Clinical trial NCT03196167
Conditions: Coronary Artery Bypass Graft and/or Aortic Valve Replacement Surgery
Keywords: sugammadex extubation CABG, AVR, CABG/AVR combination
Sponsor: Yale University
Start date: 2017-05-13; Completion date: 2020-10-10
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to demonstrate faster time to extubation after arrival in the cardiothoracic intensive care unit (ICU) in patients undergoing isolated coronary artery bypass grafting (CABG), AVR and AVR/CABG combination who receive Sugammadex as compared to placebo.

Detailed description:
Primary Efficacy Objective: To demonstrate faster time to extubation after arrival in the cardiothoracic ICU in patients having a CABG who receive Sugammadex 2mg/kg as compared to placebo.

Hypotheses: We hypothesize that the use of Sugammadex for reversal of residual neuromuscular blockade in adults undergoing CABG, AVR or CABG/AVR combination surgery in the cardiothoracic ICU will significantly decrease the time to extubation.

Prolonged intubation after cardiac surgery continues to be a common clinical challenge and is associated with significant risks and costs(1-5). Despite a Class I recommendation by the American College of Cardiology supporting care directed towards early postoperative extubation after low to medium risk Coronary Artery Bypass Grafting (CABG) surgeries (6), a sizable proportion of patients continue to have a prolonged course of cardiothoracic intensive care unit (CTICU) intubation(1). Residual neuromuscular blockade (NMB) continues to be one of the key factors leading to prolonged intubation after cardiac surgery(7). It is also a significant contributor to postoperative pulmonary and respiratory complications including hypoxia, upper airway obstruction; and decreased oxygen saturation - often prompting reintubation in critical care units(8-10). Due to the profound effects that neuromuscular reversal agents other than Sugammadex have when used in combination with muscarinic acetylcholine receptor antagonists on the autonomic nervous system and patient hemodynamics, these traditional reversal drugs are rarely used in the postoperative cardiac surgery patient population (11) as opposed to other general surgical cases.

Sugammadex, a gamma-cyclodextrin drug, rapidly reverses neuromuscular blockade by encapsulating the non-depolarizing amino steroids agents(12) and is not associated with cardiovascular effects that are commonly seen with traditional NMB reversal agents(13). It can also reverse NMB more quickly and predictably than existing agents(14). However, there have been sporadic reports of hypotension(15), anaphylaxis(16), elongated a PTT(17) with the use of Sugammadex. Additionally, although the FDA currently lists Sugammadex as indicated for reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery,(18) its use in the post cardiac surgery setting is limited due to lack of supportive data. In this context, the present study aims to test the effectiveness of a pragmatic and broadly applicable care pathway for shortening time to extubation among patients in the cardiothoracic ICU who have undergone isolated CABG, AVR or CABG/AVR combination procedure. The FDA-approved package insert is attached as an appendix to this application.

Study design: Prospective, randomized, double blind, single center placebo-controlled trial.

Number of participants: 110 enrolled with assumed randomization of 90 using 1:1 randomization between active ingredient (intervention) and control arms, to be assigned randomly using a computer generated algorithm.

Subject Recruitment: Subjects will be consented in the collaborating surgeons offices or in pre-admission testing. Every effort will be made to consent subjects prior to day of surgery. If a patient is referred or identified any time after those visits, they may be consented in the preoperative area.

Anesthetic management per protocol:For enrolled patients, anesthetic management will be left to the discretion of the attending anesthesiology provider. As per our usual clinical practice, Rocuronium or vecuronium will be used as the non-depolarizing NMB and that where sedation is desired and appropriate, The patients will be transferred to the CTICU intubated and on a propofol infusion and/or dexmedetomidine per our usual clinical practice.

Upon CTICU arrival, determination of continued eligibility will be determined. If the decision is made to continue on a fast-track extubation pathway, eligible patients will be randomized, investigational pharmacy will be contacted for study drug. 30 minutes after the ICU admission, propofol will be discontinued. Precedex may be continued per clinical discretion. The participant will be randomized to either receive Sugammadex or placebo. A qualitative train-of-four measurement will be obtained. The administration of the study and placebo compounds will be performed by CTICU nurses who will receive the drugs in a blinded fashion from the departmental research pharmacy. The level of neuromuscular blockade will be measured by accelerometer before and after the drug/placebo administration by the research coordinator. This will be done by placing a sheet over the limb being tested, so that the clinical team remains blinded to the results of the drug /placebo administration. The study drug will be supplied by Merck. Patients will be initiated on SIMV with 40% FiO2, tidal volumes 8-10 ml/kg and PEEP of 5.

Ten minutes after the drug administration, if the patient is able to lift head and remains hemodynamically stable, the patient will be switched to CPAP mode of ventilation for 30 minutes. At the end of the CPAP trial tidal volumes, Rapid Shallow Breathing Index (RSBI) and ABG will be assessed. The patient will be extubated if he/she is not hypoxic/ hypercarbic, has RSBI\<100 and has TV \>300 cc. The final clinical decision to extubate the patients will be taken by the CTICU team.

If a patient fails the 30 minute CPAP criteria, the ICU intensivist will be immediately notified. Every attempt will be made to correct the underlying cause of CPAP failure, and a prompt reassessment will be made as deemed appropriate by the intensivist to reattempt CPAP versus continuing controlled mechanical ventilation.

It is estimated conservatively that the study personnel will randomize 3 patients per week allowing for data collection to be completed within 1 year of study commencement. Data analysis and dissemination of findings will be conducted over the subsequent 6 months by the study institution investigators per the publication plan below.

Blinded analyses of the data will be performed by the study investigators along with the departmental statistician in the Department of Anesthesiology at the Yale School of Medicine.

Variables/Time Points of Interest: The primary outcome is the time to extubation, which will be the duration from arrival to the ICU to the extubation time. Participants' blood pressure, heart rate, and chest tube output will be tracked from arrival to the CTICU until extubation per ICU protocol.

Statistical Methods:Baseline comparability. We expect that the randomization process will produce reasonably comparable groups. However, the adequacy of the randomization will be assessed by comparing the distribution of baseline demographic and clinical characteristics among the intervention groups. Comparability for continuous variables will be examined graphically and by summary statistics (means, medians, quartiles, etc.). Categorical variables will be examined by calculating frequency distributions.

Proposed statistical test/analysis: Positively skewed variables will be log-transformed prior to hypothesis testing. For the primary outcome, a two-sided Student's t-test will be used to compare the time to extubation between the two groups. If necessary, covariate adjustment will be made using the multiple linear regression analysis method. Differences between means and 95% confidence intervals will be estimated to describe the magnitude of intervention difference between the two groups. As part of sensitivity analyses, the time-to-extubation outcome will be also analyzed by the Cox regression model. To compare the categorical adverse events between two groups, chi-square test or Fisher's exact test will be used.

Missing Data: Prevention is the most obvious and effective manner to control bias and loss of power from missing data. Therefore, several strategies (e.g., timely data entry and daily missing data report) will be imposed to limit the likelihood that missing data will occur during this study. This protocol will follow the intention to treat principle, requiring follow-up of all subjects randomized regardless of the actual treatment received.

Power analysis: Our 'in-house' historical data (n = 73) showed that after excluding outliers greater than the 80th percentile, patients undergoing isolated CABG demonstrated a mean of 8.39 hours to extubation (SD 2.89). Although we anticipate a Hawthorne effect demonstrating reduced time to extubation in both the active and placebo arms of the present study, we have conservatively chosen to maintain power based on historical data. We therefore estimate that 45 subjects per group will give us 90% power to detect a clinically relevant effect size of 2-hours difference between active and placebo groups at an alpha value of 0.05 using a two-sided two-sample t-test. To allow for post consent, pre-randomization study drop out, we will aim to enroll a total of 110 (90 + 20 = 110) subjects.

Per-protocol Sensitivity Analysis: In parallel with the primary analysis, if exclusions above occur post randomization but prior to drug administration, the investigators will conduct a parallel "per-protocol" sensitivity analysis.

Drug supplies will be supplied by the sponsor.

Adverse Experience Reporting: Throughout the duration of the study, researchers will adhere to good clinical practice and the guidelines of the institution. Patient vitals will be continuously monitored during and after the administration of the test drug. A data and safety monitoring board (DSMB) consisting of the head nurse and a senior critical care staff will meet monthly to discuss any serious events. Any incidence of anaphylaxis or unexplained hypotension requiring initiation of pressors or cardiac pacing within 5 minutes of drug administration will be reported an evaluated. Increases in chest tube output considered clinically significant by the critical care team will be noted. Any of these adverse events will trigger an analysis by the DSMB. If the DSMB determines that study drug may be causing an increase in adverse events, the study will be suspended until the DSMB is able to fully review the events and make a recommendation in consultation with the Yale Human Investigations Committee. The local Merck research representative will also be notified about the events. If the data monitoring board and/or institutional review board (IRB) view that the study is unsafe, the study will be discontinued.

Specific Safety Events to Be Reported During Manuscript Preparation: For manuscript preparation, the rates of hypotension, anaphylaxis, and bleeding (i.e. Chest Tube output) will be reported and compared between active and placebo groups.

Arms: arm 1: Research pharmacy will provide the Sugammadex (2m/kg) vs. Placebo in a syringe. arm 2: Research pharmacy will provide the Sugammadex (2m/kg) vs. Placebo in a syringe.
Interventions: intervention 1: Sugammadex intervention 2: Placebo
Intervention descriptions: intervention 1: The administration of the study and placebo compounds will be performed by CTICU nurses who will receive the drugs in a blinded fashion from the departmental research pharmacy. intervention 2: The administration of the study and placebo compounds will be performed by CTICU nurses who will receive the drugs in a blinded fashion from the departmental research pharmacy.

Protocol documents:
ICF_001.pdf: 
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COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
200 FR. 4 ( 2016-2)
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL
Study Title: Efficacy and Safety of Sugammadex (2mg/kg) to shorten time-to-extubation among 
postoperative ICU patients following AVR, CABG, or AVR/CABG surgery- a 
prospective randomized placebo-controlled trial.
Principal Investigator: Amit Bardia, MD
Funding Source: Merck Pharmaceuticals
Invitation to Participate and Description of Project
You are invited to take part in a research study designed to look at whether the medication 
Sugammadex decreases the time it takes to remove the breathing tube (extubation) after cardiac 
surgery. You have been asked to take part because you are undergoing a Coronary Artery Bypass 
Graft (CABG), or an aortic valve replacement (AVR), or an AVR/CABG combination procedure 
and will have a breathing tube after your surgery.
We expect to enroll approximately 110 subjects in this randomized, double blind, placebo- 
controlled trial. We anticipate completing enrollment in approximately 1 year.
There are medications routinely used during cardiac surgery that cause relaxation and/or paralysis 
of your muscles. They make putting the breathing tube in easier (intubation) and minimize muscle 
movements during surgery. The medications that cause this relaxation or paralysis are called 
Neuromuscular Blockers (NMB). These medications are sometimes associated with prolonged 
intubation and there are some risks associated with that.
We are studying the effect of the FDA approved medication Sugammadex used to reverse the 
neuromuscular relaxation caused by anesthesia in adults undergoing heart surgery on the length of 
time it takes patients to be ready to have the breathing tube removed (extubation) in the ICU. 
Sugammadex is known to rapidly reverse medications that provide neuromuscular blockade and it 
is not associated with the cardiovascular side effects commonly seen with other NMB reversal 
agents.
To decide if you wish to be a part of this research study you should know enough about its risks 
and benefits to make an informed decision. This consent form gives you detailed information about 
the study, that a member of the research team will discuss with you. This discussion  should go 
over all aspects of this research: its purpose, the procedures that will be performed, any risks of 
the procedures and possible benefits and possible alternative treatments. Once you
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understand the study, you will be asked if you wish to participate; if so, you will be asked to sign 
this form.
Description of Procedures
Your anesthesia plan will be left to the discretion of the anesthesiologist caring for your during 
your cardiac surgery. After your surgery is complete you will be transferred to the CTICU with a 
breathing tube (intubated) and on a propofol and/or dexmedetomidine (Precedex) infusion. These 
medications are sedatives and are routinely used in patients having cardiac surgery.
When you arrive to the Cardio-Thoracic Intensive Care Unit (CTICU), your surgeon and CTICU 
intensivist will do an initial assessment and decide if you are able to proceed on a fast-track 
removal of your breathing tube.
A member of the study team will also review the post-operative inclusion/exclusion criteria. If it 
is decided that you are eligible to continue to the fast-track pathway, your sedatives will be 
discontinued 30 minutes after the ICU admission and you will be randomized to receive 
sugammadex versus placebo. Randomization means your treatment assignment is random or by 
chance, like the flip of a coin with heads and tails being equal chances. A placebo is a substance 
that looks like the real drug but doesn’t contain any active ingredients. Routinely no medication is 
given at this time and the NMB medication is allowed to wear off. The study investigators will not 
know what treatment you receive. The study drug or placebo will be administered through an 
existing intravenous lines by the nurses caring for you in the CTICU under the direction of a study 
investigator. These nurses are specifically trained to administer the medication and are aware of 
its actions. The study drugs will be received from the investigational drug pharmacy in a blinded 
fashion. This means the study doctor will not know if you received active medication or placebo.
Ten minutes after the drug administration, if you can lift your head and your blood pressure is 
stable, the setting on the ventilator will be changed to allow you breath more on your own. If after 
30 minutes you have been able to take deep breaths and maintain your oxygen level the breathing 
tube will be removed.
If after 30 minutes, you can’t breathe well enough without assistance from the ventilator, every 
effort will be made to help correct that. If corrected, assisted breathing and removal of the breathing 
tube will be reattempted. If you are still having difficulty you may need to go back to having the 
ventilator breath for you.
If extubation is successful, you will continue to receive standard post-operative care in CTICU. 
Your participation in the study will be complete once you are extubated.
You will be told of any new findings that may affect your decision to participate in the research.
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.
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Risks and Inconveniences
Anesthetic management will be left to the discretion of the attending anesthesiology provider and 
that where sedation is desired and appropriate, patients will be transferred to the CTICU 
intubated and sedated. All of these medications that are routinely used as standard of care in 
patients undergoing coronary artery bypass graft surgery at Yale New Haven Hospital will be 
utilized.
Sugammadex is an FDA approved medication that reverses the effects of certain medications 
that are given during surgical procedures to relax your muscles. It is often used at the end of 
surgery, to help restore muscle function that has been blocked during surgery by the other 
medicines. In this study Sugammadex will be used in the CTICU with an aim to significantly 
decrease the time to extubation. The use of Sugammadex is associated with the following 
adverse reactions: Pain, nausea, vomiting and hypotension in more than 10% of the patients who 
have received this medication.
Headache, fever, high blood pressure, cough, chills, dizziness, trouble sleeping, EKG changes, 
high or low heart rate, itching, dry mouth and low calcium have been reported in 1-10% of 
patients receiving sugammadex.
Bleeding was originally thought to be a potential side effect of sugammadex, but studies have 
since shown that the risk is very low.
Sugammadex may cause some medications to be less effective, including hormonal 
contraceptives. If you are on any kind of contraceptive medication you should discuss this with a 
physician involved with this study. You cannot be included in the study if you are pregnant.
There is the possible risk of loss of confidentiality. Every effort will be made to keep your 
information confidential; however, this cannot be guaranteed.
There may be additional risks related to this study that are not yet known
Benefits
Potential benefits associated with participation include: early extubation; you may spend less 
time in a critical care setting; and you may have a decreased risk of pneumonia.
The study does have placebo, so you may not experience any benefit.
Economic Considerations
You will not be paid for your participation. The medication, sugammadex will be provided by 
Merck Pharmaceutical. You will receive the standard of care after your surgery that you would 
ordinarily receive after surgery. You or your insurance company will be responsible for that care.
Treatment Alternatives/Alternatives
The only alternative is to not participate. If you do not participate you will be extubated per the 
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standard of care at the discretion of the CTICU attending physician.
Confidentiality and Privacy
Any identifiable information that is obtained in connection with this study will remain confidential 
and will be disclosed only with your permission or as permitted by U.S. or State law. We will have 
access to this information, but will not keep any identified or personal health information (PHI) as 
part of your participation in this study. You will be assigned a study number. OnCore, Yale’s 
secure research data base will be utilized for study data. When data is downloaded for analysis you 
will only be identified by your study number.
Data will be collected on an encrypted and password protected laptop computer as an added 
measure to safeguard your confidentiality.
Authorized representatives of the Yale Human Research Protection Program and the Yale Human 
Investigation Committee (the committee that reviews, approves, and monitors research on human 
subjects) may inspect study records during internal auditing procedures. However, these 
individuals are required to keep all information confidential.
The database that contains your assessment data will stay on the computer until the study is 
completed. Once the study is completed your participant number will be removed and the data 
will be kept in this anonymous form indefinitely.
If the results of the research are published or discussed in conferences, no information will be 
included that would reveal your identity unless your specific consent for this activity is obtained.
The information about your health that will be collected in this study includes:
Research study records
Medical and laboratory records of only those services provided in connection with this 
Study.
The entire research record and any medical records historical and current held by YNHH 
created from: Admission to study completion.
Records about your study visits
Information about you and your health which might identify you may be used by or given to:
The U.S. Department of Health and Human Services (DHHS) agenciesRepresentatives from 
Yale University, the Yale Human Research Protection Program and the Yale Human 
Investigation Committee (the committee that reviews, approves, and monitors research on 
human subjects), who are responsible for ensuring research compliance. These individuals 
are required to keep all information confidential.

Those providers who are participants in the Electronic Medical Record (EMR) 
system.

Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments

The Principal Investigator Dr. Amit Bardia

Health care providers who provide services to you in connection with this study 
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including Co-Investigators

Study Coordinator and Members of the Research Team

Data and Safety Monitoring Boards and others authorized to monitor the conduct of 
the Study

Merck Pharmaceuticals the funding agency and provider of Sugammadex
By signing this form, you authorize the use and/or disclosure of the information described above 
for this research study. The purpose for the uses and disclosures you are authorizing is to ensure 
that the information relating to this research is available to all parties who may need it for 
research purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information. The research staff at the Yale 
School of Medicine and Yale-New Haven Hospital are required to comply with HIPAA and to 
ensure the confidentiality of your information. Some of the individuals or agencies listed above 
may not be subject to HIPAA and therefore may not be required to provide the same type of 
confidentiality protection. They could use or disclose your information in ways not mentioned 
in this form. However, to better protect your health information, agreements are in place with 
these individuals and/or companies that require that they keep your information confidential.
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.
Information about your study participation will be entered into your Electronic Medical Record 
(EMR). Once placed in your EMR, these results are accessible to all of your providers who 
participate in the EMR system. Information within your EMR may also be shared with others 
who are appropriate to have access to your EMR (e.g. health insurance company, disability 
provider.)
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.
In Case of Injury
If you are injured while on study, seek treatment and contact the study doctor as soon as you are 
able.
Yale School of Medicine and Yale-New Haven Hospital do not provide funds for the treatment of 
research-related injury. If you are injured because of your participation in this study,  treatment 
will be provided. You or your insurance carrier will be expected to pay the costs of  this treatment. 
No additional financial compensation for injury or lost wages is available.
You do not give up any of your legal rights by signing this form.
Voluntary Participation and Withdrawal
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Participating in this study is voluntary. You are free to choose not to take part in this study. 
Refusing to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled (such as your health care outside the study, the payment for your health care, and your 
health care benefits). However, you will not be able to enroll in this research study and will not 
receive study procedures as a study participant if you do not allow use of your information as 
part of this study.
If you do become a subject, you are free to stop and withdraw from this study at any time during 
its course. Prior to extubation you will be groggy but alert. If you change your mind and don’t 
want to proceed please let the study doctor know.
To withdraw from the study, you can call a member of the research team at any time and tell 
them that you no longer want to take part.
The researchers may withdraw you from participating in the research if necessary. After you have 
consented, had your surgery and are admitted to the CTICU, the Investigators on the study will 
reassess your eligibility to participate in the fast-track pathway. If you don’t meet the criteria they 
will not proceed with the study. You will be extubated at the discretion of the CTICU physician.
Withdrawing from the study will involve no penalty or loss of benefits to which you are otherwise 
entitled. It will not harm your relationship with your own doctors or with Yale-New Haven 
Hospital or, at your request, refer you to a clinic or doctor who can offer this treatment.
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time. You may withdraw your permission by telling the study staff or by writing to Dr. Amit 
Bardia, 333 Cedar St., TMP 3, New Haven, CT 06520.
If you withdraw your permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and given
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to others until the end of the research study, as necessary to insure the integrity of the study 
and/or study oversight.
Questions
We have used some technical terms in this form. Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
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Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project 
described above. Its general purposes, the particulars of my involvement and possible hazards and 
inconveniences have been explained to my satisfaction. My signature also indicates that I have 
received a copy of this consent form.
By signing this form, I give permission to the researchers to use [and give out] information about 
me for the purposes described in this form. By refusing to give permission, I understand that I 
will not be able to be in this research.
Name of Subject: 
Signature: 
Date: 
Signature of Principal Investigator
Date
or
Signature of Person Obtaining Consent
Date
If after you have signed this form you have any questions about your privacy rights, please 
contact the Yale Privacy Officer at 203-432-5919.
If you have further questions about this project or if you have a research-related problem, you 
may contact the Principal Investigator Dr. Amit Bardia at 203-785-2802. If you would like to 
talk with someone other than the researchers to discuss problems, concerns, and questions you 
may have concerning this research, or to discuss your rights as a research subject, you may 
contact the Yale Human Investigation Committee at (203) 785-4688.
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Prot_002.pdf: 
NCT03196167 
Sugammadex and Decreased Time to Extubation 
 
Study Protocol 
6/19/2020 


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PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
This template is intended to help investigators prepare a protocol that includes all the necessary information 
needed by the IRB to determine whether a study meets approval criteria. Read the following instructions 
before proceeding:
1.
Use this protocol template for a PI initiated study that includes direct interactions with research
subjects. Additional templates for other types of research protocols are available in the system Library.
2.
If a section or question does not apply to your research study, type “Not Applicable” underneath.
3.
Once completed, upload your protocol in the “Basic Information” screen in IRES IRB system.
HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2016-1)
Protocol Title: Efficacy and Safety of Sugammadex (2mg/kg) to shorten time-to-extubation among 
postoperative ICU patients following Aortic Valve Replacement, CABG surgery, or Aortic Valve 
Replacement with CABG surgery- a prospective randomized placebo- controlled trial.
Principal Investigator: Amit Bardia, M.D.
Protocol Version Number and/ or Date: Version5, June 1, 2020
(If applicable) Clinicaltrials.gov Registration #: NCT03196167
Page 1 of 19
INSTRUCTIONS
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.Jun 1 2020 9, 2019
SECTION I: RESEARCH PLAN
1.
Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.
To demonstrate faster time to extubation after arrival in the cardiothoracic ICU in patients 
undergoing Aortic Valve Replacement (AVR), Coronary Artery Bypass Graft (CABG), or AVR/CABG 
combination surgery who receive study drug (Sugammadex 2mg/kg) as compared to placebo.
2.
Probable Duration of Project: State the expected duration of the project, including all follow-up and data 
analysis activities.
Approximately 36 months
It is estimated that 3 subjects will be randomized per week allowing for data collection to be 
completed in 2 years for study start-up, with an additional 12 months for data analysis.
3.
Background: Describe the background information that led to the plan for this project. Provide references to 
support the expectation of obtaining useful scientific data.
Prolonged intubation after cardiac surgery continues to be a common clinical challenge and is 
associated with significant risks and costs1-5. Despite a Class I recommendation by the American 
College of Cardiology supporting care directed towards early postoperative extubation after low to 
medium risk Coronary Artery Bypass Grafting (CABG) surgeries6. A sizable proportion of patients 
continue to have a prolonged course of cardiothoracic intensive care unit (CTICU) intubation1.
Sugammadex, a gamma-cyclodextrin drug with a plasma elimination half-life of 2 hours. It rapidly 
reverses neuromuscular blockade by encapsulating the non-depolarizing aminosteroids agents12. 
Reversal of neuromuscular blockade with Sugammadex is not associated with cardiovascular effects 
that are commonly seen with traditional NMB reversal agents13. It can also reverse NMB more quickly 
and predictably than existing agents14. However, there have been sporadic reports of hypotension15, 
anaphylaxis16, elongated a PTT17 with the use of Sugammadex. Additionally, although the FDA 
currently lists Sugammadex as indicated for reversal of neuromuscular blockade induced by 
rocuronium and vecuronium in adults undergoing surgery,18 its use in the post cardiac surgery setting 
is limited due to lack of supportive data. In this context, the present study aims to test the 
effectiveness of a pragmatic and broadly applicable care pathway for shortening time to extubation 
among patients in the cardiothoracic ICU who have undergone AVR, CABG, or a combination 
AVR/CABG procedure. The FDA-approved package insert is attached as an appendix to this application.
4.
Research Plan: Summarize the study design and research procedures using non-technical language that can 
be readily understood by someone outside the discipline. Be sure to distinguish between standard of care vs. 
research procedures when applicable, and include any flowcharts of visits specifying their individual times and 
lengths. Describe the setting in which the research will take place.
Anesthetic management per protocol: See also study flowchart attached
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
1.
For enrolled patients, anesthetic management will be left to the discretion of the attending 
anesthesiology provider with the exception that Rocuronium or Vecuronium (both SOC) will be 
used as the non-depolarizing NMB and that where sedation is desired.
2.
Patients will be transferred to the CTICU intubated and on a propofol infusion and/or 
dexmedetomidine (Precedex) from the operating room. Both meds are used SOC.
3.
Upon CTICU arrival, the patients surgeon and CTICU intensivist will determine if patient is able to 
proceed with fast-track extubation. Determination of continued eligibility based on the post- 
recruitment pre-randomization exclusion criteria will be determined by a member of the study 
team. Eligible patients will be randomized, investigational pharmacy will be contacted for study 
drug and within 30 minutes of the ICU admission, propofol will be discontinued. Precedex may 
be continued per clinical discretion.
4.
The participant will be randomized to receive Sugammadex or placebo. The enrolled patients will 
be assigned to the study and control arms in a 1:1 ratio.
5.
IDS will provide the Sugammadex (2mg/kg) vs. Placebo in a syringe. A qualitative train-of-four 
measurement will be obtained. The administration of the study drug and placebo compounds 
will be performed by CTICU nurses who will receive the drugs in a blinded fashion from the 
departmental research pharmacy. The study drug will be supplied by Merck.
6.
The clinical care provider has the discretion to determine the appropriate ventilation settings on a 
case-by-case basis, in accordance with the suggestion that patients will be initiated on SIMV rate of 
14 with 60% FiO2, tidal volumes 8-10 ml/kg and PEEP of7.
7.
Ten minutes after the drug administration, if the patient can lift their head and remains 
hemodynamically stable, the patient will be switched to CPAP mode of ventilation for 30 
minutes. At the end of the CPAP trial tidal volumes, Rapid Shallow Breathing Index (RSBI) and 
ABG will be assessed. The patient will be extubated if he/she is not hypoxic/ hypercarbic, has 
RSBI<100 and has TV >300 cc.
8.
If a patient fails the 30-minute CPAP criteria, the ICU intensivist will be immediately notified. 
Every attempt will be made to correct the underlying cause of CPAP failure, and a prompt 
reassessment will be made as deemed appropriate by the intensivist to reattempt CPAP versus 
continuing controlled mechanical ventilation.
Study participation will end when the patient is successfully extubated. AE assessment will be 
performed in the period immediately following extubation.
5.
Genetic Testing
N/A ☒
6.
Subject Population: Provide a detailed description of the types of human subjects who will be recruited into 
this study.
Patients scheduled to have Aortic Valve Replacement (AVR), Coronary Artery Bypass Graft (CABG), or 
AVR/CABG combination procedure.. CABG may be single or multi-vessel, and may be done on-pump or 
off-pump
7. Subject classification: Check off all classifications of subjects that will be specifically recruited for enrollment in 
the research project. Will subjects who may require additional safeguards or other considerations be enrolled
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
in the study? If so, identify the population of subjects requiring special safeguards and provide a justification 
for their involvement.
☐Children
☐ Healthy
☐Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students
☐ Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐ No ☒
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Inclusion criteria for consent process:
All elective AVR, CABG cases,on-pump or off-pump, or combination of AVR/CABG surgery in adult 
patients with preoperative LVEF≥45% subject to the following exclusions:
Exclusions during consent process:
1. Emergency/unplanned cases
2. EF<45% or moderate /severe RV dysfunction
3. Estimated GFR < 30 mL/min
4. Patients on supplemental oxygen at baseline (home oxygen)
5. BMI>40 (calculated as the patient’s weight in kilograms divided by the square of the patient’s height 
in meters)
6. Patients with chronic opioid use preoperatively.
7. Patients with known neuromuscular disorders preoperatively.
8. Patients with a known sensitivity to Rocuronium or to Sugammadex.
9. Patients with known cognitivedeficitspreoperatively. 
10.Patients < 21 years of age
Exclusions after recruitment but prior to randomization:
1. Postoperative Bleeding (chest tube output >100cc/hr )
2. Treatment of anaphylactoid reaction intraoperatively.
3. Patient’s temperature<35.5 or >38.3 degree Celsius at the time of ICU arrival.
4. Determination that the patient will require prolonged mechanical ventilation possibly requiring 
muscle relaxation based on the intraoperative course and clinical judgment of the study PI or 
collaborating intensivists.
5. Intraoperative hypoxia or on arrival to the ICU. (Please see Study Flowchart).
6. Cardiac arrest
7. Sudden arrhythmia (Ventricular tachycardia runs/sudden bradycardia with improper pacemaker 
detection/function) precluding fast-track extubation protocol.
8. Need for two or more inotrope initiation precluding fast-track protocol. Only a single 
vasopressor/inotrope may be initiated without excluding the subject.
9. Postoperative ST changes.
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
10.A positive standard of care pregnancy test during your pre-operative evaluation
9. How will eligibility be determined, and by whom?
Eligibility at pre-op and post-op will be based on protocol specific inclusion and exclusion criteria 
and will be determined by the PI or Sub-I’s in collaboration with the ICU attending physician
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research.
Sugammadex is generally safe and well tolerated. Potential risks associated with sugammadex are: 
hypersensitivity, including anaphylaxis/anaphylactic shock – previous trials suggest this risk is small. 
Cardiac arrhythmias including bradycardia & tachycardia where intervention is rare and responsive 
to usual treatment. Other reported risks include nausea, vomiting, constipation.
Bleeding was originally thought to be a side effect, but studies have since showed that Sugammadex 
falsely elevates the PTT without increasing bleeding risk. (see reference on last page.)
11. Minimizing Risks: Describe the way the above-mentioned risks will be minimized.
Patients will all be in a critical care environment and monitored very closely including: blood pressure, 
heart rate, and chest tube output will be tracked from arrival to the CTICU until extubation per ICU 
protocol. Subtle changes in the patient’s hemodynamic status are easily seen and treated if necessary.
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan (DSMP) based on 
the investigator’s risk assessment stated below. (Note: the HIC will make the final determination of the risk to 
subjects.)
a.
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Greater than minimal risk
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? N/A
c.
Include an appropriate Data and Safety Monitoring Plan
1. Personnel responsible for the safety review and its frequency:
The principal investigator, with the DSMB will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews, which must be conducted at a minimum of every 3 
months (including when reapproval of the protocol is sought). During the review process, the principal 
investigator (monitor) and the DSMB will evaluate whether the study should continue unchanged, 
require modification/amendment, or close to enrollment. Either the principal investigator, the IRB or 
DSMB have the authority to stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed greater than minimal for the following 
reasons: (choose those that apply)
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
1.
We do not view the risks associated with Sugammadex used as neuromuscular blocking reversal 
agent as minimal risk.
2.
Given our experience with the administration of Sugammadex, an FDA approved medication, we 
do not view the proposed study as high risk.
Although we have assessed the proposed study as one of greater than minimal risk, the potential exists 
for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not 
possible to predict with certainty the absolute risk in any given individual or in advance of first-hand 
experience with the proposed study methods. Therefore, we provide a plan for monitoring the data and 
safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures / design by the principal investigator Dr. Amit Bardia according to the following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational procedures(s)/agent(s). 
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
3. Severe
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets the 
criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it results in any of 
the following outcomes:
1. Death;
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization;
3. A persistent or significant disability or incapacity;
4. A congenital anomaly or birth defect; OR
Page 6 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition.
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. 
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is 
important for the PI to consider the grade of the event as well as its “seriousness” when determining 
whether reporting to the IRB is necessary.
Only the following adverse events will be tracked. These AE’s will trigger an immediate DSMB review; any 
incidence of anaphylaxis; unexplained hypotension requiring initiation of pressors; cardiac pacing within 
5 minutes of drug administration; tachycardia, bradycardia or onset of atrial fibrillation; or increases in 
chest tube output considered clinically significant by the critical care team. The DSMB will be notified 
within 2 business days of determination by telephone or email. A written report will be provided within 7 
days of the determination. Any incidents meeting SAE criteria will be reported per the IRB reporting policy.
If the DSMB determines that study drug may be causing an increase in adverse events, the study will be 
suspended until the DSMB can fully review the events and make a recommendation in consultation with 
the Yale Human Investigations Committee. The local Merck research representative will also be notified 
about the events (within 2 business days in case of any serious adverse events). If the data monitoring 
board and/or IRB view that the study is unsafe, the study will be discontinued.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB:
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1.
Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol 
and informed consent document and (b) the characteristics of the subject population being 
studied; AND
2.
Is related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); AND
3.
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized.
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non- 
medical in nature, and include – but are not limited to – serious, unexpected, and related adverse 
events and unanticipated adverse device effects. Please note that adverse events are reportable to 
the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the appropriate 
forms found on the website. All related events involving risk but not meeting the prompt reporting 
requirements described in IRB Policy 710 should be reported to the IRB in summary form at the time of 
continuing review. If appropriate, such summary may be a simple brief statement that events have 
occurred at the expected frequency and level of severity as previously documented. In lieu of a 
summary of external events, a current DSMB report can be submitted for research studies that are 
subject to oversight by a DSMB (or other monitoring entity that is monitoring the study on behalf of an 
industry sponsor).
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring Committee 
(DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and regulatory agencies,  
and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be notified 
(choose those that apply):
 All Co-Investigators listed on the protocol.
 Study Grantor (Merck)
 Other Data Safety Monitoring Board (DSMB)
 Yale University IRB
The principal investigator Amit Bardia, MD will conduct a review of all adverse events upon completion 
of every study subject. The principal investigator will evaluate the frequency and severity of the adverse 
events and determine if modifications to the protocol or consent form are required.
See also DSMB charter attached.
13. Statistical Considerations: Describe the statistical analyses that support the study design.
Variables/Time Points of Interest
The primary outcome is the time to extubation, which will be the duration from arrival to the ICU to 
the extubation time.
Proposed statistical test/analysis: Positively skewed variables will be log-transformed prior to 
hypothesis testing. For the primary outcome, a two-sided Student’s t-test will be used to compare
Page 8 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
the time to extubation between the two groups. If necessary, covariate adjustment will be made 
using the multiple linear regression analysis method. Differences between means and 95% 
confidence intervals will be estimated to describe the magnitude of intervention difference between 
the two groups. As part of sensitivity analyses, the time-to-extubation outcome will be also analyzed 
by the Cox regression model. To compare the categorical adverse events between two groups, chi- 
square test or Fisher’s exact test will be used.
Missing Data: Prevention is the most obvious and effective manner to control bias and loss of power 
from missing data. Therefore, several strategies (e.g., timely data entry and daily missing data 
report) will be imposed to limit the likelihood that missing data will occur during this study. This 
protocol will follow the intention to treat principle, requiring follow-up of all subjects randomized 
regardless of the actual treatment received.
Power analysis: Our ‘in-house’ historical data (n = 73) showed that after excluding outliers greater 
than the 80th percentile, patients undergoing isolated CABG demonstrated a mean of 8.39 hours to 
extubation (SD 2.89). Although we anticipate a Hawthorne effect demonstrating reduced time to 
extubation in both the active and placebo arms of the present study, we have conservatively chosen 
to maintain power based on historical data. We therefore estimate that 45 subjects per group will 
give us 90% power to detect a clinically relevant effect size of 2-hours difference between active and 
placebo groups at an alpha value of 0.05 using a two-sided two-sample t-test. To allow for post 
consent, pre-randomization study drop out, we will aim to enroll a total of 110 (90 + 20 = 110) 
subjects.
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
If NO, an FDA issued IND is required for the investigational use unless RDRC assumes oversight.
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the section.
A. RADIOTRACERS
1.
Check one: ☐IND# Write here or ☐RDRC oversight (RDRC approval will be required prior to use)
B. DRUGS/BIOLOGICS
1.
If an exemption from IND filing requirements is sought for a clinical investigation of a drug product that is 
lawfully marketed in the United States, review the following categories and complete the category that 
applies (and delete the inapplicable categories):
Exempt Category 1: The clinical investigation of a drug product that is lawfully marketed in the United States 
can be exempt from IND regulations if all of the following are yes:
1. The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for
the drug.
☒
2. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the
product.
☒
3. The investigation does NOT involve a route of administration or dosage level or use in populations
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product
☒
2. The investigation will be conducted in compliance with the requirements for institutional (HIC) 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 and 
21 CFR Part 56).
☒
3. The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.
☒
Page 10 of 19
☐N/A
☒N/A
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1 2020 9, 2019
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in detail how the PI 
will oversee these aspects of drug accountability, storage, and preparation.
2.
Background Information: Provide a description of previous human use, known risks, and data addressing 
dosage(s), interval(s), route(s) of administration, and any other factors that might influence risks. If this is the first 
time this drug is being administered to humans, include relevant data on animalmodels.
BRIDION® (sugammadex) Injection, for intravenous use Initial U.S. Approval: 2015
3.
Source: Identify the source of the drug or biologic to be used. Sugammadex 2 mg/kg
a)
Is the drug provided free of charge tosubjects? ☒YES
☐NO
If yes, by whom? Merck Pharmaceuticials
4.
Storage, Preparation and Use: Describe the method of storage, preparation, stability information, and for 
parenteral products, method of sterilization and method of testing sterility andpyrogenicity.
Sugamadex is an FDA approved medication used to reverse neuromuscular blocking agents utilized 
for anesthesia. Sponsor will provide the medication and preparation & dispensing will be done by 
YNHH IDS.
Check applicable Investigational Drug Service utilized:
☒ YNHH IDS
☐ CMHC Pharmacy
☐ West Haven VA
☐PET Center
☐ None
☐Other:
5.
Use of Placebo:
☐ Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a)
Describe the safety and efficacy of other available therapies. If there are no other available therapies, state 
this.
Currently there are no available therapies utilized for anesthesia reversal in this population. 
Standard of care is to let the NMB agent wear off.
b)
State the maximum total length of time a participant may receive placebo while on the study.
Patient will only receive placebo once.
c)
Address the greatest potential harm that may come to a participant as a result of receiving placebo.
We don’t expect any potential harm to come to participants associated with receiving placebo. The 
standard of care is to wait for anesthesia to wear off. Therefore, in absence of study drug treatment, 
the patient will be allowed to wake from anesthesia as he/she would if they weren’t participating.
d)
Describe the procedures that are in place to safeguard participants receiving placebo.
Patients will be monitored per standard of care in the CTICU until extubation, regardless of what 
treatment they are assigned.
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
Page 12 of 19
.May 9, 2019
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES
6.
Continuation of Drug Therapy After Study Closure ☒Not applicable to this project
B. DEVICES
1.
Are there any investigational devices used or investigational procedures performed at Yale-New Haven 
Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and Vascular Center)? ☐Yes ☒No
1. Targeted Enrollment: Give the number of subjects:
Targeted for enrollment at Yale for this protocol: 110 enrolled with assumed randomization of 90 
subjects.
a.
If this is a multi-site study, give the total number of subjects targeted across all sites:N/A
2.
Indicate recruitment methods below. Attach copies of any recruitment materials that will be used.
☐Flyers
☐ Internet/web postings
☐ Radio
☐Posters
☐ Mass email solicitation
☒ Telephone
☐Letter
☐ Departmental/Center website
☐ Television
☒ Medical record review*
☐ Departmental/Center research boards
☐ Newspaper
☐Departmental/Center newsletters
☐YCCI Recruitment database
☒ Other: pre-admission testing, 
with subsequent chart review or 
referral by collaborating surgeons.
☐Web-based clinical trialregistries
☐Social Media(Twitter/Facebook):
☐Clinicaltrails.gov
☒N/A
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
* Requests for medical records should be made through JDAT as described at
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3. Recruitment Procedures:
a. Describe how potential subjects will be identified.
Many subjects will be identified by screening pre-admission testing. Patients having planned AVR, 
CABG procedure (on-pump or off-pump), or a combination procedure of AVR/CABG will be 
approached by a member of the study team and the study opportunity will be presented.
Additionally, the cardiac surgeons may refer patients for participation from their practices. Consent will 
be obtained at least 24 hours prior to surgery when possible. If potential subjects are missed in the pre- 
admission testing center, potential subjects may be contacted by phone by the clinical research nurse 
prior to the date of their surgery to determine if the subject is interested in learning of the study. If the 
potential subject is interested, the research nurse will provide a description of the study and a copy of 
the consent form via email, fax, or first-class mail based on the subject’s preference. Once the subject 
has received and reviewed the consent, the clinical research nurse will answer any questions about 
participation by phone. Once the research nurse is satisfied that the potential subject understands the 
study and wishes to participate, the clinical research nurse will obtain a signed copy of the consent form 
from the subject using either email, fax or photograph of the entire document including their signature 
on the form and document it in the medical record. A copy of the signed form will be provided to the 
subject.
b. Describe how potential subjects are contacted.
Patients will be contacted in person in their surgeon’s office or in the pre-admission testing area, 
by phone, or in their hospital room if they are hospitalized. When in-person contact is not possible, 
we will contact patients by phone.
c. Who is recruiting potential subjects?
All members of the study team
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical relationship with any 
potential subject?
☐Yes, all subjects
☒Yes, some of the subjects
☐No
If yes, describe the nature of this relationship. The PI and members of the research team may be the 
treating anesthesiologist or the CTICU attending, providing care to the patient.
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only. Note: if you are collecting PHI as part of a phone or email 
screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one:
☐For entire study
☒ For recruitment/screening purposes only
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
The investigator assures that the protected health information for which a Waiver of Authorization has 
been requested will not be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research study, or as specifically 
approved for use  in another study by an IRB.
☒ For inclusion of non-English speaking subject if short form is being used and there is no translated HIPAA 
research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
i.
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of this 
data: Chart review will be utilized as a pre-screening tool before patients are approached 
regarding participation
ii.
If requesting a waiver of signed authorization, describe why it would be impracticable to obtain the 
subject’s signed authorization for use/disclosure of this data: Referral to the study team for 
potential participation will occur prior to consent being obtained.
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APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided. Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
6.
Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be obtained, 
including parental permission or surrogate permission and the steps taken to ensure subjects’ independent 
decision-making.
When the study team identifies, or is referred a patient who may be study eligible, the patient will be 
informed about the study. If the patient is interested they will have the opportunity to read the consent 
form and ask questions. The investigator or research staff will review the full Compound Authorization 
and Consent document with the subject discussing the purpose and scope of the study, explaining any 
risks and/or potential benefits, procedures associated with participation, economic considerations, 
confidentiality of the subject’s information, and their ability to voluntarily participate and withdraw at 
any time during the study. will be explained in person. It will be explained to the subject that 
participation is completely voluntary and that they may withdraw at any time without penalty. Only 
after the patient has a thorough understanding of the study and what is being asked of them and after 
all their questions have been answered by a coordinator and an investigator, will they be asked to 
indicate a decision to participate by signing the consent form. Consent will be obtained at least 24 hours 
prior to surgery If potential subject are missed or not seen in-person in the Pre-Admission Testing 
Center, subjects may be contacted by phone by the clinical research nurse prior to the date of their 
surgery to determine if the subject is interested in learning of the study. If the potential subject is 
interested, the research nurse will provide a description of the study and a copy of the consent form via 
email, fax, or first-class mail based on the subject’s preference. Once the subject has received and 
reviewed the consent, the clinical research nurse will answer any questions about participation by 
phone. Once the research nurse is satisfied that the potential subject understands the study and wishes 
to participate, the clinical research nurse will obtain a written consent via email, mail, fax or photograph 
of the entire document including the subject’s signature on the consent form and document it in the 
medical record. A copy of the signed form will be provided to the subject.
7.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the personnel obtaining 
consent will assess the potential subject’s ability and capacity to consent to the research being proposed. 
Once the explanation of the study is complete and the subject and/or surrogate verifies 
understanding, the study staff and/or investigators will ask questions of the participant and/or 
surrogate to elicit as to whether the participant understands the study and that participation is 
voluntary. Patients ability to sign consent on their own behalf may also be assessed by the surgeon 
and/or PAT staff if possible. If there are any doubts about the patient’s cognition and surrogate will 
be approached to sign on the patient’s behalf.
Page 14 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
Note* If more than 2 study participants are enrolled using a short form translated into the same language, then 
the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated HIPAA 
Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the IRB office for 
approval via modification prior to enrolling the subject. Please review the guidance and presentation on use of 
the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a HIPAA 
waiver in the section above.
For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research? YES ☒NO ☐
Does a breach of confidentiality constitute the principal risk to subjects? YES ☒ NO
☐OR
Does the research pose greater than minimal risk? YES ☐ NO☐
Does the research include any activities that would require signed consent in a non-research context? YES ☐ 
NO ☐
8.
Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving 
non-English speaking subjects. If enrollment of these subjects is anticipated, translated copies of all consent 
materials must be submitted for approval prior to use.
If potential subjects are Non-English speaking a short form and translator will be used to obtain 
consent. If more than 2 participants are consented in any one language the full compound 
authorization and consent will be translated for future patients.
As a limited alternative to the above requirement, will you use the short form* for consenting process if you 
unexpectedly encounter a non-English speaking individual interested in study participation and the translation of 
the long form is not possible prior to intended enrollment? YES ☒ NO ☐
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full waiver 
of consent, depending on the study. If you will request either a waiver of consent, or a waiver of signed consent 
for this study, complete the appropriate section below.
☐Not Requesting any consent waivers
☒Requesting a waiver of signed consent:
☒ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐Entire Study (Note that an information sheet may be required.)
☐Requesting a waiver of consent:
Page 15 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
For a full waiver of consent, please address all of the following:

Does the research pose greater than minimal risk to subjects?
☐Yes If you answered yes, stop. A waiver cannot begranted.
☐No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐ NO☐

Why would the research be impracticable to conduct without the waiver? Write here

Where appropriate, how will pertinent information be returned to, or shared with subjects at a later date?
Write here
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
All portable devices must contain encryption software, per University Policy 5100. If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and Compliance 
Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
☐Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐Entire Study
Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research? Name, MRN, DOB, historical & current; medical history and 
laboratory results, and study related assessments.
2.
How will the research data be collected, recorded and stored?
Data will be collected from the patient’s medical record and kept in a paper file maintained by the 
study coordinator as source. Data will then be entered on a laptop computer in an OnCore database 
that is password protected and encrypted. Patient’s will be assigned a study number in the research 
data base and the link will be maintained by the coordinator.
3.
How will the digital data be stored? ☐CD ☐DVD ☐Flash Drive ☐Portable Hard Drive ☐Secured Server
☒Laptop Computer ☐Desktop Computer ☐Other
4.
What methods and procedures will be used to safeguard the confidentiality and security of the identifiable 
study data and the storage media indicated above during and after the subject’s participation in the study?
Participants will be assigned a study number in the Oncore database and the link will be maintained 
by the coordinator. Paper charts will be kept in a locked file cabinet in the coordinators locked office.
Page 16 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
SECTION V: POTENTIAL
SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
5.
What will be done with the data when the research is completed? Are there plans to destroy the identifiable 
data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe how the data and/or 
identifiers will be secured.
Once the data analysis is complete and all publications have been finalized, the paper charts will be 
destroyed leaving only coded data.
6.
If appropriate, has a Certificate of Confidentiality been obtained? N/A
Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, either to 
the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this context of the risk 
benefit assessment.)
Potential benefits associated with participation include early extubation and participants may spend less 
time in a critical care setting. The risk of pneumonia may also be reduced. The study does have placebo, 
so participants may not experience any benefit.
1.
Alternatives: What other alternatives are available to the study subjects outside of the research?
The alternative is to not participate and be extubated per the standard of care
2.
Payments for Participation (Economic Considerations): Describe any payments that will be made to subjects, 
the amount and schedule of payments, and the conditions for receiving this compensation.
There is no payment for participation
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs associated with 
participation in the research, and the interventions or procedures of the study that will be provided at no cost 
to subjects.
There is no cost to participate and study drug will be provided by Merck
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal 
risk research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs? Yes
b.
Where and from whom may treatment be obtained? If the patient is still hospitalized, care 
will be provided by the patient’s treating physician or CTICU intensivist. If the patient has 
been discharged, while injuries or adverse events are not expected, care should be 
sought and the PI should be notified as soon as possible.
c.
Are there any limits to the treatment being provided? No
Page 17 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
d.
Who will pay for this treatment? Yale School of Medicine and Yale-New Haven Hospital will 
not provide funds for the treatment of research-related injury. If there are study related 
injuries treatment will be provided. The patient or their insurance carrier will be 
expected to pay the costs of this treatment.
e.
How will the medical treatment be accessed by subjects? Care will be provided if necessary 
while the patient is hospitalized. If not in the hospital the patient should seek care as 
needed and notify the study team.
Page 18 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020


APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020
HIC # 2000021124
PI: Dr. Amit Bardia
.Jun 1, 2020
APPROVED BY THE YALE UNIVERSITY IRB 5/22/2019
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, would 
normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s 
insurer. The service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include x-rays, MRIs, CT 
scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. There is no distinction made 
whether the service is paid for by the subject or their insurance (Standard of Care) or by the study’s funding 
mechanism (Research Sponsored). 2. This generally includes new services or orders placed in EPIC for research 
subjects.
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research management system, for 
Epic to appropriately route research related charges. Please contact oncore.support@yale.edu
If you answered “no” to question 4a, or "yes" to question 4b or c, please contact the YNHH Department of 
Physician Services (688-2615) for prior approval before commencing with your research protocol.
IMPORTANT
Will this study have a billable service? Yes ☐
No☒
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated entities?
Yes ☒ No ☐
If Yes, please answer questions a through c and note instructions below.
a. Does your YNHH privilege delineation currently include the specific procedure that you will perform? Yes ☒ No
☐
b. Will you be using any new equipment or equipment that you have not used in the past for this procedure? Yes
☐No ☒
c. Will a novel approach using existing equipment be applied? Yes ☐ No☒
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the HRU, the 
Principal Investigator and any co-investigators who are physicians or mid-level practitioners (includes PAs, APRNs, 
psychologists and speech pathologists) who may have direct patient contact with patients on YNHH premises 
must have medical staff appointment and appropriate clinical privileges at YNHH. If you are uncertain whether 
the study personnel meet the criteria, please telephone the Physician Services Department at 203-688-2615. By 
submitting this protocol as a PI, you attest that you and any co-investigator who may have patient contact has a 
medical staff appointment and appropriate clinical privileges at YNHH.
Additional Reference: Bleeding risk
Rahe-Meyer N, Fennema H, Schulman S, Klimscha W, Przemeck M, Blobner M, Wulf H, Speek M, McCrary Sisk 
C, Williams-Herman D, Woo T, Szegedi A. Effect of reversal of neuromuscular blockade with sugammadex versus 
usual care on bleeding risk in a randomized study of surgical patients. Anesthesiology. 2014 Nov;121(5):969-77
Page 19 of 19
APPROVED BY THE YALE UNIVERSITY IRB 6/19/2020

SAP_003.pdf: 
NCT03196167 
Sugammadex and Decreased Time to Extubation 
 
SAP 
6/19/2020 


Study Protocol: 
Subject Recruitment: Subjects will be consented in the collaborating surgeons offices or in pre-
admission testing. Every effort will be made to consent subjects prior to day of surgery. If a 
patient is referred or identified any time after those visits, they may be consented in the 
preoperative area. 
Anesthetic management per protocol: For enrolled patients, anesthetic management will be left 
to the discretion of the attending anesthesiology provider. As per our usual clinical practice, 
Rocuronium or vecuronium will be used as the non-depolarizing NMB and that where sedation is 
desired and appropriate, The patients will be transferred to the CTICU intubated and on a 
propofol infusion and/or dexmedetomidine per our usual clinical practice. 
Upon CTICU arrival, determination of continued eligibility will be determined. If the decision is 
made to continue on a fast-track extubation pathway, eligible patients will be randomized, 
investigational pharmacy will be contacted for study drug. 30 minutes after the ICU admission, 
propofol will be discontinued. Precedex may be continued per clinical discretion. The participant 
will be randomized to either receive Sugammadex or placebo. A qualitative train-of-four 
measurement will be obtained. The administration of the study and placebo compounds will be 
performed by CTICU nurses who will receive the drugs in a blinded fashion from the 
departmental research pharmacy. The level of neuromuscular blockade will be measured by 
accelerometer before and after the drug/placebo administration by the research coordinator. This 
will be done by placing a sheet over the limb being tested, so that the clinical team remains 
blinded to the results of the drug /placebo administration. The study drug will be supplied by 
Merck. Patients will be initiated on SIMV with 40% FiO2, tidal volumes 8-10 ml/kg and PEEP 
of 5. 
Ten minutes after the drug administration, if the patient is able to lift head and remains 
hemodynamically stable, the patient will be switched to CPAP mode of ventilation for 30 
minutes. At the end of the CPAP trial tidal volumes, Rapid Shallow Breathing Index (RSBI) and 
ABG will be assessed. The patient will be extubated if he/she is not hypoxic/ hypercarbic, has 
RSBI<100 and has TV >300 cc. The final clinical decision to extubate the patients will be taken 
by the CTICU team. 
If a patient fails the 30 minute CPAP criteria, the ICU intensivist will be immediately notified. 
Every attempt will be made to correct the underlying cause of CPAP failure, and a prompt 
reassessment will be made as deemed appropriate by the intensivist to reattempt CPAP versus 
continuing controlled mechanical ventilation. 
It is estimated conservatively that the study personnel will randomize 3 patients per week 
allowing for data collection to be completed within 1 year of study commencement. Data 
analysis and dissemination of findings will be conducted over the subsequent 6 months by the 
study institution investigators per the publication plan below. 
Blinded analyses of the data will be performed by the study investigators along with the 
departmental statistician in the Department of Anesthesiology at the Yale School of Medicine. 
Variables/Time Points of Interest: The primary outcome is the time to extubation, which will 
be the duration from arrival to the ICU to the extubation time. Participants' blood pressure, heart 
rate, and chest tube output will be tracked from arrival to the CTICU until extubation per ICU 
protocol. 


Statistical Methods: Baseline comparability. We expect that the randomization process will 
produce reasonably comparable groups. However, the adequacy of the randomization will be 
assessed by comparing the distribution of baseline demographic and clinical characteristics 
among the intervention groups. Comparability for continuous variables will be examined 
graphically and by summary statistics (means, medians, quartiles, etc.). Categorical variables 
will be examined by calculating frequency distributions. 
Proposed statistical test/analysis: Positively skewed variables will be log-transformed prior to 
hypothesis testing. For the primary outcome, a two-sided Student's t-test will be used to compare 
the time to extubation between the two groups. If necessary, covariate adjustment will be made 
using the multiple linear regression analysis method. Differences between means and 95% 
confidence intervals will be estimated to describe the magnitude of intervention difference 
between the two groups. As part of sensitivity analyses, the time-to-extubation outcome will be 
also analyzed by the Cox regression model. To compare the categorical adverse events between 
two groups, chi-square test or Fisher's exact test will be used. 
Missing Data: Prevention is the most obvious and effective manner to control bias and loss of 
power from missing data. Therefore, several strategies (e.g., timely data entry and daily missing 
data report) will be imposed to limit the likelihood that missing data will occur during this study. 
This protocol will follow the intention to treat principle, requiring follow-up of all subjects 
randomized regardless of the actual treatment received. 
Power analysis: Our 'in-house' historical data (n = 73) showed that after excluding outliers 
greater than the 80th percentile, patients undergoing isolated CABG demonstrated a mean of 
8.39 hours to extubation (SD 2.89). Although we anticipate a Hawthorne effect demonstrating 
reduced time to extubation in both the active and placebo arms of the present study, we have 
conservatively chosen to maintain power based on historical data. We therefore estimate that 45 
subjects per group will give us 90% power to detect a clinically relevant effect size of 2-hours 
difference between active and placebo groups at an alpha value of 0.05 using a two-sided two-
sample t-test. To allow for post consent, pre-randomization study drop out, we will aim to enroll 
a total of 110 (90 + 20 = 110) subjects. 
Per-protocol Sensitivity Analysis: In parallel with the primary analysis, if exclusions above occur 
post randomization but prior to drug administration, the investigators will conduct a parallel 
"per-protocol" sensitivity analysis. 
Drug supplies will be supplied by the sponsor. 
Adverse Experience Reporting: Throughout the duration of the study, researchers will adhere 
to good clinical practice and the guidelines of the institution. Patient vitals will be continuously 
monitored during and after the administration of the test drug. A data and safety monitoring 
board (DSMB) consisting of the head nurse and a senior critical care staff will meet monthly to 
discuss any serious events. Any incidence of anaphylaxis or unexplained hypotension requiring 
initiation of pressors or cardiac pacing within 5 minutes of drug administration will be reported 
an evaluated. Increases in chest tube output considered clinically significant by the critical care 
team will be noted. Any of these adverse events will trigger an analysis by the DSMB. If the 
DSMB determines that study drug may be causing an increase in adverse events, the study will 
be suspended until the DSMB is able to fully review the events and make a recommendation in 
consultation with the Yale Human Investigations Committee. The local Merck research 


representative will also be notified about the events. If the data monitoring board and/or 
institutional review board (IRB) view that the study is unsafe, the study will be discontinued. 
Specific Safety Events to Be Reported During Manuscript Preparation: For manuscript 
preparation, the rates of hypotension, anaphylaxis, and bleeding (i.e. Chest Tube output) will be 
reported and compared between active and placebo groups. 
Protocol Amendments: 
Three changes were made to the protocol within the first year of initiation to generalize the 
inclusion criteria due to slow recruitment rates: 
1. Originally the trial’s inclusion criteria was patients undergoing isolated coronary artery bypass 
grafting. It was expanded to allow for coronary artery bypass grafting (CABG), aortic valve 
replacement (AVR) or coronary artery bypass grafting and aortic valve replacement (CABG and 
AVR). 
2. The exclusion criteria for postoperative temperature was changed from 36.2° C to 35.5° C. 
3. Low dose pressors infusion was allowed as long as it did not preclude fast track protocol as 
adjudicated by the clinical team that was blinded to the arm allocation.