Use of Sugammadex for Reversal of Paralysis in Microlaryngoscopy
Phase: PHASE4
Conditions: Microlaryngoscopy, Rigid Bronchoscopy
Sponsor: West Virginia University

       
 
 
 
Use of Sugammadex for Reversal of Paralysis in Microlaryngoscopy  
 
NCT03111121 
 
01Sep2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

       
 
 
 
 
 
 
Requirements for Submitting a Full Proposal 
 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
  
The title of the protocol should include study design, indication and, where applicable, dosage, 
dosage form, and comparative agent(s). 
 
Use of Sugammadex for Reversal of Paralysis in Microlaryngoscopy  
 
 
Request Date: 
September 1 2016 
Institution Name 
 
West Virginia University 
Investigator 
Contact 
Information: 
- Full address  
- Phone No. 
- Fax  No. 
- e-mail address 
 
Pavithra Ranganathan, MD 
1 Medical Center Drive P. O. Box 8255 
Morgantown, WV 26506 
office (304)598-4929 coordinator: (304)598-4737 
Fax (304)-598-4930 
ranganathanp@wvumedicine.org 
 
 
 
 
 
 

       
 
Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
2.1 List the objectives.  
 
Outcome measures measured in the two groups: 
 
Primary outcome 
 
Time to extubation after end of procedure 
 West Virginia University Hospitals use an electronic medical record 
(EMR) to chart the end of the procedure.  When the surgeon states 
“We are done”, always at withdrawal of the scope, extubation 
begins.  From the time we chart end of procedure to the time of 
extubation is the extubation time.  The start and end times for 
extubation will be recorded in the EMR. 
 
The OR time is billed in 15 minute increments and it is a tremendous 
cost saving even for every 5 minutes saved.  It is anticipated that 
extubation using sugammadex will provide at least a 5 min reduction 
in extubation time when compared to the combination of 
neostigmine and glycopyrrolate (8, 11).  This translates to a possible 
45.8 % reduction (12, 13, 14).  
 
 
 Secondary outcomes 
 
1. Subjective interpretation of optimal surgical conditions as evaluated 
by the surgeon for ease of exposure graded from  1-10 ( 1 being 
difficult and 10 being the best  surgical conditions) 
2. Hemodynamic parameters – intra-op and post-op. ∆ in BP, HR and 
CO2  from base–line and incidence /frequency of 20% change in BP 
from baseline vitals ( baseline= pre-induction vitals) 
3. Respiratory parameters – intra op and post op 
4. Inhaled anesthetic concentration  intra-op 
5. Narcotics required intra op and post op  
6. Total OR time 
7. Time taken to meet ALDRETE criteria in PACU 
8. Time to discharge from PACU 
9. Any adverse event and severe adverse events such as - hypotension, 
arrhythmia, hypoxia, stridor and re-intubation will be compared in 
both groups 

       
2.1.1 List the clinical hypotheses.  
 
Hypotheses: 
 
Primary Hypothesis: Use of Muscle relaxant and reversal with 
Sugammadex at end of airway procedures will reduce the time to 
extubation after end of procedure 
 
 
Secondary Hypotheses:            
 
➢ Surgeon will report optimal surgical conditions for ease of exposure 
➢ Have less hemodynamic changes in the OR and PACU. ∆ in BP, HR and 
CO2  from base–line and incidence /frequency of 20% change in BP 
from baseline vitals (baseline= pre-induction vitals) 
➢ Decrease the amount of inhaled anesthetics  
➢ Decreased narcotics needed intra-operatively and post operatively 
➢ Decrease the total OR time 
➢ Subjects will meet ALDRETE PACU discharge criteria quicker in the 
PACU  
➢ Subject will have less adverse events and severe adverse events such 
as - hypotension, arrhythmia, hypoxia, stridor and re-intubation. 
 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Microlaryngoscopy and rigid bronchoscopy for vocal cord and tracheal 
procedures causes an intense sympathetic response during the procedure 
(1). Abrupt increases in heart rate, blood pressure can be seen in these 
procedures(1). Patients have to be extremely still for these highly stimulating 
procedures and hence have to be deeply anesthetized(2) (3). Ideal surgical 
exposure often depends on relaxation of muscles of mastication. Most of 
these procedures are done as outpatient procedures and many of these 
patients have significant co-morbidity. 
Deeply anesthetizing these patients can cause profound hypotension which 
can worsen the medical status of the patient and have longer PACU stay and 
can cause increased post-operative complications. 
Muscle relaxation with non-depolarizing muscle relaxants are rarely used in 
these procedures as the duration of action of the muscle relaxant is 
significantly longer than the actual procedure and time to extubation from 
end of procedure is significantly longer than without using muscle relaxation 
or a Succinylcholine drip.(4)  
Muscle relaxants are synergistic with inhaled anesthetics, and narcotics. 
Hence, the total amount of anesthetics and narcotics used can be 
significantly reduced when combined with muscle relaxants if we are able to 

       
fully reverse the paralysis at the end of the procedure.(5) 
 
2.3 Study Design 
 
 
This is a prospective, clinical interventional, randomized single blinded single 
center study.  We note that the nurses in PACU will be blinded to whether 
the subjects were in Group 1 or 2. 
 
After IRB approval, subjects will be consented in the clinic by the PI or CO-I 
for the study.  
 
After written consent is obtained and a copy provided to the subject; the 
following inclusion and exclusion criteria will be reviewed. The subject must 
meet all inclusion criteria and no exclusion criteria to qualify for the 
treatment phase. The subject that does not qualify will not be included in 
this study. 
Inclusion Criteria: 
➢ Age 18 years or older,  
➢ ASA physical status I-III 
➢ Ability to give written informed consent.  
 
Exclusion criteria: 
➢ Known or suspected neuromuscular disease/pre-existing weakness, 
➢ Creatinine clearance less than 30 ml/min,  
➢ Bradycardia of less than 40 beats/min, 
➢ Pregnancy, breast feeding women, 
➢ Known or suspected allergy to BRIDION® (sugammadex), neostigmine 
or rocuronium. 
➢ Patients with contraindications towards sugammadex, neostigmine 
or rocuronium 
➢ Patients included in another trial within the last 30 days 
➢ Patients with legal guardians or surrogate decision making 
➢ Patients who refuse to use non-hormonal contraceptive method or 
back-up method of contraception (such as condoms and spermicides) 
for the next 7 days if receiving sugammadex.  Ref (6)  
 
 
Patients will be randomized, using a block randomization scheme, to one of 
the two anesthetic groups.  The block randomization scheme will use 
random block sizes varying from 2 to 6 patients per block.  Subjects will 

       
receive a unique study id number (subject 1: i.e. 0001-{3 initial i.e. A-B-C}).  
The randomization scheme will be developed by the statistician; the master 
list of study ids and reversal treatment allocations will be held by the PI and 
research coordinator.  Strict adherence to the sequence of treatment 
allocations will be maintained. 
 
Group 1: Inhaled anesthetics: sevoflurane at 1 MAC, remifentanil and 
intubation with rocuronium at 0.6-1.2 mg/kg (vitals maintained within 20% 
of baseline).  Group 1 will receive reversal with neostigmine (0.04 mg/kg and 
glycopyrrolate (0.01 mg/kg)  
 
Group 2: Inhaled anesthetics: sevoflurane at 1 MAC, remifentanil and 
intubation with rocuronium at 0.6 -1.2 mg/kg (vitals maintained within 20% 
of baseline). Group 2 will receive reversal with sugammadex 4mg/kg  
 
Both groups will receive standard anti-nausea prophylaxis – Ondansetran 
and Decadran intraoperative. 
 
After induction, the amount of inhaled anesthetic and remifentanil used will 
be titrated based on hemodynamic parameters (maintained within 20% from 
baseline) and a BIS monitor.  
 
All subjects will have TOF testing done every 5 minutes throughout the 
procedure and tabulated in the Electronic Medical Record (EMR). 
 
At the end of the procedure patient will be extubated when the subject 
meets the following criteria: 
 
Tidal volume : > 5 cc /Kg 
Respiratory rate: >8 /min 
O2sat > 95% ON 100% inspired oxygen 
 
With vitals at 20% of baseline.  Extubation will begin when the surgeon 
states, “We are done”.  This usually coincides with the withdrawal of the 
scope.  The start and end times for extubation will be recorded in the 
Electronic Medical Record. 
 
 
The PACU nurses will evaluate ALDRETE discharge criteria and make a note 
in the electronic medical records for the subject discharge time from PACU. 
The nurses in PACU will be the only evaluators of the subject who will be 
blinded to the two groups 
 
 

       
Independent Data and Safety Committee Monitoring: 
Data and safety monitoring is a requirement of our institutional IRB (WVU 
IRB) and is standard for all clinical studies.  Independent Data and Safety 
Monitoring Committee: Individuals not involved with the study will review 
the data and make recommendations to continue or stop the study to the 
Principal Investigator.  
 
Following the WVU IRB Independent Data and Safety Monitoring Plan, a 
quality assurance audit will be performed by the IDSMC when 20% of the 
patients have been recruited (n=17).  This audit will include, but not be 
limited to, the review of informed consent process, eligibility confirmation, 
adherence to protocol procedures and treatment plans, pharmacy records 
and storage, and regulatory documentation. Adverse events and severe 
adverse events such as - hypotension, arrhythmia, hypoxia, stridor and re-
intubation will be compared in both groups. 
 
No analysis related to or involving the primary outcome is required or will 
be performed at this time.  
 
ADVERSE EVENT ASSESSMENT: any unfavorable and unintended medical 
occurrence, symptom or disease temporally associated with the use of a 
medical treatment of the subjects whether or not it is associated related to 
the medical treatment. The Principal Investigator will identify and make 
adverse events assessments. Adverse events and severe adverse events such 
as - hypotension, arrhythmia, hypoxia, stridor and re-intubation will be 
compared in both groups. 
 
 
SINGLE BLIND: The nurses in PACU will be the only evaluators of the subject 
who will be blinded to the two groups. The PACU nurses will evaluate 
ALDRETE discharge criteria and make a note in the electronic medical 
records for the subject discharge time from PACU. 
 
Subject total: 84 completed 
 
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 subjects.  At most, the Web site will 
include a summary of the results. 
 
 

       
2.4 Study Flowchart 
 
After contract signed and IRB approval 
 
 
 
Timetable of Investigation: 
 
Year 0.25 
September 
2016 – 
December 
2016 
Year 1 
January 2017 – December 2017 
 
Q4 
Q1 
Q2 
Q3 
Q4 
IRB approval/ 
Renewal 
 
 
 
 
 
Subject 
Screening/Enrollment 
 
 
 
 
 
Data Collection 
 
 
 
 
 
Statistical Analysis 
 
 
 
 
 
Writing/Presentation 
 
 
 
 
 
 
 
 
2.5 Study 
Procedures 
 
Screening: After IRB approval, Subjects will be consented in the clinic by 
the PI or CO-I for the study.  
 
After consenting: The following inclusion and exclusion criteria will be 
reviewed. The subject must meet all inclusion criteria and no exclusion 
criteria to qualify for the treatment phase. The subject that does not qualify 
will not be included in this study. 
 
Inclusion Criteria: 
➢ Age 18 years or older,  
➢ ASA physical status I-III 
➢ Ability to give written informed consent.  
 
Exclusion criteria: 
➢ Known or suspected neuromuscular disease/pre-existing weakness, 
➢ Creatinine clearance less than 30ml/min,  
➢ Bradycardia of less than 40 beats/min, 
➢ Pregnancy, breast feeding women, 
➢ Known or suspected allergy to BRIDION® (sugammadex), neostigmine 
or rocuronium. 
➢ Patients with contraindications towards sugammadex, neostigmine 

       
or rocuronium,  
➢ Subjects included in another trial within the last 30 days 
➢ Patients with legal guardians or surrogate decision making.  
➢ Patients that refuses to use non-hormonal contraceptive method or 
back-up method of contraception (such as condoms and spermicides) 
for the next 7 days if receiving sugammadex 
 
Treatment Phase: Surgery 
Subjects will receive a unique study id number (subject 1: i.e. 0001-{3 initial 
i.e. A-B-C}) if surgery is performed. 
 
Patients will be randomized, using a block randomization scheme, to one of 
the two groups, as outlined in the Study Design section.  Strict adherence to 
the sequence of treatment allocations will be maintained.  
 
Group 1: Inhaled anesthetics: sevoflurane at 1 MAC, remifentanil and 
intubation with rocuronium at 0.6-1.2 mg/kg (vitals maintained within 20% 
of baseline).  Group 1 will receive reversal with neostigmine (0.04 mg/kg and 
glycopyrrolate (0.01 mg/kg)  
 
Group 2: Inhaled anesthetics: sevoflurane at 1 MAC, remifentanil and 
intubation with rocuronium at 0.6 -1.2 mg/kg (vitals maintained within 20% 
of baseline). Group 2 will receive reversal with sugammadex 4mg/kg  
 
Both groups will receive standard anti-nausea prophylaxis – Ondansetran 
and Decadran intraoperative. 
 
After induction; amount of inhaled anesthetic and remifentanil used will be 
titrated based on hemodynamic parameters (maintained within 20% from 
baseline) and a BIS monitor.  
 
All subjects will have TOF testing done every 5 minutes throughout the 
procedure and tabulated in the EMR. 
 
 
Follow-Up: PACU 
 
The PACU nurses will evaluate ALDRETE discharge criteria and make a note 
in the electronic medical records for the subject discharge time from PACU. 
The nurses in PACU will be the only evaluators of the subject who will be 
blinded to the two groups 
 
Adverse events and serious adverse events such as - hypotension, 
arrhythmia, hypoxia, stridor and re-intubation will be followed until 

       
resolution or 30 days post treatment by phone call from research 
coordinator (16). 
 
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 subjects.  At most, the Web site will 
include a summary of the results. 
 
 
Subject total: 84 completed 
 
2.6 Study Duration 
The estimate time for subject enrollment is 12 months, publication and 
presentation of data will follow completion of data analysis. 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
Power/Sample Size: 
 
All patients have a clearly defined time at which extubation begins and ends 
(See Section 2.3, Study Design).  There will be no patients with unobserved 
end points (e.g. no loss to follow-up, attrition, or right censoring).  
Additionally, the Data and Safety Monitoring does not require the analysis of 
the primary research question prior to the completion of the study (See 
Section 2.3, Study Design, Data and Safety Monitoring subsection).   
 
Based on these considerations, powering for the primary outcome of 
extubation time used the log-rank test, Schoenfeld’s method, and balanced 
allocation of patients to each group (9-10).  With minimum power of 80%, an 
alpha-level of 0.05, and an effect size of 0.542, a total of 84 patients are 
required providing 42 patients per group.   
 
The effect size was derived using median times-to-extubation to estimate 
the hazard ratio.  An estimate of the median extubation time for 
sugammadex is 6.4 minutes (8, 11) with a minimum differential of 5.4 
minutes for the combination of neostigmine and glycopyrrolate (i.e. 11.8 
min).  The 5.4 min differential is twice the differential between sugammadex 
and pyridostigmine (8), and is motivated by longer extubation times for 
neostigmine and glycopyrrolate when compared against pyridostigmine (15).  
The anticipated minimal differential has positive clinical and financial 
ramifications (Section 2.1 Objective & Hypotheses). 
 
 
 
 
 
 
Statistical Analysis: 
 

       
We will use univariate statistics (e.g. mean, median, standard deviation, 
interquartile range) to summarize the collected data.  Balance between the 
two groups for key patient variables (see Section 2.1 for examples) will be 
assessed using a two-sided two-sample t-test using unequal variances and 
the Welch modification to the degrees of freedom.  For categorical variables, 
the Chi-square test will be used.  If non-parametric tests or exact methods 
are required, we will use the Mann-Whitney U test and the Fisher-Freeman-
Halton exact test respectively. 
 
The primary comparison of extubation time between the two groups will be 
assessed using the Kaplan-Meier method and log-rank test.  Statistical 
significance will be assessed using a two-sided test with an alpha-level of 
0.05. All statistical analysis will be performed using the R software 
environment for statistical computing and graphics (7). 
 
2.8 Specific Drug 
Supply 
Requirements  
Phase 4 study: Drug: BRIDION®, sugammadex, will be supplied by Merck: 
Budget for cost for research in-patient pharmacist to receive drug from 
Merck, dispense drug, keep research accountability, and keep blind for 
research study is included at $70/subject. 
2.9 Adverse 
Experience 
Reporting 
Phase 4 study: FDA policy on reporting Form 3500 
 
 
2.10 Itemized Study 
Budget  
Please see attached budget  
2.11 References 
(1) Cardiac complications of microsurgery of the larynx: etiology, incidence 
and prevention. Strong MS, Vaughan CW, Mahler DL, Jaffe DR, Sullivan RC, 
Laryngoscope. 1974 Jun; 84(6):908-20. 
 
(2) Anesthesia for laryngoscopy. Benjamin B. Ann Otol Rhinol Laryngol. 1984 
Jul-Aug; 93(4 Pt 1):338-42.   
 
(3) Effects of anesthetic technique on the hemodynamic response to 
microlaryngeal surgery. Ayuso A, Luis M, Sala X, Sánchez J, Traserra J Ann 
Otol Rhinol Laryngol. 1997 Oct; 106(10 Pt 1):863-8. 
 
(4) Assessment of depth of anesthesia and postoperative respiratory 
recovery after remifentanil- versus alfentanil-based total intravenous 
anesthesia in patients undergoing ear–nose–throat surgery. Anesthesiology. 
2001; 94:211–7. 
 

       
(5) Basics of Anesthesia–sixth edition Ronald C. Miller page 152 
(pharmacodynamics responses) 
 
(6) Package circular for BRIDION (sugammadex) U.S. approval 2015 
 
(7) R Development Core Team (2016): R: A Language and Environment for 
Statistical Computing, R Foundation for Statistical Computing, Vienna, 
Austria, URL http://www.R-project.org, ISBN 3-900051-07-0. 
 
(8) Eui-Seok Park, Byung Gun Lim*, Won-Joon Lee and Il Ok Lee.  
Sugammadex facilitates early recovery after surgery even in the absence of 
neuromuscular monitoring in patients undergoing laryngeal microsurgery: a 
single-center retrospective study.  BMC Anesthesiology (2016) 16:48.  DOI 
10.1186/s12871-016-0221-2 
 
(9) David W. Hosmer, Stanley Lemeshow, Susanne May (2008),  Applied 
Survival Analysis: Regression Modeling of Time-to-Event Data, 2nd Ed.  Wiley 
Series in Probability and Statistics, John Wiley & Sons, Hobooken, NJ, USA. 
[Section 9.7, pp 340-346] 
 
(10) David Collett (2003), Modelling Survival Data in Medical Research, 2nd 
Ed.  Chapman & Hall/CRC, Boca Raton, Florida, USA.  [Section 10.2.1, pp 302-
304] 
 
(11) Vymazal T, Krecmerova M, Bicek V, Lischke R. Feasibility of full and rapid 
neuromuscular blockade recovery with sugammadex in myasthenia gravis 
patients undergoing surgery – a series of 117 cases. Therapeutics and Clinical 
Risk Management. 2015;11:1593-1596. doi:10.2147/TCRM.S93009. 
 
(12) Paton F1, Paulden M, Chambers D, Heirs M, Duffy S, Hunter JM, 
Sculpher M, Woolacott N 2010 Oct 8.:Sugammadex compared with 
neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a 
systematic review and economic evaluation. Br J Anaesth. 2010 
Nov;105(5):558-67. doi: 10.1093/bja/aeq269. Epub 
 
(13) D Chambers, M Paulden, F Paton,M Heirs, S Duffy, D Craig, J Hunter,J 
Wilson, M Sculpher and N Woolacott: Sugammadex for the reversal of 
muscle relaxation in general anaesthesia: a systematic review and economic 
assessment: Health Technology Assessment 2010; Vol. 14: No. 39 
 
(14)Chambers D1, Paulden M, Paton F, Heirs M, Duffy S, Hunter JM, Sculpher 
M, Woolacott N.:Sugammadex for reversal of neuromuscular block after 
rapid sequence intubation: a systematic review and economic assessment. 
Br J Anaesth. 2010 Nov;105(5):568-75. doi: 10.1093/bja/aeq270. Epub 2010 

       
Oct 11. 
 
(15)Edoardo De Robertis,1 Geremia Zito Marinosci,1 Giovanni Marco 
Romano,1 Ornella Piazza,2 Michele Iannuzzi,1 Fabrizio Cirillo,1 Stefania De 
Simone,3 and Giuseppe Servillo1The use of sugammadex for bariatric 
surgery: analysis of recovery time from neuromuscular blockade and 
possible economic impact: Clinicoecon Outcomes Res. 2016; 8: 317–322. 
Published online 2016 Jun 29.  doi: 10.2147/CEOR.S109951:PMCID: 
PMC4934482:Table 2 : Pharmacological data and costs of reversal drugs 
 
(16)Boon M1, Martini C1, Broens S1, van Rijnsoever E2, van der Zwan T3, 
Aarts L1, Dahan A4: Improved postoperative oxygenation after antagonism 
of moderate neuromuscular block with sugammadex versus neostigmine 
after extubation in 'blinded' conditions: Br J Anaesth. 2016 Sep;117(3):410-1. 
doi: 10.1093/bja/aew246. 
 
 
 
  
2.12 Publication 
Plan 
 
 
Publications in Anesthesiology Journal and presentations at ASA meetings in 
fall of 2017 and/or Spring 2018 
 
2.13 Curriculum 
Vitae 
 
Please see Attached in vision tracker  
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
U.S. protocols should be submitted by US investigators directly or through 
the Global Research Specialist at  www.merckiisp.com   
 
Non U.S. protocols should be submitted to the MSD office by the 
investigators.