN*, eGFR* 
Presence or absence of inotrope use. 
                 * Standard of care.  
Baseline 
Daily up to 28 days 


 
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B. Introduction 
 
B.1 Background and Rationale 
 
Presently, the majority of patients testing positive for COVID-19 do not require hospitalization, have a 
self-limited course, and appear to have complete clinical recovery within 2-3 weeks [1]. However, 20% become 
hospitalized; approximately 5% of the total require critical care management; and overall mortality ranges from 1-
3% [1,2]. However, progression to severe disease, intubation, and death varies with underlying risks, including 
advanced age. For example, mortality ranges from 3-11% for patients aged 64-85 years and 10-27% for those > 
85 years old [2]. A treatment preventing disease progression in patients with mild to moderate hypoxemia, but at 
high risk for severe worsening, would represent a major healthcare advancement, with potential for substantial 
reduction in morbidity and mortality, as well as marked reduction in overall healthcare utilization and cost. 
 
Clinical worsening in COVID-19 is characterized by progressive dyspnea, reduced oxygenation, 
radiographic abnormalities, often leading to a pattern consistent with acute respiratory distress syndrome (ARDS). 
Patients who succumb often manifest sudden progression, pressor-resistant hypotension, massive systemic release 
of cytokines, and inability to oxygenate, with progressive alveolar-arterial oxygen gradients. Apparent clinical 
differences from other causes of ARDS include the rapidity of deterioration, the prominence of cytokine release, 
relatively maintained lung compliance, greater responsiveness to proning, and myocardial depression (likely 
cytokine-mediated), and vasoplegia, resulting in shock [3,4]. 
 
The COVID-19 virus enters the lungs via the receptor angiotensin converting enzyme-2 (ACE-2) [5]. 
Associated functional down-regulation of ACE-2 may play a role in mediating lung injury, through imbalance 
between angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), an ACE-2 cleavage product of Ang II [6]. The 
clinical syndrome may be mediated, at least in part, via pulmonary vasoconstriction, vascular inflammation and 
formation of microthrombi, increased oxidative stress, increased leukocyte and macrophage adhesion, reduced 
nitric oxide (NO) production and stability, endothelial dysfunction, and fibrosis.  
 
The pattern of risk factors identified for severe COVID-19 shows some overlap with complications of 
other viral infections, yet appears to be unique. High risk is associated with advanced age, type-2 diabetes 
mellitus (T2DM), hypertension, and obesity [7,8]. These are the precise risk factors for a specific form of heart 
failure with preserved ejection fraction (”HFpEF”), an end-product of what has been called metabolic-
inflammatory cardiovascular disease (M-I CVD) [9-11]. The likely pathobiology of the M-I CVD syndrome has 
been well-described, including cytokine-mediated vascular inflammation, endothelial dysfunction, reduced 
production of NO and cGMP and cardio-myocyte hypertrophy with interstitial fibrosis [12]. This pattern is 
strikingly similar to, and may be synergistic with, the likely pathologic mechanisms of severe COVID-19.  
 
We therefore postulate that therapeutic mitigation of this biologic pattern, likely characteristic of both M-I 
CVD and advanced COVID-19, will prevent the clinical progression, in patients at high risk, from the early stages 
of acute COVID-19 to extremis and death. One of the earliest manifestations of M-I CVD is impaired production 
of NO by endothelial cells [13,14]. Although nitrate therapies have not proven beneficial in patients with 
established HFpEF, in that case, treatment was aimed at improving diastolic function in patients with established 
cardiac disease. These patients were no longer likely to benefit from addressing the basic mechanisms that led to 
the ultimate cardiac structural and functional changes.  
 
Inhaled NO (iNO) is a potent pulmonary vasodilator, with established safety in patients with ARDS [15-17] 
and in those with right heart failure following cardiac transplant. It functions to maintain the anti-inflammatory 
and anti-thrombotic functions of the vascular endothelium.  It improves oxygenation in patients with ARDS with 
minimal systemic effects [15], though it is not proven to improve survival in studies of established ARDS [16-17]. 
However, prior non-confirmatory studies of iNO in patients with ARDS enrolled a heterogeneous population, in 
terms of etiology and underlying disease mechanism. Also, in contrast to patients with acute COVID-19, the lung 
injury of these patients was associated with increased lung stiffness. Those studies also focused on patients with 


 
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advanced disease, who might not have had an opportunity for maximal benefit from the mechanisms of iNO 
action. 
SPECIFIC AIM: To test the hypothesis that early supplementation of NO in the lung will prevent the 
progression of COVID-19 to fulminant ARDS by attenuating pulmonary vascular inflammation and microthrombi 
formation and by reversing pulmonary vasoconstriction to improve oxygenation.  Thus, we intend to investigate 
the protective role of inhaled NO in hospitalized COVID-19 patients with early systemic oxygen desaturation and 
risk factors for progression. We propose a randomized, open-label pilot study of 42 hospitalized, higher-risk 
COVID-19+ patients, with mild to moderate systemic oxygen desaturation, with the goal of preventing worsening 
oxygenation and need for increasing oxygen supplementation and/or ventilatory support. Based on the results of 
this study, we intend to proceed with a large scale investigation to definitively assess the impact on major clinical 
outcomes. Our presently  [18] proposed trial is unique in 1) focusing on prevention of progression in patients 
before they become severely ill and 2) aiming to provide clinically valuable data within the next 3 months. 
 
B.2 Risks to Subjects 
Inhaled Nitric Oxide is generally well tolerated without significant side effects. Adverse hemodynamic 
effects such as hypotension are very brief and are immediately reversible after discontinuation of the iNO due to 
the short half-life. Methemoglobinemia is a rare occurrence at the dose we are administering. NO2 monitoring is 
not available on the INOPulse device and is not deemed necessary because at the dose to be used (125 
mcg/kgIBW/min, corresponding approximately to 20 ppm), the level of NO2 generated is far below potentially 
toxic levels (18). Finally, iNO administration carries a small risk of renal dysfunction. [19]  
 
 
Patients randomized to the placebo group will receive inhaled nitrogen (N2, 99.999%) gas. Nitrogen is a 
colorless, odorless gas that makes up to 78% of the air we breathe. Since nitrogen is part of the atmospheric air, 
inhalation of nitrogen is well tolerated without side effects.  
Physical risks associated with the blood draw include bruising and/or some bleeding around the catheter 
and, rarely, infection. Lightheadedness and fainting may result from the blood sampling procedure.  
Non-physical risks to subjects include breach of privacy, all patient information will be de-identified and 
coded to mitigate this risk. No PHI will be retained for the purposes of this study. A unique, numeric code will be 
assigned to each patient.  The log linking the numeric code to the patient's health information will be maintained 
on a secure, password-protected computer in a locked research room.  Only study personnel will have access to 
the log. 
 
The study investigators and the staff performing this study are at risk of being infected by SARS-COV2 
and developing COVID-19. In order to minimize the risk, the investigators will use personal protective equipment 
(PPE) according to the Tufts Medical Center guidelines. We will also implement the remote consent process. This 
process includes virtual meeting via Zoom or Facetime among the investigator, the research team and the 
participant. Once the ICF has been reviewed and all questions have been answered, DocuSign app will be used to 
acquire electronic signatures. A copy of the ICF will be printed and given to the participant. Another copy will be 
printed and given to the unit coordinator to put in the patient’s medical records. The team will also create a 
template note that will be added to the patient record in Soarian. The note will document how consent was done 
and with whom. 
 
B.3 Potential Benefits to Subjects 
 
Although there, may be benefit from iNO, there is presently equipoise around this question. Therefore, 
there will be no direct benefits to the study subjects. However, successful completion of this study will provide 
significant scientific information on the effect of a relatively safe and readily available agent (iNO) on the 
prevention of COVID-19 progression. 
 
B.4 Alternatives 
 


 
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Participation in this study is completely voluntary. Patients can decide to participate or not to participate. 
Instead of being in this research study, treatment choices include standard supportive care with oxygen 
supplementation as needed based on the severity of your clinical presentation. Patients participating in this trial 
will not be prohibited from participating in any other trial and will be able to receive any other therapy deemed 
appropriate by the care team. We will exclude patients already receiving iNO. However, if, in the unusual event 
that the clinician determines that a study patient  requires iNO, he/she may discontinue study drug (without 
breaking the blind) and initiate open label iNO. The patient will, nevertheless, remain in the trial, with appropriate 
collection of endpoints. 
 
C. Objectives 
 
 
Our primary objective is to investigate the hypothesis that inhaled NO will reduce clinical worsening of 
hospitalized, high-risk patients with early COVID-19 to progressive systemic de-oxygenation, intubation, and 
death. 
Our secondary objective is to investigate the hypothesis that the beneficial effects of inhaled NO occur 
coincident with a decrease in systemic inflammation in COVID-19. 
 
D. Enrollment and Withdrawal  
 
D.1 Inclusion Criteria 
 
1. 
Age 18-90 years. 
2. 
Admitted to the hospital (med-surg or critical care) with dyspnea 
3. 
Diagnosis of COVID-19 based on either 
a) 
positive nasal or oral pharyngeal swab by PCR, or 
b) 
highly probable clinical picture based on clinical and CXR/CT scan  
4. 
Requiring oxygen supplementation OR O2 saturation on room air of ≤ 94%  
5. 
At least 1 of the following 4 risk factors for clinical worsening: 
a) 
Age ≥ 60 years 
b) 
T2DM or pre-diabetes as evidenced by either treatment with a hypoglycemic agent or any 
documented HgA1c ≥ 5.6 
c) 
Obesity, based on BMI ≥ 30 kg/m2 
d) 
Hypertension, based on treatment with an antihypertensive medication or systolic or diastolic 
blood pressure measurement ≥ 140 or ≥ 90 mmHg, documented at enrollment or at any time 
within the prior 6 months. 
 
D.2 Exclusion Criteria 
 
A subject is not eligible for inclusion if any of the following criteria apply: 
1. Intubated or prior intubation (during present hospitalization) or anticipated intubation within the 
subsequent 2 hours. 
2. Receiving > 5L/min flow nasal O2 to maintain O2sat ≥ 92% 
3. Using high-flow nasal cannula (HFNC) or non-invasive ventilation (NIV) 
4. Receiving iNO, a PDE5 inhibitor, oral or intravenous nitrates, nitroprusside, prilocaine, 
sulfonamides, or riociquat. 
5. Other major pulmonary, cardiac, such as chronic obstructive lung disease or heart failure, or 
systemic illness or disease involvement with potential to represent the primary driver for clinical 
deterioration within the next 3 days. 
6. History of group 1 pulmonary hypertension. 
7. Pregnancy 
8. Active breast feeding 
9. Acute kidney injury (AKI), evidenced by acute doubling of serum creatinine within previous 48 
hours  


 
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10. Clinically relevant spontaneous alteration of mental state 
11. Inability for the patient (or proxy) to provide written informed consent. 
 
Eligibility will be assessed after reviewing medical records, obtaining medical history and performing 
physical exam. 
  
Eligibility will be determined by the PI or the Co-I.  
 
Study subjects can participate in another research study while participating in this research study. 
 
D.3 Withdrawal of Subjects 
Subjects may withdraw at any time. Data collected up to the point of withdrawal will be retained in study 
documents.  
 
D.4 Recruitment and Retention 
 
D.4.1 Local Recruitment Methods 
PI and Co-Is will identify potential study candidates from the COVID-19 positive patients who are 
admitted at Tufts Medical Center. A HIPAA waiver for screening is requested to identify potential 
subjects. No recruitment materials will be given to potential subjects. No identifiable data will be retained 
for subjects that are determined to be ineligible.  
 
D.4.2 Study-Wide Recruitment Methods 
Is this  a multicenter study where subjects will be recruited by methods not under the control of the local 
Tufts site (e.g., call centers, national advertisements)?  
Yes
No
 
  
D.4.3 Payment  
Will subjects receive money, gifts, or any other incentive for participating in this study?  
This does not include reimbursement for expenses, which is considered in the next section.                   
Yes
No
     
  
D.4.4 Reimbursement  
Will subjects be reimbursed for their expenses, such as travel, parking, meals, or any other study related 
costs? 
Yes
No
   
                                  
 
E. Costs to Subjects 
Does the research involve any costs to subjects?  
Yes
No
  
 
F. Study Design 
 
F.1 Study Timelines 
 
From April 2020 through April 2021 we plan to enroll 42 hospitalized patients with COVID-19, at risk 
for worsening, based on baseline systemic oxygenation and at least one  of the major risk factors of age ≥ 60 
years, type II DM, hypertension, and obesity. The patient will be followed, and clinical stage determined 
                                                 
 
 


 
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daily, through discharge, death or 28 days post-randomization. Study drug will be given for up to 2 weeks 
unless the patient deteriorates and requires escalation to high flow oxygen or intubation or improves and is no 
longer deemed to need therapy. If the study drug is discontinued at 2 weeks or because of improvement and 
the patient subsequently deteriorates, the study drug may be resumed. 
 
F.2 Procedures 
 
Eligible subjects will be identified by an investigator or study coordinator and screened by a study 
coordinator. A HIPAA waiver for screening is requested to identify potential subjects. Subjects will be 
approached for informed consent and, upon consenting (see details about the remote consent process below), 
the following procedures will be followed. Pregnancy will be ruled out in women of child-bearing age with a 
pregnancy test prior to randomization. 
 
 
Randomization and iNO administration: 
 
 
We will perform computerized block randomization (on day zero) with a 2:1 study drug-to-placebo ratio 
to receive blindly either pulsed inhaled nitric oxide, in addition to standard of care, or inhaled nitrogen gas 
(N2, 99.999%) in addition to standard of care. Randomization will be stratified by being in clinical severity 
stage 1 or stage 2 (see Table 1, below). Randomization will occur in blocks of 6 subjects: 4 iNO and 2 
placebo. Subjects will receive iNO using the INO pulse device at a dose of 125 mcg/kg IBW/hr (equivalent to 
approximately 20 ppm). The INO pulse device will also be used for administration of inhaled nitrogen as 
placebo at a dose of 125 mcg/kg IBW/hr. The randomization will be performed by the research pharmacy as 
described below.  
 
The device: 
  is the size of a paperback book and weighs approximately 2.5 pounds 
  has a battery life of approximately 16 hours when fully charged 
  has a simple and intuitive interface that is user friendly 
  is compatible with many long-term oxygen therapy systems that operate via a nasal cannula 
  ensures a steady and accurate dose is administered by automatically adjusting to a patient’s breathing 
pattern.  
 
The clinical disease severity will be assessed pre-randomization as the worse of 2 scores measured 2 
hours apart. Patients eligible for randomization will be those with scores of 1 or 2 (below), and randomization 
will be stratified according to score (1 or 2). Study drug will begin within 1 hour of randomization. Beginning 
on the day following randomization (“day 1”), we will calculate clinical score, daily, as the average of 3 
measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM according to the following 
table:  
 
TABLE 1 
The following severity score 3 times daily, based on the level of oxygenation / ventilation support, where the 
treatment target is 92% ≤ O2 saturation < 96%: 
 
Stage 
Oxygen support 
0 
Not receiving O2 supplementation; AND room air O2 saturation ≥95% 
1 
Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94% 
2 
Supplemental nasal O2 >2 and ≤ 5 liters/min 
3 
Supplemental nasal O2 >5 liters/min 
4 
HFNC or NIV with FiO2 > 50% 
5 
Intubation, ECMO, or need to intubate with “Do not intubate” order 
6 
Death 
 
 
HFNC = high-flow nasal cannula; NIV = non-invasive ventilation 


 
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The primary endpoint is the maximum daily disease severity score recorded  from day 1 through discharge, 
death or 28 days post-randomization. We will test the difference in the average maximum disease severity 
score between the two treatment groups (see analysis section below). 
 
 
 
Experimental Procedures: 
 
Venous blood samples will be drawn as described in paragraph F3. 
 
Clinical Data Collection 
• 
Medical record will be reviewed for medical history, admission characteristics, diagnostic values, 
hemodynamic data, and other relevant data. 
• 
Clinical characteristics including age, date of birth, gender, BMI, comorbidities (such as 
hypertension, diabetes, history of cardiovascular disease) will be collected from medical 
records. 
• 
Baseline vital signs will be collected from chart review. 
• 
Clinically indicated lab results will be collected from medical records.  
 
 
Our study has a control arm. Patients randomized in the control arm will receive inhaled nitrogen gas 
(placebo) in addition to standard of care as opposed to iNO plus standard of care, in a double blinded fashion.  
The research pharmacy will be responsible to randomize the patient and dispense the study drug in a blinded 
fashion. The active study drug, iNO, will be supplied by the drug company to the research pharmacy in size 
0.074 liter aluminum cartridges at a concentration of 6.0 mg/L (4880 ppm). Placebo to match study drug will 
also be supplied by the drug company to the research pharmacy in size 0.074 liter aluminum cartridges 
containing nitrogen (N2, 99.999%) gas. 
 
Both the nitric oxide and placebo cartridges will be labeled identically to maintain the blind throughout the 
study. All study drug kits and cartridges will be labeled with informative language that each cartridge contains 
up to 6.0 mg/L (4880 ppm) NO or nitrogen gas to allow for compliance with compressed gas transportation 
regulations while maintaining a blinded label.  Prior to shipment to the investigational site, all study drug will 
be labeled with unique identification numbers that will be used to trace the units to the specific treatment type 
and subject.  Drug kits and cartridges are intended for use by a single subject.   
 
The research pharmacy staff will serve as the unblinded personnel.  They will be responsible for securing the 
list of unique numbers and their corresponding treatment types (6.0mg/L (4880ppm) NO gas or matching N 
(placebo), as well as assigning the specific kit and cartridge numbers that correspond to the treatment 
assignment of each individual subject.  
 
The blind may be broken only if specific urgent treatment would be dictated by knowing the treatment status 
of the subject. In such cases, the Investigator or designee will contact the unblinded team member to request 
the subject treatment be unblinded.  The date, time, and reason for the unblinding will be documented. 
  
Because of the significant limitations of making clinical assessments on COVID-19 positive subjects we will 
use the oxygen saturation and oxygen support recorded by nursing as part of routine care. The recorded 
oxygen support and oxygen saturation will be verified by the research personnel without the need for research 
personnel to use personal protective equipment. 
 
Dyspnea score endpoint. Dyspnea will be assessed using a visual analog scale from 0 (not at all) to 10 (very 
severe). Patients will be asked “How short of breath are you?” and directed to indicate their response on the 
scale. They will mark their response with ink, which will be timed and enables patients to track their 
responses. The scoring sheet will be photographed during a routine clinical visit, using a secure iPad, with the 


 
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image transformed into a pdf to maintain documentation. Dyspnea ratings will be done at baseline, after 6±2 
hrs of therapy and daily thereafter up to a week or as long as therapy continues. This score has been described 
in prior studies by Dr Hill. There is no added risk to the patient. (Kramer N, Meyer TJ, Meharg J, Cece RD, 
Hill NS. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory 
failure. Am J Respir Crit Care Med. 1995 Jun;151(6):1799-806.) 
 
F.3 Evaluations 
Will you perform any laboratory tests for this study? 
Yes
No
  
If Yes, describe the following 
• 
As is routine for standard of care, blood tests for fibrinogen, CRP, ferritin, D-dimer levels will be 
measured at baseline, 24 hours, 72 hours, and one week. These will be processed through the clinical 
pathology laboratory, and in compliance with Clinical Laboratory Improvement Amendments (CLIA) of 
1988 
• 
An extra tube of blood will be drawn at baseline, 24 hours, 72 hours, and one week, and analyzed 
in the MCRI laboratory for the measurement of IL6 and TNFa for research purposes only. (See 
Section F4) An extra tube of blood will be drawn at 24 hours and at one week and processed 
through clinical pathology for the measurement of methemoglobin if patients are still receiving 
iNO or inhaled nitrogen gas at these time points.  
• 
Blood draw for these additional tests will be timed to coincide with those done for routine clinical care so 
as to avoid additional blood draws.  
 
F.4 Collection and Storage of Human Biological Specimens (Tissue Banking) 
Will biological specimens be stored for future, unspecified, research?  
Yes
No
  
 
Venous blood will be collected from the patient prior to iNO initiation and at 24 hours, 72 hours and 1 week after 
iNO initiation. One venous blood sample will be placed into an EDTA-treated vacutainer tube and the second 
sample will be placed into a vacutainer tube without anticoagulant. The tubes will be immediately placed on ice 
and transferred to the laboratory for processing. The blood samples will be centrifuged for 12 minutes at 1500 x g 
at 4°C. After centrifugation, the supernatant from the EDTA treated tube (plasma) and the supernatant from the 
vacutainer tube without anticoagulant (serum) will be transferred to microcentrifuge tubes using a disposable bulb 
pipette. The microcentrifuge tubes containing the plasma and the serum will be stored in a -80°C freezer in the 
MCRI for at least 2 years. The plasma and the serum will be used for the investigational measurement of IL6, 
TNFa and future research investigations. Samples will be labeled with the patient’s study ID and may be released 
to outside investigators. 
 
 
G. Ethics and Protection of Human Subjects 
 
G.1 Informed Consent Process 
Will subjects be required to provide informed consent? Yes, and non-English speakers will be permitted to 
enroll using interpreters and IRB approved Short Forms 
Yes
No
   
We will follow the remote consenting process in order to minimize the risk of viral transmission to 
the research staff and the patient’s legal representatives: 
 
After we identify the potential participant (or the legal representative if the potential participant is 
unable to consent) we will set up a time for a Zoom or Facetime call with an investigator (PI or Co-I), the 
participant, an impartial witness (not on the study team), and a study coordinator. The investigator will review 
the entire ICF with the participant (or legal representative) via Zoom or Facetime. If an interpreter is needed, 
they can be on the call, or a family member can interpret. Everyone on the phone call listens to the ICF review 


 
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and has an electronic copy in front of them. Once the ICF has been reviewed and all questions answered, 
DocuSign app will be used to acquire electronic signatures. Specifically, through DocuSign, the ICF will be 
sent first to the participant (or legal representative), then to the PI. Once all electronic signatures are acquired, 
a copy with be saved at the study files. Another copy will be printed and given to participant (or legal 
representative) to keep. Finally, a third hard copy will be printed and given to unit coordinator to put in the 
patient´s medical records. They research team will also use a remote consent verification document to verify 
how consent was given by the participant or their legal representative. The document will be placed into the 
electronic medical records and electronically signed and time stamped by the investigator. It will serve to 
document the process of obtaining consent. 
 
If the potential participant is unable to electronically sign the document, the following process will be used. A 
witness, who is not a member of the study team, will be present on the call explaining the ICF to the participant or 
their legal representative. The witness will be present on the call when the participant consents to join the study. 
The witness will then electronically sign the ICF document using DocuSign. The research team will also use the 
remote consent verification document to verify how consent was given by the participant (or legally authorized 
representative) and the witness who was present. The document will be signed and dated by the PI or Co-I. The 
time will also be documented. A hardcopy of the electronically signed ICF will be printed and given to the 
participant. A copy will also be filed electronically in the patient’s medical record along with the consent 
verification document.  
 
 
G.2 Waiver or Alteration of Consent Process 
This applies for studies where informed consent will not be obtained, required information will not be disclosed, or the 
research involves deception. 
1. Is a waiver or alteration of the consent process being requested for this study?  
Yes
No
  
 
2. Is a waiver of the consent process being requested for parents for research involving children?  
 
Yes
No
  
  
3. Is a waiver of the consent process for planned emergency research being requested?  
Yes
No
  
 
G.3 International Research 
Refer to the IRB’s International Checklist and International Guidance and include all relevant information 
described in those documents in this protocol: N/A 
 
G.4 Confidentiality 
 
Procedures to protect subject confidentiality:  
 
All study documentation will be stored in the PI’s locked office. All subjects will be assigned 
study ID numbers and wherever possible all data will be marked with the study ID number instead of the 
name or personal identifier. Any research material sent to the Sponsor will be redacted and de identified.  
All study records will be retained for the timeframe described in the record retention policy of the “SOP – 
Records Retention Timeframe – Investigators.” Any research information that is part of the subject’s 
medical records will be kept indefinitely. All paper research records will be kept on campus at Tufts 
Medical Center, de identified and in a locked office. 
 
How data will be coded, recorded, and stored to protect confidentiality: 
 


 
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Subjects will be identified on the Case Report Form (CRF), documents where study-related data 
will be collected, by an identification number.  The investigator will maintain a confidential list of the 
subjects involved in the study, separate from the CRFs that will serve as a means of linking the subject 
identification number to the medical records.  All data used in analysis and reports will be used without 
identifiable reference to the patient.    
 
Only the PI and study coordinators will have access to the code key for the CRF. 
 
PI, Co-Is, Research Coordinators, will have access to study records. 
 
We confirm that we will follow the “Confidentiality and Data Security Guidelines for Electronic Research 
Data” for electronic data 
 
G.5 Screening Data Collection Form/Screening Log  
This section specifically refers to data collected about potential subjects who are screened, but have not signed consent, 
for example potential subjects whose medical record is reviewed to see if they are potentially eligible, potential subjects 
who respond to a telephone screening call where the research team records information about the potential subject, etc. 
In this section “Screening Data / Screening Log” refers to any form of data collection on potential subjects who have not 
yet signed consent. For more information, refer to https://privacyruleandresearch.nih.gov/clin_research.asp. 
 
Will a screening data/screening log be used in this research study?  
Yes
No
  
 
G.6 Provisions to Protect the Privacy Interests of Subjects 
 
In order to protect the privacy interests of the study subjects we will ensure that discussion of the study 
will take place in a private area where subjects cannot be overheard. We will also make sure that the study 
subjects are comfortable with the research team members. 
  
G.7 Provisions to Monitor the Study to Ensure the Safety of Subjects 
 
Inhaled NO is a colorless, odorless gas that offers a substantial safety margin at the doses contemplated. It 
is rapidly deactivated by combination with hemoglobin upon entry into the systemic circulation. Therefore, it 
is unlikely to lower blood pressure or cause systemic side effects. An excess of methemoglobin is exceedingly 
unlikely with doses being administrated. Renal impairment caused by iNO appears to be rare.  
 
The principal investigator, with the assistance of the study coordinator, will be reviewing the safety data 
at least monthly. Additional safety monitoring will be performed by a physician who otherwise has no 
involvement in the study. The Data Monitoring Committee will meet to monitor unblinded safety data after 
the first 20 participants. Blinded SAEs will be reviewed weekly. The data will be obtained from chart review 
and from the study database.  
By protocol, we will discontinue iNO if the patient needs to escalate care to HFNC, NIV, or intubation. In 
addition, we will discontinue iNO if: 
• 
there is any suspicion that iNO is leading to harm and, specifically if:  
• 
the patient develops sustained hypotension with systolic blood pressure < 85mmHg, unresponsive 
to fluids; 
• 
the patient develops AKI, evidenced by a doubling of serum creatinine compared to baseline; 
• 
methemoglobin level exceeds 5%  
 
The inhaled nitrogen is a colorless, odorless gas that makes up to 78% of the air we breathe and does not 
impose any risk on the patient. 
 


 
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G.8 Vulnerable Populations 
If the research involves individuals who are vulnerable to coercion or undue influence, describe the rationale for their 
inclusion and the additional safeguards included to protect their rights and welfare. 
1. Can or will pregnant women be enrolled?   
Yes
No
  
 
2. Can or will the research involve neonates of uncertain viability or non-viable neonates?  
Yes
No
  
 
 
3. Can or will subjects who are not yet adults (neonates, children, teenagers) be enrolled?  
Yes
No
  
 
4. Can or will minors who are:  
i) 
married, widowed, divorced; or  
ii) 
the parent of a child; or  
iii) 
a member of any of the armed forces; or  
iv) 
pregnant or believes herself to be pregnant; or  
v) 
living separate and apart from his/her parent or legal guardian, and is managing his/her own 
financial affairs  
be approached for study participation for either themselves or their child?  
 
Yes
No
  
 
 
 
5. Can or will wards of the state and/or children at risk of becoming wards of the state be enrolled (this 
includes foster children or any child that is in state custody)?            
 
Yes
No
  
 
6. Can or will cognitively impaired adults (adults with impaired-decision making capacity) or adults who 
may lose the capacity to consent be enrolled?  
Yes
No
  
 
 
7. Can or will prisoners be enrolled?   
Yes
No
  
 
8. Can or will students and/or employees be enrolled in this research?  
Yes
No
 
 
 
H.  Adverse Event Monitoring 
 
H.1 Definitions 
 
Adverse Events: (Examples and not limited to) 
• 
Hematoma 
• 
Bleeding at needle puncture site 
• 
Infection  
• 
Hypotension 
Serious Adverse Events: 
• 
Death  


 
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• 
Methemoglobinemia 
• 
Renal failure 
 
 
H.2 Reporting Procedures 
 
Study subjects will be monitored for the occurrence of adverse events defined as any clinically 
significant undesirable experience, from the day of enrollment until discharge. All adverse events will be 
recorded on an adverse event case report form and will include a description of all undesirable 
experiences, required interventions, subject’s condition after the event, an estimate of the extent of injury 
and potential strategies to prevent future occurrences. The principal investigator will classify the 
relationship of the study protocol to the event. The principal investigator will report serious adverse 
events (death, life threatening, new, serious or permanent disability or adverse event culminating in 
hospitalization) according to IRB requirements. An adverse event is considered to be serious (SAE) if it 
results in any of the following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or 
• 
A congenital anomaly/birth defect 
 
Non-serious adverse events will be summarized quarterly for the IRB.  The adverse event case 
report form will include a description of all undesirable experiences or unanticipated benefits, required 
interventions, patient’s condition after the event, an estimate of the extent of injury, and prevention 
strategies. The principal investigator will classify the relationship of the study protocol to the event as 
follows: 
• 
Not related: An AE that is clearly and incontrovertibly due to extraneous causes (disease, 
environment, other drugs etc.)  
• 
Unlikely related:  An AE may be considered unlikely related if: 
o Event or laboratory test abnormality, with a time to drug intake that makes a relationship 
improbable (but not impossible)  
o Disease or other drugs provide plausible explanations  
• 
Possibly related: An AE may be considered ‘possibly related’ if it meets at least 1 of the 
following criteria: 
o It follows a reasonable temporal sequence from administration of investigational product. 
o It may readily have been produced by the subject's clinical state or by environmental or 
toxic factors. 
o It follows a known response pattern to investigational product. 
• 
Probably related: An AE that is considered to be related to investigational product with a high 
degree of certainty. An AE may be considered probably related if it meets all of the following 
criteria: 
o It follows a reasonable temporal sequence from administration of investigational product. 


 
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o It cannot be reasonably explained by the known characteristics of the subject's clinical 
state. 
o It follows a known pattern of response to investigational product treatment. 
o It reappears upon re-challenge 
 
 
The severity of an adverse event in both groups is defined as a qualitative assessment of the degree of 
intensity of an adverse event as determined by the principal investigator as follows:  
• 
Mild: Discomfort noticed, but no disruption to daily activity  
• 
Moderate:  Discomfort sufficient to reduce or affect normal daily activity  
• 
Severe: Inability to work or perform normal daily activity 
 
The principal investigator will follow-up on all serious events on a case-by-case basis. All adverse events 
will be summarized and reviewed on a quarterly basis 
 
H.3 Reportable New Information 
 
Reportable new information will be reported to the IRB per the Tufts Health Sciences IRB’s Reportable 
New Information policy.  
 
I. Statistical Considerations 
 
I.1 Study Endpoints 
 
1. Primary Endpoint: Prevention of progressive systemic de-oxygenation, with escalation to higher levels of 
oxygen and ventilatory support. Between-group differences in the average maximum disease severity score 
(Table 1) assessed through 28 days, through the following severity states: a) increased liter oxygen flow, 
through a high flow nasal cannula; b) non-invasive ventilation; c) intubation or institution of ECMO; or d) 
death. 
 
2. 
Secondary Endpoints: 
 
• 
Assessment based on an alternate 8-point Ordinal Outcome Scale, 
assigned daily from the data accrued, as above, through 28 days post-
randomization or through discharge. Scale is as follows (a score of 
either 7 or 8 will be assigned at time of discharge): 
 1 Death  
 2 Hospitalized, requiring mechanical ventilation or ECMO  
 3 Hospitalized, requiring non-invasive ventilation or high flow 
oxygen  
 4 Hospitalized, requiring supplemental oxygen  
 5 Hospitalized, not requiring supplemental oxygen - requiring 
ongoing medical care (COVID-19 related or otherwise)  
 6 Hospitalized, not requiring supplemental oxygen - not 
requiring ongoing medical care (COVID-19 related or 
otherwise)  
7 Not hospitalized - limitation on activities and/or requiring 
home oxygen 
8 Not hospitalized, no limitations on activities 
 
• 
Time to reaching maximal disease severity score 
• 
Proportion of patients in each stage at maximum severity 


 
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• 
Dyspnea score, measured at baseline, 6±2 hrs after initiation and then daily until patient stops iNO or 
reaches 7 days 
• 
PaO2/FIO2 or SaO2/FIO2 ratio, measured daily 
• 
Length of hospital Stay (death assigned as worst case) 
• 
Intubation, ECMO, or need to intubate with an “Do Not Resuscitate” order 
• 
Mortality 
• 
Levels of inflammatory mediators, including IL6, TNFα, fibrinogen, CRP, ferritin, D-dimer 
 
I.2 Statistical Analysis 
 
 
We plan to enroll 42 patients (28 iNO and 14 placebo). Data will be reported using means or medians, 
depending on patient distributions, and confidence intervals. The primary endpoint is the difference in 
average maximum disease severity between treatment groups through discharge, death or 28 days post-
randomization. 
 
 
Statistical Methods: Data analysis will be based on Intention-to-Treat.  The primary endpoint will be 
compared using a two-sample t-test. If our data show significant departures from normality we will employ an 
appropriate non-parametric test. Secondary analyses will include comparisons between groups using the Chi-
square or Fisher’s exact test for categorical variables and two-sample t-test, repeated measures analysis, non-
parametric statistical methods or time-to-event analyses as appropriate. Secondary analyses will include 
comparison of oxygen saturation and source as continuous variables. For this pilot study, no adjustments will 
be made for testing secondary hypotheses. P-values <0.05 will be considered significant. 
 
 
Power considerations: Based on our experience with standard of care, we estimate that sample sizes of 28 
and 14 in the study drug and control group, respectively, achieve 80% power to reject the null hypothesis of 
equal average maximum severity score when the mean is 3.36 in the standard of care group and 1.91 in the 
nitric oxide group with a standard deviation for both groups of 1.54 (effect size of 0.94) and with a 
significance level of 0.05 using a two-sided two-sample equal-variance t-test.  The power calculation was 
performed using PASS 16. 
 
I.3 Number of Subjects 
 
We plan to enroll 42 patients (28 iNO and 14 placebo). 
 
I.4 Data Management 
 
Data collected will be stored and managed in a secure study database hosted through Tufts Medical 
Center. Access to the database will be managed by the clinical data manager.  The study coordinator and the 
co-PIs of the study will enter data into the EDC via hospital-approved password-protected computers in 
locked offices in the hospital. 
Stored Specimens: 
a. Will be de-identified and labeled with study name, sample type, and purpose  
b. Will be stored for 2 years in a -80⁰C or colder freezer, at Tufts MC. 
c. Only the Study Team will have access to specimen and data  
  
  
I.5 Randomization  
Will subjects be randomized?  
 
If Yes respond to all of the following: 
Yes
No


 
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1. Describe the randomization procedures, including the ratio of subjects randomized to each study arm: 
Patients will be randomized 2:1 to blindly receive pulsed inhaled nitric oxide, in addition to standard of 
care, or placebo (inhaled nitrogen gas) in addition to standard of care in blocks of 6 subjects. A 
computerized block randomization program will be used. 
2. Describe the blinding procedures  or ☐N/A the study will not be blinded. 
 
 
The research pharmacy will be responsible to randomize the patient and dispense the study drug in a blinded 
fashion. Please see section F2 for randomization process.  
 
J. Drugs or Devices 
1. Will the research involve drugs?   
Yes
No
  
2. Will the research involve devices?   
Yes
No
   
If Yes to either, respond to all of the following: 
 Who on the research team, in addition to the Principal Investigator, will be accountable for drug(s): 
The research coordinator, Abbey Haynes, as well as Dr Hill who is a Co-Investigator  
 Who will interface with the pharmacy? Abbey Haynes and Dr. Diakos  
 If pre-printed orders will be created to obtain study drug(s) from the pharmacy, describe the 
procedures for reviewing and verifying the accuracy of the pre-printed orders prior to their being 
implemented:       or ☒N/A, there are no pre-printed orders  
 If computerized order sets are created and/or infusion devices need to be programmed to administer 
an investigational drug, indicate the mechanism to pre-review and verify their accuracy, including 
who will be involved in this process from the research team, pharmacy, and nursing:       or  
☒N/A, there are no computerized orders sets and/or infusion devices.  
 The study drug, device, or procedure (including beneficial health care procedures) will be available 
to subjects after participation in the study: ☐Yes   ☒N/A    
 There are medications or other substances that should not be taken while participating in the study. A 
list of these are incorporated into the ICF a subject handout: ☐Yes   ☒N/A  
 Handouts or instructions sheets that will be given to subjects on how to administer study drug(s) or 
use study device(s) have been submitted to the IRB: ☐Yes   ☒N/A 
 
K. Study Administration 
K.1 Setting 
 
 Describe the sites / locations where your research team will conduct the research:  
Research will be conducted at in-hospital med-surg or critical care unit of Tufts Medical Center. Standard 
personal protective equipment will be mandated when it is necessary for any clinical trial personnel to 
enter the patient room.  
 The research will take place at an international site, and the International Guidance and International 
Checklist were utilized: ☐ Yes   ☒ N/A  
 
K.2 Registration 
 
The study coordinator will ensure study subject eligibility and whether informed consent has been signed 
prior to any intervention. 
 
K.3 Resources Available 
Team: 
• 
PI: Dr. Marvin Konstam is a board-certified cardiologist and advanced heart failure specialist 
who has extensive experience with the design and performance of clinical trials. 


 
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• 
In the absence of the PI, Dr. Hill will serve as acting PI.  
• 
Co-Investigators: Dr. James E. Udelson, Dr. Iris Z. Jaffe and Dr. Navin K. Kapur are board 
certified cardiologists and will be responsible for data collection and analysis, screening, and 
consent processes.  
• 
Co-Investigators: Dr. Nicholas Hill and Dr. Harrison Farber are board certified pulmonologist 
and critical care physicians and will be responsible for data collection and analysis, screening, 
and consent processes.  
• 
Co- Investigator: Dr. John Adam Reich is a board certified anesthesiologist and critical care 
physician and will be responsible for data collection and analysis, screening, and consent 
processes. 
• 
Co-Investigator: Leslie Lussier, MS, RRT, Director of Respiratory Therapy at Tufts Medical Center 
will oversee her team in instituting and maintaining therapy with iNO study drug, as well as 
managing administration of oxygen treatment. She will work closely with the research pharmacy to 
assure delivery of the correct agent to which the patient has been randomized. 
• 
Co- Investigators: Dr. Nikolaos Diakos, Dr. Gaurav Gulati, and Dr. Mehak Dhande are 
cardiology fellows training at Tufts Medical Center and will be responsible for data collection 
and analysis, screening, and consent processes.  
• 
Coordinator: Abbey Haynes is a clinical research coordinator and will be responsible for 
helping with data collection and analysis, screening, and consent processes 
All study team members will be trained in the protocol and sign a delegation log acknowledging 
their responsibilities for the study.  
 
K.4 IRB Review 
1. ☒Check to confirm that an appropriate IRB registered with the OHRP, will review and approve this 
study.   
2. ☒Check to confirm that any amendments to the protocol or informed consent documents will be reviewed 
and approved by the IRB prior to use, unless required to eliminate an apparent immediate hazard to 
subjects.    
    
K.5 Multi-Site Research 
Is this a multi-site study where Tufts is the sponsor, primary grant recipient, or coordinating site?: 
Yes
No
  
 
K.6 Community-Based Participatory Research 
Note: “Community-based Participatory Research” is a collaborative approach to research that equitably involves all 
partners in the research process and recognizes the unique strengths that each brings. Community-based Participatory 
Research begins with a research topic of importance to the community, has the aim of combining knowledge with action 
and achieving social change to improve health outcomes and eliminate health disparities. 
Can or will this study involve community-based participatory research?  
Yes
No
  
 
K.7 Sharing Results with Subjects 
Will results (overall study results or individual subject results, such as results of investigational diagnostic 
tests, genetic tests, or incidental findings) be shared with subjects or others (e.g., the subject’s primary care 
physician or the subject’s treating physician)?   
Yes
No
  
 
 
References  


 
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1.Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 
2020. doi: 10.1056/NEJMoa2002032. [Epub ahead of print]. 
2.Team CC-R. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, 
February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69:343-6. 
3.Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, 
China. Lancet 2020;395:497-506. 
4.Gattinoni L, Coppola S, Cressoni M, Busana M, Chiumello D. Covid-19 Does Not Lead to a "Typical" Acute 
Respiratory Distress Syndrome. Am J Respir Crit Care Med 2020. doi: 10.1164/rccm.202003-0817LE. [Epub 
ahead of print]. 
5.Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 
and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020. doi: 10.1016/j.cell.2020.02.052 [Epub ahead 
of print]. 
6.Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-
Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 2020. doi: 10.1056/NEJMsr2005760. 
[Epub ahead of print]. 
7.Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in 
Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-62. 
8.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. doi:10.1001/jama.2020.1585. 
9.Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved 
ejection fraction. Circulation 2015;131:269-79. 
10.Jumean MF, Konstam MA. Heart Failure With Preserved Ejection Fraction: What Is in a Name? Cardiol Rev 
2015;23:161-7. 
11. Konstam MA, Abboud FM: Ejection Fraction: Misunderstood and Overrated: Changing the Paradigm in 
Categorizing Heart Failure. Circulation. 2017;135:717-719. 
12.Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 
2014;11:507-15. 
13.Silberman GA, Fan TH, Liu H, et al. Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. 
Circulation 2010;121:519-28. 
14.van Heerebeek L, Hamdani N, Falcao-Pires I, et al. Low myocardial protein kinase G activity in heart failure 
with preserved ejection fraction. Circulation 2012;126:830-9. 
15. Gerlach H, Keh D, Semmerow A et al. Dose-response characteristics during long-term inhalation of nitric 
oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. 
American journal of respiratory and critical care medicine 2003;167:1008-15. 
16.Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results 
of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive care medicine 
1999;25:911-9. 
17.Taylor RW, Zimmerman JL, Dellinger RP et al. Low-dose inhaled nitric oxide in patients with acute lung 
injury: a randomized controlled trial. Jama 2004;291:1603-9. 
18.  INVESTIGATOR’S BROCHURE: INHALED NITRIC OXIDE/INOPULSE® DELIVERY DEVICE FOR 
USE IN THE TREATMENT OF SUBJECTS WITH COVID-19. (Bellerophon Therapeutics, Inc., Warren NJ) 
March 28, 2020.   
19. Ruan S-Y, Wu H-Y, Lin H-H et al. Inhaled nitric oxide and the risk of renal dysfunction in patients with acute 
respiratory distress syndrome: a propensity-matched cohort study. Crit Care. 2016; 20: 389. 
 
 

ICF_001.pdf: 
Prevention of COVID-19 Progression Through Early Administration of Inhaled Nitric Oxide 
         
PI: Marvin Konstam, MD 
ICF version: 07/24/2020 
 
Page 1 of 12 
 
 
VERSION 07/24/20 
TUFTS MEDICAL CENTER 
TUFTS UNIVERSITY 
Cardiology 
 
INFORMED CONSENT TO PARTICIPATE IN RESEARCH  
 
Prevention of COVID-19 Progression Through Early Administration of Inhaled Nitric Oxide 
 
Protocol Number: STUDY00000554 
 
Principal Investigator: Marvin A. Konstam, MD 
 
Co-Investigators: Nicholas Hill, MD 
     Iris Jaffe, MD 
     James Udelson, MD 
     John Adam Reich, MD 
     Navin Kapur, MD,  
     Harrison Farber, MD 
     Nikolaos Diakos, MD 
     Gaurav Gulati, MD 
     Mehak Dhande, MD 
     Leslie Lussier, MS, RRT 
 
Study Coordinator: Abbey Haynes 
 
Study team telephone number: Marvin Konstam, MD: 617-636-6293 
 
 
 
 
  Abbey Haynes: 617-636-4990 
  24 Hour Number: 617-636-5114 
 
Key Information: The following is a short summary of this study to help you decide whether 
or not to be a part of this study. More detailed information is listed later on in this form. 
 
Why am I being invited to take part in a research study? 
We invite you to take part in a research study because you have been diagnosed with 
Coronavirus Disease 2019 (COVID-19). 
 
What should I know about a research study? 
• Someone will explain this research study to you. 
• Please also read all of the following information carefully. 
• Whether or not you take part is up to you. 
• You can choose not to take part. 
• You can decide to take part and later change your mind. 
• Your decision will not be held against you. 


Prevention of COVID-19 Progression Through Early Administration of Inhaled Nitric Oxide 
         
PI: Marvin Konstam, MD 
ICF version: 07/24/2020 
 
Page 2 of 12 
 
• You can ask all the questions you want before you decide. Do not sign unless you 
understand the information in it and have had your questions answered to your 
satisfaction.   
• If you sign this form and decide to take part in this research study, keep a copy of the 
signed form for your records. It has information, including important names and 
telephone numbers, which you may wish to refer to. 
 
Why is this research being done? 
The purpose of this study is to investigate the effect of inhaled nitric oxide (iNO) in the 
prevention of progression of COVID-19. iNO has been used by doctors for many years to treat 
many different conditions. If you agree to participate, you will be randomly assigned to receive 
either iNO or a placebo (nitrogen gas). You will have a two out of three chance of receiving iNO.  
 
How long will the research last and what will I need to do? 
Regardless of which agent (iNO or nitrogen) you are assigned to receive, we expect that it will 
continue for up to 2 weeks, until your condition changes or you are discharged. It will stop if 
your condition improves or if you require higher flow oxygen, or a breathing tube.  Regardless of 
whether your condition improves, we will continue to observe your condition for 28 days or until 
you are discharged, whichever comes first. 
 
You will be given the agent (either iNO or nitrogen) through an iNO device. Blood samples, for 
your routine clinical care will be collected regularly. An extra tube of blood will be collected at 
baseline, at 24 hours, at 72 hours and 1 week for this study as well. Regardless of whether you 
are receiving iNO or nitrogen, another extra blood tube will be collected at 24 hours and at one 
week for measurement of methemoglobin in order to monitor for iNO toxicity. The amount of 
oxygen in your blood will be tested continuously with pulse oximeter or arterial blood gas 
measurements, according to the standard of care for subjects with acute respiratory disease. A 
pulse oximeter is a small, lightweight device that attaches painlessly to your fingertip and is 
sending light through your finger to measure the amount of oxygen carried by your body. It is 
called “pulse” because it responds to the pulsation of your small arteries of your fingertip in 
order to measure the oxygen.  
 
More detailed information about the study procedures can be found under the “Procedures to be 
Followed” section. 
 
Is there any way being in this study could be bad for me?  
Inhaled Nitric Oxide is well tolerated without significant side effects. Blood pressure drop is the 
most common side effect and lasts for a short period of time. Methemoglobinemia is a condition 
in which hemoglobin, which is the oxygen delivering molecule, is changed by the iNO and 
becomes unable to transfer adequate oxygen to the tissues. We will be testing your blood for this 
effect, which is another rare side effect of iNO, particularly with the dose being administered. 
Nitrogen is a non-reactive gas that makes up 78% of the air we breathe. There are no known 
risks to inhaling the small amount of extra nitrogen that would occur with this study. Nitrogen 
does not carry a risk of blood pressure drop or methemoglobinemia. Neither the iNO or nitrogen 
will interfere with oxygen that you may be receiving as part of your care for COVID-19. 


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There are some possible risks associated with having your blood drawn including bruising and/or 
some bleeding at the needle puncture site. Rarely an infection may develop. Lightheadedness and 
fainting may result from the blood sampling procedure. 
 
More detailed information about the risks of this study can be found under the “Risks” section. 
 
Will being in this study help me in any way? 
We cannot promise any benefits to you or others from your taking part in this research.  
 
What happens if I do not want to be in this research? 
Participation in research is completely voluntary. You can decide to participate or not to 
participate. Instead of being in this research study, your choices may include standard supportive 
care with oxygen supplementation as needed based on the severity of your clinical presentation. 
If in your doctor’s opinion you should receive treatment with iNO, your doctor will not be 
prohibited to prescribe iNO to you, even if you decide not to participate in this study or even if 
you participate in the study and you are selected to be in the control group.  
Subjects participating in this trial will not be prohibited from participating in any other 
trial and will be able to receive any other therapy deemed appropriate by the care team. 
However, additional ongoing research trials of treatments being investigated may be closed to 
you, since they may exclude subjects participating in other trials like this one. 
 
 
Detailed Information: The following is more detailed information about this study in 
addition to the information listed above. 
 
PURPOSE OF STUDY 
 
The purpose of this study is to investigate the effect of inhaled nitric oxide (iNO) in the 
prevention of progression of Coronavirus Disease 2019 (COVID-19). COVID-19 is a global 
pandemic which is caused by a virus called Severe Acute Respiratory Syndrome Coronavirus-2 
(SARS CoV-2). The majority of subjects testing positive for COVID 19 do not require 
hospitalization but get better and appear to have complete clinical recovery without requiring any 
specific treatment within 2-4 weeks. One out of five subjects experience clinical worsening and 
require hospitalization and five out of a hundred subjects need admission to the intensive care 
unit. The subjects who get worse experience shortness of breath due to reduced body 
oxygenation and develop a specific type of lung injury called Acute Respiratory Distress 
Syndrome (ARDS). iNO relaxes the blood vessels of the lung and improves the oxygen delivery 
from the lung to the blood in subjects with ARDS. iNO has minimal effects in the tone of blood 
vessels outside the lungs, and as a result, it does not cause significant decrease in the blood 
pressure. With this study, we want to investigate whether giving iNO in the lung early will 
prevent the progression of COVID-19 from the early stages to more advanced disease stages and 
ARDS. 
 
This study will be conducted entirely at Tufts Medical Center and we will enroll 42 subjects. 


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Inhaled nitric oxide is approved by the FDA, but is experimental as used in this study. The FDA 
has allowed iNO to be used for research purposes specifically for this study.  
 
 
PROCEDURES TO BE FOLLOWED 
 
The study will be performed during your hospitalization at Tufts Medical Center. After you 
provide informed consent to participate in the study, you will be randomized to either receive 
iNO or nitrogen. Regardless of which agent you are assigned to receive, the rest of your medical 
care will be the same as that for anyone else being treated for COVID-19.  
 
The intervention that you will receive will be chosen by chance. Neither you nor the study doctor 
will choose whether you get iNO or nitrogen. You will have a two out of three chance of being 
given inhaled nitric oxide. This study is “blinded,” which means neither you, your study doctor, 
nor the doctors taking care of you for COVID-19 will know whether you were randomized to 
receive iNO or nitrogen. This is to ensure that the clinical information collected during the study 
is not influenced by knowledge about whether or not you are receiving iNO. Your condition will 
be monitored daily (as it would for clinical purposes regardless) regardless of whether you are 
receiving iNO or nitrogen. 
 
Regardless of which agent you are assigned to receive, it will be administered using the iNO 
pulse device at a dose of 125 mcg/kg IBW/hr. The iNO pulse device is a portable delivery 
system that weighs about 2.5 pounds. It has battery life of approximately 16 hours when fully 
charged. It supplies the agent into the nose through a nasal cannula. The cannula attaches to both 
the device containing the nitric oxide or nitrogen and a separate source of oxygen. The doses of 
the agent (either iNO or nitrogen) and oxygen can be adjusted separately, and the agent does not 
interfere with the delivery of oxygen. The agent will be provided for 24 hours per day. Pulse 
technology detects when you are about to inhale and delivers a bolus (pulse dosage) of iNO or 
nitrogen at the start of your breath The iNO or nitrogen will be administered for up to two weeks 
unless your clinical status deteriorates and you require higher flow oxygen or a breathing tube 
placement, in which case the study intervention will be stopped. The study intervention will also 
be stopped if your clinical condition, including the amount of oxygen in your blood, improves.  
 
We will ask you to rate your shortness of breath on a 0-10 scale after you agree to enter but 
before you actually start receiving your assigned agent, and then at various times afterwards. 
This is a simple scale that poses no risk to you.   
 
Blood samples will be collected as part of the standard of care. During these blood draws, extra 
tubes of blood will also be collected before the study starts, after 24 hours, after 72 hours and at 
one week.  These samples will be tested for levels of proteins involved in inflammation, called 
IL6 and TNFa. This test will allow us to investigate the effect of iNO on inflammation which is 
thought to be an important factor leading to progression of COVID-19. Regardless of whether 
you are assigned to receive iNO or nitrogen, additional blood is also taken after 24 hours and at 
one week to measure methemoglobin levels. Drawing blood for this test will require an 


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additional needle stick, and will be performed by respiratory therapists that are trained in this 
procedure. 
 
Each blood draw will collect 9 ccs of blood (about 2/3 of a tablespoon), to be stored in a tissue 
bank at Tufts Medical Center. A total of less than 6-7 tablespoons of blood will be collected over 
the course of the study. Blood samples deposited in the Tissue Bank will be used for the purpose 
of academic, scientific research and may include the analysis of expression of biological 
molecules including inflammatory mediators or other biological markers that will be defined in 
the future.  Your participation in the blood banking part of the study is completely voluntary, and 
your participation is not a condition for enrollment in the main study or for participation in any 
other research study or for your future care or treatment at Tufts Medical Center or Tufts 
University. Blood samples may be released to outside investigators for future research studies 
without your additional informed consent. The released samples will be completely de-identified 
to protect your confidentiality. The investigators will have expertise in the measurement of the 
biological marker of interest and could be affiliated with a university or an independent 
laboratory. You will be able to withdraw your consent for future use at any time unless the tissue 
bank has already distributed the samples, the samples have been completely exhausted, or the 
code to match the sample to the subject is no longer available. Please contact Dr. Konstam if you 
wish to withdraw your consent to the future use of samples. The storage of samples for future 
research has the possible risk of loss of confidentiality. You will receive no direct benefit from 
participating in this banking. Once your specimens have been transferred to the tissue bank, the 
results of research performed on those specimens will not be communicated to you or to your 
primary care doctor, and/or placed in your medical record. Blood samples will be stored for at 
least two years. 
 
We will also review your medical record to document information about your medical history 
and treatment in a computer database. All collected information will be completely de-identified 
to protect your confidentiality. 
 
WITHDRAWAL 
 
If you are eligible to participate and decide to be in the study, the Principal Investigator may still 
choose to discontinue the inhaled agent (either iNO or nitrogen) if he thinks it is in your best 
medical interest. You can also leave the research at any time and it will not be held against you.  
If you refuse to participate in the study or stop being in this study, it will not affect your care or 
treatment outside this study, payment for your health care, or your health care benefits.  
 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in the research. 
 
If you withdraw from the study or the Principal Investigator decides to discontinue 
administration of iNO or nitrogen, any data collected from you before your withdrawal will still 
be used for the study. If the Principal Investigator decides to discontinue iNO or nitrogen 
administration, we will continue to follow you and collect clinical data in order to investigate 
your response to the intervention.  


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If you stop being in the research, already collected data may not be removed from the study 
database. You will be asked whether the investigator can collect data from your routine medical 
care. If you agree, these data will be handled the same as research data. 
 
If you withdraw from the study the study investigators will not access your medical record or 
other confidential record requiring your consent. 
 
RISKS 
 
Inhaled Nitric Oxide is generally well tolerated without significant side effects. Blood pressure 
decrease is a rare side effect and lasts for a brief period of time. Methemoglobinemia is another 
rare side effect. In this condition, the hemoglobin, which is the oxygen delivering molecule, is 
changed by the iNO and becomes unable to transfer adequate oxygen to the human tissues. 
Methemoglobinemia is unusual when iNO is administered within the dose range used for this 
study. Methemoglobin level in the blood will be measured 24 hours and one week after initiation 
of iNO treatment and iNO will be discontinued if methemoglobin level exceeds 5%. iNO may 
increase the risk of kidney dysfunction, especially with prolonged use. Kidney disfunction 
appears to be rare and temporary. Finally, the risk of death from iNO administration is extremely 
low, especially for the dose range used for this study.  
 
The FDA categorizes iNO into category C with regards to safety for use during pregnancy. This 
means that there are no well-controlled studies that have been done in humans. Therefore, this 
study drug may be used if the potential benefits to the mother outweigh the potential risks to the 
unborn child. In addition, there are no adequate data from the use of iNO during breastfeeding. 
Based on that, we have decided to exclude from this study women who are pregnant or actively 
breastfeeding.  
 
Nitrogen is a non-reactive gas that makes up 78% of the air we breathe normally. There are no 
known risks to inhaling the small amount of additional nitrogen that you would receive through 
the device if you are assigned to receive nitrogen. Nitrogen has been used in a similar way in 
other research studies investigating the iNO pulse device and no risks have been observed for the 
participants assigned to receive nitrogen in those studies.  
 
All or almost all needle sticks for blood draw will occur, regardless, as part of your standard 
care. There are some possible risks associated with having your blood drawn including bruising 
and/or some bleeding at the needle puncture site. Rarely an infection may develop. 
Lightheadedness and fainting may result from the blood sampling procedure. 
 
There is also a possible risk of breach of confidentiality. Storing your medical information and 
storing samples for future research includes the possible loss of confidentiality. To minimize this 
risk, information that personally identifies you as a subject is not being captured. All stored 
samples will be completely de-identified and no research results will be placed in your medical 
records or communicated to you or to your treating physician. Study data will be stored in a 
secure, password-protected database accessible by only the research team on password-protected 
hospital computers in locked offices. 


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RESEARCH RELATED INJURY 
 
Emergency medical treatment will be given to you if you are hurt or get sick as a direct result of 
being in this research study. You or your insurance carrier will be required to pay for any such 
medical care. Any needed medical care is available at the usual cost. All needed facilities, 
emergency treatment, and professional services are available to you, just as they are to the 
general public. The institution will not pay for your treatment if you become ill or injured as part 
of this study.  
 
Due to the coronavirus public health crisis, the federal government has issued an order that may 
limit your right to sue if you are injured or harmed while participating in this COVID-19 clinical 
study. If the order applies, it limits your right to sue the researchers, healthcare providers, any 
study sponsor or manufacturer or distributor involved with the study. However, the federal 
government has a program that may provide compensation to you or your family if you 
experience serious physical injuries or death. To find out more about this “Countermeasures 
Injury Compensation Program” go to https://www.hrsa.gov/cicp/about/index.html or call 1-855-
266-2427. 
 
COSTS 
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only. These include the measurement of inflammatory mediators in the 
collected blood samples. You or your insurance provider will not have to pay for the iNO or 
nitrogen while you take part in this study.  
 
PAYMENT 
 
Study subjects will not be paid for their participation in the study.  
 
PRIVACY AND CONFIDENTIALITY 
 
All information collected during the study is confidential to the extent permitted by law. The 
blood samples will be labeled with a number, not your name, and only authorized personnel 
working on the study will have access to the code that links the number with your identity. The 
results of studies using material from the Tissue Bank may be presented at meetings or in 
publications, however, your identity will not be revealed. You will not be contacted at any time 
by the Tissue Bank or anyone who receives your samples from the tissue bank. 
 
If you decide to take part in this research study, your personal information will not be given to 
anyone unless we receive your permission in writing. It will only be given if the law requires it. 
It will also only be given for regular hospital treatment, payment, and hospital management 
activities.  
 
We will make every effort to keep your information private, but it cannot be completely 
guaranteed. Certain government agencies, like the Office for Human Research Protections, 


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Department of Health and Human Services, U.S. Food and Drug Administration, and the 
Institutional Review Board of Tufts Medical Center and Tufts University Health Sciences, may 
check records that identify you. This might include your medical or research records and the 
informed consent form you signed. The records of this study might also be reviewed to make 
sure all rules and guidelines were followed. 
 
For any questions about this, please contact Dr. Patrice Nickens, desvignp@nhlbi.nih.gov.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this web site at any time. 
 
AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH 
INFORMATION  
 
If you sign this document, you give permission to the Principal Investigator named above and 
research staff at Tufts Medical Center as well as other individuals at Tufts Medical Center who 
may need to access your information to do their jobs (such as for treatment, payment (billing) or 
health care operations) to use or disclose (release) your health information that identifies you for 
the research study described above.   
 
The parties listed in the preceding paragraph may disclose the health information described 
below to the following persons and organizations for their use in connection with the research 
study:  
• Individuals or organizations working under the direction of the Principal Investigator(s) 
for the study,  
• Outside individuals or entities that have a need to access this information to perform 
activities relating to the conduct of this research, such as analysis by outside laboratories 
on behalf of Tufts Medical Center or Tufts University Health Sciences. 
• Other researchers and institutions that are conducting or participating in this study,  
• The study sponsor and any companies that they use to oversee, manage, or conduct the 
research. 
• The Office for Human Research Protections in the U.S. Department of Health and 
Human Services, the United States Food and Drug Administration (FDA) and other 
federal and state agencies that have the right to use the information as required by law, 
and 
• The members and staff of any Institutional Review Board (IRB) and a study safety 
monitor, not otherwise involved in the study.  
 
The health information that we may use or disclose (release) for this research study includes all 
information in your medical record related to the diagnosis and management of COVID-19, 
including the record of your care, as well as any information collected or created during the 
course of this study. 
 


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Tufts Medical Center is required by law to protect your health information. By signing this 
document, you authorize Tufts Medical Center or Tufts University Health Sciences to use and/or 
disclose (release) your health information for this research. Those persons who receive your 
health information may not be required by Federal privacy laws (such as the Privacy Rule) to 
protect it and may share your information with others without your permission, if permitted by 
laws governing them. You may not be allowed to see or copy the information described on this 
form as long as the research is in progress, but you have a right to see and copy the information 
upon completion of the research in accordance with hospital policies. 
 
Tufts Medical Center may not withhold or refuse to provide you with clinical care based on 
whether or not you sign this form.  
 
This authorization does not have an expiration date. You may change your mind and revoke 
(take back) this authorization at any time. Even if you revoke this authorization, this site’s 
clinical, administrative and research staff may still use or disclose health information they 
already have obtained about you as necessary to maintain the integrity or reliability of the current 
research. To revoke this authorization, you must write to: HIPAA Privacy Officer for Research, 
800 Washington Street, Box 5100, Boston, MA 02111. If you revoke this authorization, you may 
no longer be allowed to participate in the research described in this form.  
 
WHOM TO CONTACT 
 
If you have questions, concerns, or complaints, or think the research has hurt you, please contact 
the Principal Investigator, Dr. Marvin Konstam, at Tufts Medical Center as soon as possible at 
617-636-6293 or via the hospital page operator at 617-636-5114. You can also feel free to 
contact any member of the research team below:  
• Project Coordinator: Abbey Haynes (617-636-4990) 
• Co-Investigator: Gaurav Gulati, MD (pager number: 617-705-1904) 
• Co-Investigator: Mehak Dhande, MD (pager number: 617-705-1282) 
 
If you have question about your rights as a research study subject, call the Tufts Medical Center 
and Tufts University Health Sciences Institutional Review Board (IRB) at (617) 636-7512. The 
IRB is a group of doctors, nurses, and non-medical people who review human research studies 
for safety and protection of people who take part in the studies. Federal law requires the IRB to 
review and approve any research study involving humans. This must be done before the study 
can begin. The study is also reviewed on a regular basis while it is in progress. This research 
study has been reviewed and approved by the IRB of Tufts Medical Center and Tufts University 
Health Sciences.   
 
 
 
 
 
 
 
 


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Documentation of Consent 
 
 
I have been given a copy of this form. I have read it or it has been read to me. I understand the 
information and have had my questions answered to my satisfaction. I agree to take part in this 
study.  
 
I understand that I will be informed of any new findings developed during the course of this 
research study that may affect my willingness to stay in this research study. 
 
 
_________________________________________        ___________  
  __________  
Participant’s Signature 
 
 
 
       Date 
 
         Time  
 
 
 
I consent that my de-identified blood samples can stored in a central tissue bank at Tufts Medical 
Central.  
 
___YES 
 
___NO 
 
 
 
 
I consent that my de-identified blood samples may be used for future research by investigators. 
 
 
___YES 
 
___NO 
 
 
 
_________________________________________  
 
_____________________ 
Participant’s Signature 
 
 
 
 
 
Date 
 
 
 
 
 
I have fully explained to ________________________________ the nature and purpose of the 
above-described study and the risks that are involved in its performance.  I have answered all 
questions to the best of my ability. 
 
 
_____________ 
 
 
____________________________________________ 
Date 
 
 
 
 
Principal Investigator or Representative’s Signature 
 


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Witness Signature: 
 
My signature below documents that the information in the consent document and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that consent was freely given by the subject.  
 
 
_________________________________________        ___________  
  __________  
Witness’ Signature 
 
 
 
        
        Date 
 
  Time  
 
 
________________________________________ 
Witness Printed Name 
 
 
 
 
 
_____________________________________ 
      _____ 
 
________ 
 
Legally Authorized Representative’s Signature                Date 
 
  Time 
 
 
_________________________________________  
Legally Authorized Representative’s Printed Name  
 
 
 
_________________________________ 
 
Assent  
Assent 
 Obtained 
 Not obtained because the capability of the subject is so limited that the subject cannot reasonably be 
consulted. 
 
Check the relationship of the legally authorized representative to the subject (list is in order of 
recognized hierarchy):  
 
 1. The health care agent, upon proper invocation of the health care proxy 
 2. Legally appointed guardian or conservator 
 3. Spouse 
 4. Adult children – (majority consensus encouraged) 
 5. The subject’s parent – (consensus encouraged) 
 6. Adult siblings – (majority consensus encouraged) 


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I have fully explained to ________________________________ the nature and purpose of the  
 
 
 
      Legally Authorized Representative 
 
above-described study and the risks that are involved in its performance.  I have answered all 
questions to the best of my ability. 
 
 
________________________________________ 
 
__________________ 
Printed Name of Principal Investigator or 
 
Position 
Person Conducting the Informed Consent Discussion 
 
 
_____________ 
 
________________________________________________ 
Date 
 
 
 
Signature of Principal Investigator or Person Conducting Informed  
 
 
 
 
Consent Discussion