Clinical trial NCT03210376
Conditions: Malignant Neoplasms of Digestive Organs Malignant Neoplasms of Female Genital Organs Malignant Neoplasms of Male Genital Organs Malignant Neoplasms of Urinary Tract
Keywords: Malignant neoplasms of digestive organs Malignant neoplasms of female genital organs Malignant neoplasms of male genital organs Malignant neoplasms of urinary tract Neuromuscular blockade NMB Sugammadex Neostigmine Pain Assessment Survey
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-11-17; Completion date: 2020-10-22
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Insufflation pressure (IP) is the creation of a pressure barrier of air/gas within the abdomen to allow the surgeon more space to work during abdominal surgery. Shoulder pain is a common complaint from patients who have had abdominal surgery and the pain is thought to be related to the use of IP.

In addition to anesthesia (which keeps you asleep during surgery), the current standard practice is to block the nerve-muscle junction with a type of drug called neuromuscular blockade (NMB) which paralyzes the abdominal muscles. This means that a lower level of insufflation pressure is needed by the surgeon.

To reverse the effects of NMB after surgery, a drug called neostigmine is given.

The goal of this clinical research study is to compare the use of standard-of-care moderate NMB and neostigmine to the use of deep NMB and a drug called Sugammadex when given to elderly patients (patients who are 65 years of age or older) who are scheduled to have robotic abdominal surgery. "Deep" and "moderate" in this study refers to the dose or strength of the NMB given.

This is an investigational study. Sugammadex and neostigmine are FDA approved and commercially available for the reversal of NMB. It is considered investigational to compare Sugammadex and neostigmine to learn if the use of one or the other in elderly patients can reduce the level of shoulder pain after surgery.

Up to 100 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups before your surgery. This is done because no one knows if one group is better, the same, or worse than the other.

* In Group 1, you will receive deep NMB and Sugammadex.
* In Group 2, you will receive moderate NMB and neostigmine.

Neither you nor the surgeon or surgical staff will know to which group you have been assigned. The surgeon will not know which group you are in because researchers want to learn how much, if at all, the surgeon needs to adjust the insufflation pressure during surgery. However, if needed for your safety, the surgeon will be able to find out which group you are in.

For your safety, the anesthesiologist will know to which group you have been assigned.

Surgery and Study Drug Administration:

After you have been assigned to a study group, you will have your surgery as scheduled. You will sign a separate consent form for surgery which describes the procedure and its risks in more detail. You will also sign a separate consent form to receive anesthesia.

Before your surgery, blood (about 2 teaspoons) will be drawn for biomarker testing. Biomarkers are found in the blood/tissue and may be related to the status of the disease and/or your reaction to the study drug(s).

During the surgery, the insufflation pressure that is being used, including any changes that are made to the pressure, will be recorded. After the surgery has been completed, you will receive either Sugammadex or neostigmine by vein until the effects of the NMB have been reversed.

You will recover after surgery in the post-anesthesia care unit (PACU). At about 15, 45, and 90 minutes after your surgery, a PACU nurse will ask you about any shoulder pain you are feeling and if so, how intense the pain is. Information about how long you stay in the hospital after surgery and if you have any side effects after surgery (such as nausea/vomiting or shoulder pain) will also be collected from your medical record.

Follow-Up:

After 30 days after you leave the hospital, you will be called by a member of the study staff to ask how you are doing and if you have had any additional hospitalizations since leaving the hospital. This phone call should last about 5-10 minutes.

Length of Study Participation:

Your participation in this study will be over after completing the 30-day follow up phone call.

Arms: arm 1: Deep Neuromuscular Blockade (NMB) given during surgery.

Sugammadex intravenously as a single bolus injection after surgery.

Pain assessment done at about 15, 45, and 90 minutes after surgery. arm 2: Moderate Neuromuscular Blockade (NMB) given during surgery.

Neostigmine intravenously slowly over a period of at least 1 minute after surgery.

Pain assessment done at about 15, 45, and 90 minutes after surgery.
Interventions: intervention 1: Deep Neuromuscular Blockade (NMB) intervention 2: Moderate Neuromuscular Blockade (NMB) intervention 3: Sugammadex intervention 4: Neostigmine intervention 5: Pain Assessment
Intervention descriptions: intervention 1: Deep Neuromuscular Blockade (NMB) given during surgery. intervention 2: Moderate Neuromuscular Blockade (NMB) given during surgery. intervention 3: 4 mg/Kg, intravenously as a single bolus injection after surgery. intervention 4: 70 mcg/Kg up to a total of 5 mg, intravenously slowly over a period of at least 1 minute after surgery. intervention 5: Pain assessment done at about 15, 45, and 90 minutes after surgery.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2017-0046 
May 2, 2018 
Page 1 of 20 
 
The effect of deep neuromuscular blockade with 
Sugammadex reversal on shoulder pain of elderly 
patients undergoing Robotic Prostatectomy: A single-
center double-blinded randomized controlled trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: Wendell Williams M.D. 
Co – Principal Investigator: Juan Cata M.D. 
 
Collaborators: Vijaya Gottumukkala M.D. 
 
 
 
 


Protocol 2017-0046 
May 2, 2018 
Page 2 of 20 
The effect of deep neuromuscular blockade with Sugammadex reversal on shoulder pain of 
elderly patients undergoing Robotic Prostatectomy: A single-center double-blinded randomized 
controlled trial 
Objectives 
Primary: To compare the effect of deep neuromuscular 
blockade with Sugammadex reversal versus moderate 
neuromuscular blockade with neostigmine reversal 
(standard of care) on postoperative shoulder pain.  
Secondary: 
To 
assess 
the 
effect 
of 
deep 
neuromuscular blockade with Sugammadex reversal 
versus 
moderate 
neuromuscular 
blockade 
with 
neostigmine reversal on intraoperative insufflation 
pressures, perioperative recovery and morbidity for 
robotic prostatectomy. 
Hypothesis 
1. Elderly patients undergoing robotic prostatectomy who 
receive continuous deep neuromuscular blockade and 
its reversal with Sugammadex will have adequate 
surgical exposure with lower insufflation pressures 
which will be associated with lower postoperative 
shoulder pain, less morbidity and a faster recovery when 
compared 
to 
patients 
receiving 
moderate 
neuromuscular blockade. 
2. The adoption of continuous deep neuromuscular 
blockade combined with lower insufflation pressures 
during robotic prostatectomy will have the most 
significant 
effects 
for 
patients 
with 
multiple 
comorbidities, such as obesity, age greater than 65, 
history of congestive heart failure, chronic obstructive 
pulmonary disease, chronic renal insufficiency, diabetes 
mellitus, peripheral vascular disease and sarcopenia. 
Study Design 
Single-center randomized controlled double-blind trial. 
Patients will receive either the Deep Neuromuscular 
Blockade (DNMB group) with Sugammadex reversal or 
Moderate Neuromuscular Blockade (MNMB group) with 
neostigmine reversal. 
Number of Patients 
100 
Site 
M. D. Anderson Cancer Center 
Duration of Study 
December 2017 to December 2019 
Duration of Patient Participation 
Until postoperative day 7 or discharge 
Primary Endpoints 
Incidence of postoperative shoulder pain 


Protocol 2017-0046 
May 2, 2018 
Page 3 of 20 
Secondary Endpoints 
1. Quantitative grading of Shoulder Pain using Visual 
Analog Scale (VAS) for pain score 
2. Cumulative intraoperative insufflation pressure (mmHg 
min) during the surgery 
3. Subjective grading of quality of surgical exposure 
expressed by surgeon at end of case using Surgical 
Rating Scale (Martini, Boon, Bevers, Aarts, & Dahan, 
2013) 
4. Readiness to discharge from the PACU as determined 
by a modified version of the DASAIM discharge criteria 
scoring system to be completed at 15, 45 and 90 minutes 
after admission to the PACU  
5. Degree of PONV per Visual Analog Scale and number 
of episodes of emesis per nurse in PACU  
6. Length of ICU & Hospital stay, 30-Day Mortality and 
Readmission Rate 
7. Measures of organ dysfunction and perfusion by the 
Postoperative Morbidity Survey (De novo need for oxygen 
supplementation, ability to tolerate an enteral diet, oliguria 
or Acute Kidney Injury, Delirium or new neurological 
deficits) and postoperative lactate 
Exploratory Outcomes: 
1. Optional: Incidence of residual muscle relaxation upon 
admission to PACU as defined by TOF ratio <0.9, if TOF-
Watch® SX is available 
2. Optional: Subgroup analysis on elderly patients with 
comorbidities including laboratory evidence of sarcopenia 
(creatinine/cystatin c ratio)  
Inclusion Criteria 
1. Patients 65 years of age or older 
2. Patients having robotic prostatectomy 
3. Written informed consent  
Exclusion Criteria 
1. Patient with known hypersensitivity to Rocuronium, 
Sugammadex or its components 
2. Patients with severe renal insufficiency, defined and 
confirmed by an estimated creatinine clearance equal or 
lower than 30 mL/min 
3. Patients with history of severe liver disease, defined as 
and confirmed by elevated ALT and AST greater than 1.5 
times the Upper Limit of Normal along with Albumin less 
than 3 OR INR 1.5 or greater per institutional laboratory.  
 


Protocol 2017-0046 
May 2, 2018 
Page 4 of 20 
1. Background 
Along with other minimally invasive techniques, the use of robotic laparoscopic surgical 
techniques require smaller incision sites, are often associated with lower intraoperative blood 
loss, postoperative pain and shorter recovery when compared with open techniques. (O'Neil, et 
al., 2016) (Sert, et al., 2016) The use of insufflation pressure (IP) required to maintain 
adequate pneumoperitoneum during robotic surgery can have numerous deleterious effects that 
are directly correlated with higher pressures (10-15 mmHg or more). These effects include lower 
respiratory compliance and higher inspiratory pressures, impaired cardiac function, systemic 
and portal venous stasis, hypercoagulopathy, decreased urine output, decreased organ 
perfusion and postoperative pain. Shoulder pain is common following laparoscopic abdominal 
surgery and is thought to be caused by irritation of the diaphragm by the carbon dioxide used for 
abdominal insufflation. (Fredman, Jedeikin, Olsfanger, Flor, & Gruzman, 1994) The 
intraoperative maintenance of deep neuromuscular blockade (NMB) has the advantage of 
potentially decreasing the insufflation pressure required by the surgeon to maintain adequate 
visualization. (Staehr-Rye, et al., 2014) (Koo, et al., 2016) (Kim, Lee, Lee, Min, & Yoo, 2016) By 
lowering the patients’ cumulative exposure to pressurized carbon dioxide pneumoperitoneum, it 
is possible to decrease the incidence of shoulder pain during the recovery period. (Kim, Lee, 
Lee, Min, & Yoo, 2016) (Madsen, et al., 2016) Historically, the practice of maintaining deep 
continuous neuromuscular blockade was limited because excessive NMB would prevent timely 
extubation of the patient at the end of surgery.  
Several studies have demonstrated decreased morbidity from laparoscopic surgery with the use 
of deep neuromuscular blockade (DNMB). Using data from laparoscopic colorectal surgery, 
patients in the DNMB vs. moderate NMB (MNMB) group had IP of 9.3 +/- 1.3 vs. 12.0 +/- 0.5 
mmHg group respectively. The DNMB group had lower Numeric Rating Scale (NRS) pain 
scores [2.3(0.6) to 2.9(0.3)], incidence of shoulder pain (3.3% to 25.8%; a reduction of 87%) 
Gas Passing Time in hours [40(11.3) to 64(31)] and estimated blood loss (20.2 +/- 13.7 vs 60 
+/- 95.3 mL). (Kim, Lee, Lee, Min, & Yoo, 2016) In another study which focused on 99 patients 
undergoing laparoscopic hysterectomy, 28.6% of the DNMB group (IP 8mmHg) vs. 60% in the 
MNMB group (IP 12mmHg) experienced shoulder pain. (Madsen, et al., 2016) Robotic surgery 
may differ from conventional laparoscopic surgery in that the duration of surgery is often more 
prolonged and the patient may be maintained in different positions (steep Trendelenburg or 
reverse Trendelenburg), both of which may increase the physiologic effects of 
pneumoperitoneum.  
Sugammadex is a gamma cyclodextrin which directly encapsulates steroid NMB agents such as 
Vecuronium and Rocuronium thus allowing for safe, rapid and more complete reversal of 
muscular paralysis. (Flockton, et al., 2008) (Geldner, et al., 2012)  With the use of 
Sugammadex, it is now possible to maintain a continuously deep level of muscular relaxation 
while also extubating the patient at the end of the operation in a safe and efficient manner. 
(Carron, Baratto, & Ori, 2016) (Ledowski, et al., 2014) (Duvaldestin, et al., 2010) 
The Train of Four (TOF) ratio (or TOFR) is a technique for monitoring the degree of blockade by 
non-depolarizing neuromuscular blocking agents at the nicotinic acetylcholine receptors 
(neuromuscular junction).  An electrical stimulus is applied by transcutaneous nerve stimulator 
as a group of four stimuli.  The quantity and quality of muscular response to nerve stimulation 
correlates with the degree of neuromuscular blockade.  The number of muscular responses to 
stimulation (TOF count) of 4, 3, 2 and 1 correlates with approximately 75%, 85%, 90% and 95% 
neuromuscular blockade.  The TOF ratio of T4/T1 is a more objective and sensitive method to 
quantify the degree of neuromuscular blockade calculated by comparing the strength of 
muscular response of the last TOF stimuli compared to the first. It was previously thought that a 


Protocol 2017-0046 
May 2, 2018 
Page 5 of 20 
TOFR greater than 0.7 indicated sufficient neuromuscular recovery for extubation. Evidence 
now suggests that one can have an increased risk of upper airway obstruction and aspiration 
due to residual neuromuscular blockade with a TOFR less than 0.9, though more prospective 
studies are needed.    
Elderly patients compared to the general population may receive more benefit from the reversal 
of NMB with Sugammadex as opposed to neostigmine but more prospective studies are 
needed.  In a large retrospective study of 1444 patients, those who had an age greater than 60 
and an ASA score of 3 or 4 had a small but significantly higher incidence of postoperative 
pulmonary complications when treated with neostigmine compared to Sugammadex. (Ledowski, 
et al., 2014) Additional investigation may identify subgroups within the elderly population who 
are the highest risk for complications of elevated insufflation pressures or residual 
neuromuscular blockade.  
While there is no universal age which defines the elderly, we chose the age of 65 years or 
greater to be our threshold based on the Phase 3 trial which demonstrated the safety and 
efficacy of Sugammadex in the elderly population. Overall, 150 patients were treated and had at 
least one post-baseline efficacy assessment; 48 were aged 18-64 yr (adult), 62 were aged 65-
74 yr (elderly), and 40 were aged 75 yr or older (old-elderly). The geometric mean time (95% 
confidence interval) from Sugammadex administration to recovery of the TOF ratio to 0.9 
increased with age, from 2.3 (2.0-2.6) min (adults) to 2.9 (2.7-3.2) min (elderly/old-elderly 
groups combined). Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in adults 
compared with patients aged 65 yr or older (P = 0.022). Sugammadex was well tolerated by all 
patients. (McDonagh DL, 2011) 
One possible subgroup that may receive the greatest benefit from the use of Sugammadex are 
cancer patients with sarcopenia and sarcopenic obesity.  Cancer cachexia affects 60-80% of 
patients with advanced cancer and is associated with increased morbidity and mortality. 
(Baracos, 2011)  Though criteria for cancer cachexia has traditionally varied, an international 
panel of cachexia experts recently agreed upon a common definition which includes recent 
weight loss, BMI and sarcopenia.  Among 1,077 cancer patients, those classified as cachectic, 
as defined by weight loss greater than 5% over the last 6 months or greater than 2% with a BMI 
less than 20 kg/m2, had a shorter median survival than for non-cachectic patients. (139 versus 
269 days; P < 0.001) (Blum, 2014)  Among cancer patients to receive chemotherapy, those with 
sarcopenia had a mortality hazard ratio of 5.19 when controlled for BMI, age and tumor stage. 
(Gonzalez, 2014)  
A laboratory indicator of sarcopenia is the creatinine to cystatin c ratio, which can account for 
the majority of individual variability of total body muscle mass and has been used to detect 
sarcopenia and sarcopenic obesity. (Kim, et al., 2016)  Cystatin C also has greater prognostic 
value than creatinine. (K Suzuki, 2015) (Y Otaki, 2015) (Graf, 2015) (Wannamethee, 2015)  
The Postoperative Morbidity survey is a 9-point scale used to systematically assess short-term 
morbidity and multi-organ dysfunction following surgery. (Bennett-Guerrero, et al., 1999)  
(Davies, et al., 2013)  It has been shown to have good reliability and validity with an association 
with greater hospital length of stay in the general population and increased mortality in the 
elderly. (Howes, et al., 2015)   
 
 
 


Protocol 2017-0046 
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Page 6 of 20 
2. Hypotheses 
2.1 Elderly patients undergoing robotic prostatectomy who receive continuous deep 
neuromuscular blockade and its reversal with Sugammadex will have adequate surgical 
exposure with lower insufflation pressures which will be associated with lower 
postoperative shoulder pain, less morbidity and a faster recovery when compared to 
patients receiving moderate neuromuscular blockade. 
2.2 The adoption of continuous deep neuromuscular blockade combined with lower 
insufflation pressures during robotic prostatectomy will have the most significant effects for 
patients with multiple comorbidities, such as obesity, age greater than 65, history of 
congestive heart failure, chronic obstructive pulmonary disease, chronic renal insufficiency, 
diabetes mellitus, peripheral vascular disease and sarcopenia. 
3. Objectives 
3.1 Primary: To compare the effect of deep neuromuscular blockade with Sugammadex 
reversal versus moderate neuromuscular blockade with neostigmine reversal (standard of 
care) on postoperative shoulder pain.  
3.2 Secondary: To assess the effect of deep neuromuscular blockade with Sugammadex 
reversal versus moderate neuromuscular blockade with neostigmine reversal on 
intraoperative insufflation pressures, perioperative recovery and morbidity for robotic 
prostatectomy. 
4. Study Design 
4.1. Primary Outcome 
Incidence of postoperative shoulder pain 
4.2. Secondary Outcomes 
4.2.1 Quantitative grading of Shoulder Pain using Visual Analog Scale (VAS) for pain score  
4.2.2 Cumulative intraoperative insufflation pressure (mmHg min) during the surgery 
4.2.3 Subjective grading of quality of surgical exposure expressed by surgeon at end of 
case using Surgical Rating Scale (Martini, Boon, Bevers, Aarts, & Dahan, 2013) 
4.2.4 Readiness to discharge from the Post-Anesthesia Care Unit (PACU) as determined 
by a modified version of the Dansk Selskab for Anæstesiologi og Intensiv Medicin 
(DASAIM) discharge criteria scoring system to be completed at 15, 45 and 90 minutes after 
admission to the PACU  
4.2.5 Degree of Post-Operative Nausea and Vomiting (PONV) per Visual Analog Scale and 
number of episodes of emesis per nurse in PACU  
4.2.6 Length of Intensive Care Unit (ICU) & Hospital stay, 30-Day Mortality and 
Readmission Rate  
4.2.7 Measures of organ dysfunction and perfusion by the Postoperative Morbidity Survey 
(De novo need for oxygen supplementation, ability to tolerate an enteral diet, oliguria or 
Acute Kidney Injury, Delirium or new neurological deficits) and postoperative lactate 


Protocol 2017-0046 
May 2, 2018 
Page 7 of 20 
4.3. Exploratory Outcomes 
4.3.1. Optional: Incidence of residual muscle relaxation upon admission to PACU as 
defined by Train-Of-Four (TOF) ratio <0.9, if TOF-Watch® SX is available 
4.3.2. Optional: Subgroup analysis on elderly patients with comorbidities including 
laboratory evidence of sarcopenia (creatinine/cystatin c ratio)  
4.4. Design 
Single-center randomized controlled double-blind trial. Patients will be randomized to receive 
either the Deep Neuromuscular Blockade (DNMB group) or Moderate Neuromuscular Blockade 
(MNMB group).  
4.5. Eligibility 
4.5.1. Inclusion Criteria: 
 
Patients 65 years of age or older 
 
Patients having robotic prostatectomy 
 
Written informed consent  
4.5.2. Exclusion Criteria: 
 
Patient with known hypersensitivity to Rocuronium, Sugammadex or its components 
 
Patients with severe renal insufficiency, defined and confirmed by an estimated 
creatinine clearance equal or lower than 30 mL/min, per institutional laboratory. 
 
Patients with history of severe liver disease, defined as and confirmed by elevated 
ALT and AST greater than 1.5 times the Upper Limit of Normal along with Albumin 
less than 3 OR INR 1.5 or greater per institutional laboratory.  
 
Patients will be identified when scheduled for Robotic Prostatectomy. Eligible subjects will be 
approached before scheduled surgery to obtain Informed Consent. Consent will be obtained by 
Investigator, Co-Investigator and/or Collaborators; the process will be documented in EPIC. 
 
After Informed Consent is obtained, we will collect Demographics, Laboratory Test results of 
interest for the study, Concomitant Medications taken within 30 days prior surgery and 
Neoadjuvant Chemotherapy if any.  
4.6. Randomization 
Once it has been determined that the patient meets all eligibility criteria, they will be randomized 
on a 1:1 ratio for Deep Neuromuscular Blockade and Sugammadex or Moderate Neuromuscular 
Blockade and neostigmine administration. Randomization will be done the morning of surgery 
by using REDCap randomization tool.  
4.7. Blinding, Allocation and Concealment 
Patients and TOF-watch assessors will be blinded to the study drug. The assessor of the 
primary outcome will not be involved in randomization, or allowed in the operating room during 
surgery. Anesthesiologists will not be blinded to study drug but he/she will be blinded to the TOF 
watch response. The surgeon and PACU staff will be blinded to the group assignment. 
4.8. Sample Size Justifications 
For 99 patients undergoing laparoscopic hysterectomy, 28.6% of the DNMB group (IP 8mmHg) 
vs. 60% in the MNMB group (IP 12mmHg) experienced shoulder pain. (Madsen, et al., 2016) 


Protocol 2017-0046 
May 2, 2018 
Page 8 of 20 
Using the data from the aforementioned study, a sample size of 48 per group will enable the 
study 88% power to detect the decrease in the rate of postoperative shoulder pain from 60% for 
the control group to 28.6% for the group with deep Neuromuscular Blockade and Sugammadex, 
assuming a two-sided type I error rate of 0.05 using a two-group Chi-square test (nQuery 
Advisor 7.0). Postoperative shoulder pain is defined as any shoulder pain recorded before the 
discharge from PACU. We predict that the typically increased length of robotic surgery in 
combination with potentially lower insufflation pressures (6-7mmHg) may result in an even 
greater difference between the two groups. We want to factor in a 4% drop-out rate, therefore, 
we will enroll a total of 100 patients. 
4.9. Analysis Plans 
Patients’ demographic information, laboratory test results and concomitant medications, 
including neoadjuvant chemotherapy at baseline will be analyzed, with data summarized in 
tables listing the distributions of the variables along with the number of subjects per treatment 
arm in order to assess comparability. Patients’ information on post-operative shoulder pain, 
nausea, vomiting, intubation and measures from Postoperative Morbidity Survey will be 
collected. The Fisher’s exact test or Chi-square test will be applied to assess the association 
between two categorical variables. We will summarize the distribution of average and 
cumulative intraoperative insufflation pressure, Post Anesthesia discharge DASAIM scores, 
length of ICU and hospital stay by each treatment. We will use the student t-test or the Wilcoxon 
rank sum test to compare continuous variables between two different patient groups. Logistic 
regression will be utilized to assess the effects of patient prognostic factors, comorbidities and 
treatment on postoperative shoulder pain and postoperative morbidity.   
Adverse event (AE) data will be summarized by frequency tables.  The association between the 
types and severity of AE and the treatment will be evaluated.  
5. Study Drug Information 
Since both Sugammadex and Neostigmine are FDA approved, Insert recommendations and 
Institutional Standards will be followed for all study agents. 
5.1. Sugammadex  
5.1.1. Dosage Forms And Strengths: 200 mg/2 mL (100 mg/mL) in a single-dose vial for 
bolus injection and 500 mg/5 mL (100 mg/mL) in a single-dose vial for bolus injection. 
5.1.2. Recommended Dose and Administration: 4 mg/Kg, intravenously as a single 
bolus injection. 
5.2 Neostigmine 
5.2.1 Dosage Forms and Strengths: 0.5 mg/mL, 5 mg of Neostigmine in 10 mL vials and 
1 mg/mL, 10mg of Neostigmine in 10 mL vials. 
5.2.2 Recommended Dose and Administration: 70 mcg/Kg up to a total of 5 mg, 
intravenously slowly over a period of at least 1 minute. 
6. Study Procedures 
6.1. Intraoperative Anesthesia Care 
All patients will receive a balanced general anesthesia with endotracheal intubation and volatile 
anesthetic agents. In order to avoid excessive sedation in the PACU, no long acting anesthetic 
agents (ketamine, dexmedetomidine, etc.) or narcotics (hydromorphone, morphine) will be 
allowed. Short acting narcotics (fentanyl) are allowed.  


Protocol 2017-0046 
May 2, 2018 
Page 9 of 20 
Patients will be randomized to receive either the Deep Neuromuscular Blockade (DNMB group) 
with Sugammadex reversal or Moderate Neuromuscular Blockade (MNMB group) with 
neostigmine reversal. The patients will be started on a continuous Rocuronium intravenous 
infusion following intubation. Insert recommendations and Institutional Standards will be used 
for Rocuronium. For the DNMB group, the rate will be adjusted and boluses given to maintain 1-
2 post tetanic responses during the pneumoperitoneum. NMB will be reversed with 
Sugammadex at the end of surgery. For the MNMB group, the Rocuronium infusion rate will be 
adjusted to maintain 1-2 TOF responses and will be reversed with neostigmine at the end of 
surgery. The level of NMB will be assessed by the anesthetist with a standard nerve stimulator 
at 20 minute intervals for both groups.  
During the surgical time-out and at the time of insufflation, the surgeon will be instructed to 
maintain the lowest insufflation pressure necessary for good surgical exposure and safety 
throughout the operation. All adjustments to the insufflation pressure will be directed by 
surgeon. 
A clinical coordinator will calibrate the acceleromyography (TOF-Watch® SX, Organon Ireland 
Ltd., a subsidiary of Merck & Co., Inc., Swords, Co. Dublin, Ireland; pending availability due to 
product discontinuation by manufacturer) at the adductor pollicis muscle during induction prior to 
neuromuscular blockade, will record insufflation pressure changes during surgery and acquire 
the TOF ratio (TOFR) with the TOF-Watch® SX upon arrival of each patient to the PACU. Data 
will be collected from the electronic medical record (Anesthetic Record, PACU notes, Progress 
notes, Discharge summary, etc.) as well as a PACU survey.  
6.2. Assessment of Outcomes 
6.2.1. Depth of Neuromuscular Blockade: When possible, acceleromyography (TOF-
Watch® SX, Organon Ireland Ltd., a subsidiary of Merck & Co., Inc., Swords, Co. Dublin, 
Ireland) at the adductor pollicis brevis muscle will be calibrated during induction but prior to 
muscle relaxation. The responses from the peripheral nerve stimulator and the site of 
application used by the anesthetist will be recorded at 20 minute intervals throughout the 
procedure. A TOF ratio per acceleromyography will be measured upon arrival to the PACU. 
6.2.2. Insufflation pressure: Intra-abdominal insufflation time and pressure will be directed 
by the surgeon and recorded continuously by the clinical coordinator until the time of 
desufflation. 
6.2.3. Surgical Exposure: At the end of the procedure, the surgeon will use the Surgical 
Rating Scale to describe the quality of surgical exposure. (Martini, Boon, Bevers, Aarts, & 
Dahan, 2013) 
Table 1  
 
The surgical rating score 
1 
Extremely poor conditions: the surgeon is unable to work because of coughing or because 
of the inability to obtain a visible laparoscopic field because of inadequate muscle 
relaxation. Additional neuromuscular blocking agents must be given  
2 
Poor conditions: there is a visible laparoscopic field, but the surgeon is severely hampered 
by inadequate muscle relaxation with continuous muscle contractions, movements, or 


Protocol 2017-0046 
May 2, 2018 
Page 10 of 20 
both with the hazard of tissue damage. Additional neuromuscular blocking agents must be 
given  
3 
Acceptable conditions: there is a wide visible laparoscopic field but muscle contractions, 
movements, or both occur regularly causing some interference with the surgeon's work. 
There is the need for additional neuromuscular blocking agents to prevent deterioration  
4 
Good conditions: there is a wide laparoscopic working field with sporadic muscle 
contractions, movements, or both. There is no immediate need for additional 
neuromuscular blocking agents unless there is the fear of deterioration  
5 
Optimal conditions: there is a wide visible laparoscopic working field without any 
movement or contractions. There is no need for additional neuromuscular blocking agents  
 
6.2.4. Postoperative Pain: A Survey will be completed by the PACU nurse. The patient will 
be asked if INCISIONAL, VISCERAL and/or SHOULDER PAIN are present. The nurse will 
record Visual Analog Scale (VAS) pain score (1-10) for pain in general and for Shoulder 
Pain if present, recording these separately. All these will be recorded at 15, 45 and 90 
minutes (if patient not previously discharged). Opioids administrated by the PACU nurse 
will be measured in morphine equivalents. 
6.2.5. Readiness to Discharge from PACU: Readiness to discharge from the PACU as 
determined by a modified version of the DASAIM discharge criteria scoring system 
(Gartner, Callesen, Kroman, & Kehlet, 2010 ) (Phillips, Street, Kent, Haesler, & Cadeddu, 
2013) to be completed at 15, 45 and 90 minutes (if patient not previously discharged) after 
admission to the PACU. A patient will be considered ready for discharge if cumulative score 
is 4 or less and no single category has a score greater than 1.  
 
DASAIM Discharge Criteria Scoring System (Gartner, Callesen, Kroman, & Kehlet, 2010 ) 
Sedation 
0 
Patient is fully awake 
(Nurse Evaluation) 
1 
Patient is asleep, aroused by verbal stimulation 
2 
Patient is asleep, aroused by physical stimulation 
3 
Patient is asleep, cannot be aroused 
Respiratory Rate 
0 
Respiratory rate > 10 
(Nurse count) 
1 
Snoring, 10 < RR <30 
2 
RR < 10 or RR > 30/min 
3 
Periods of apnea or obstructive patterns 
Oxygen Saturation 
0 
SpO2 ≥ 94% 
(No supplemental oxygen for 
10 minutes) 
1 
90% ≤ SpO2 < 94% 
2 
85% ≤ SpO2 < 90% 
3 
SpO2 < 85% 


Protocol 2017-0046 
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Systolic Blood Pressure 
0 
SBP ≥ 100mmHg 
 
1 
90mmHg ≤ SBP < 100mmHg 
2 
80mmHg ≤ SBP < 90mmHg or SBP > 220mmHg 
3 
SBP < 80mmHg 
Heart Rate 
0 
50 < HR ≤ 100 
 
1 
100 < HR ≤ 120 
2 
40 < HR ≤ 50 or 120 < HR ≤ 130 
3 
HR < 40 or HR > 130 
Pain at rest 
0 
No pain 
(Patient evaluation) 
1 
Light pain 
2 
Moderate pain 
3 
Severe pain 
Nausea 
0 
No nausea or vomiting 
 
1 
Light nausea or vomiting without previous nausea 
2 
Moderate nausea and/or vomiting 
3 
Severe nausea and/or vomiting 
 
6.2.6. Postoperative Morbidity: Cystatin C will be drawn during pre-procedure and sent to 
external laboratory for analysis and calculation of the Cystatin C/Creatinine Ratio, to 
determine if the patient shows laboratory evidence of Sarcopenia. Postoperative lactate 
level will be drawn in the PACU as well as an arterial blood gas when an arterial line 
catheter is present. Overall postoperative morbidity will be recorded on POD 1, 3, 5 and 7 
using the Postoperative Morbidity Survey assessed by chart review.  
 


Protocol 2017-0046 
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(Bennett-Guerrero, et al., 1999) 
6.2.7. 30-Day Mortality and Readmission Rate: Patients will be contacted via phone 30 
days after being discharged from the Hospital to collect mortality and readmission data. If 
research staff is not able to contact the patient, this data will be obtained from available 
medical records. 
7. Adverse Events 
7.1. General 
All adverse events (AE) and serious adverse events (SAE) from study drug administration until 
hospital discharge. An AE is defined as an undesirable clinical outcome regardless of whether it 
was directly caused by the study drug. An AE applies to any unintended event with an onset 
during the study or an exacerbation in the severity of a preexisting condition. All reported AEs 
will be recorded in the database with their respective description, date, actions taken, outcomes 
and assessment of the relationship with the study drug and protocol. AEs will be categorized 
using the Common Terminology Criteria for Adverse Events (CTACE) version 4.0. For the 
events not characterized by CTACE, the following definitions for severity will be applied: 
Mild: Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; 
causing no loss of time from normal activities; symptoms would not require medication or a 
medical evaluation; signs or symptoms are transient. 
Moderate Interferes with the patient’s usual activity and/or requires symptomatic treatment. 
Severe: Symptom(s) causing severe discomfort and significant impact of the patient’s 
usual activity and requires treatment. 
A Serious Adverse Event (SAE) is defined as an event which leads to: 
 
Death due to any cause 
 
Life-threatening condition 
 
Results in persistent or significant disability/incapacity 
 
Requires in-patient hospitalization or prolonged hospitalization 
 
Necessitates an intervention to prevent a permanent impairment of a body function or 
permanent damage to a body structure 
 
Results in congenital abnormality 
All SAE’s will be reported. 
7.2. Drug-Related Adverse Event 
An adverse event that may be reasonably attributed, in the judgment of the Investigator, to the 
study drug based on the time sequence of drug administration and is unlikely to be attributed to 
concurrent disease or another source. 
7.3. Procedure-Related Adverse Event 
An adverse event that may be reasonably attributed to the procedure itself and not to the study 
drug. Other anesthesia or surgical techniques are more likely to have contributed to the 
occurrence of the adverse event. 
7.4. Concomitant Medication-Related Adverse Event 
An adverse event that may be more reasonably attributed to the use of another medication and 
not to the study drug. 


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7.5. Pre-Existing Condition-Related Adverse Event 
An adverse event that may be more reasonably attributed to the existence of a pre-existing 
condition and not to the study drug. Pre-existing conditions with an increase in severity during 
the study will be evaluated to determine whether the study drug was likely responsible for the 
exacerbation. 
The Investigator should assess all adverse events considered to be drug-related for potential 
reportability to the FDA. 
The Investigator should follow all unresolved serious adverse events until their resolution, the 
patient is lost to follow-up, the patient has withdrawn consent or the adverse event is otherwise 
explained. 
For purposes of this study, the following events are not considered adverse events, because 
they are expected to normally occur in conjunction with surgical procedures: 
 
Early postoperative pain (within 24 hours post-procedure)  
 
Chest or shoulder pain without associated ECG changes 
 
Hematocrit changes not to exceed a 30% change from baseline or requiring a blood 
transfusion 
 
Electrolyte imbalance without clinical sequelae, even if requiring correction 
 
Low grade temperature increase (≤38.3°C/≤101°F) 
 
Any pre-planned surgical procedures or interventions 
7.6. Reporting of Serious and Non-Serious Adverse Events 
Sugammadex is FDA-approved for the reversal of steroidal neuromuscular blocking drugs and 
the potential risks are well-documented. We will only collect adverse events that rise to the level 
of grades 3 and 4 with an attribution of possible, probable, or definitely related to the device. 
Serious Adverse Events, regardless of attribution, will be reported per MDACC’s standard 
practice and requirements, and per sponsor guidelines. 
8. Ethical considerations 
8.1. Institutional Review Board 
A copy of the proposed protocol, Informed Consent form, other written patient information and 
any proposed advertising material must be submitted to the IRB for written approval. A copy of 
the written IRB approval of the protocol and Informed Consent form must be received by Merck 
Inc. before recruitment of patients into the Study and shipment of product. 
The Investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent significant protocol amendments and significant changes to the Informed Consent 
form. The Investigator should notify the IRB of deviations from the protocol or SAEs. 
8.2. Informed Consent form 
The written Informed Consent documents should be prepared in the language(s) of the potential 
patient population.  
The IRB must first approve the Informed Consent forms that are used. The Informed Consent 
forms that are used should be in accordance with the current guidelines as outlined by the Good 
Clinical Practices (GCP) guidelines, Declaration of Helsinki and the International Conference on 
Harmonization (ICH).  


Protocol 2017-0046 
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Prior to participation in the clinical Study, each patient must give written Informed Consent after 
the context of the study has been fully explained to the patient in language that is easily 
understood by the patient. The patients must also be given the opportunity to ask questions and 
have those questions answered to their satisfaction. 
Written Informed Consent must be recorded appropriately by means of the patient’s, or their 
legal representative’s dated signature. The patient will receive a copy of the Informed Consent 
form. 
8.3. Amending the Protocol 
An Investigator may not make protocol changes without prior approval by Merck, Inc. All 
significant protocol changes that may affect the following must be submitted and approved by 
the IRB before initiating the change: 
 
validity of the data or information resulting from the completion of the approved protocol; 
 
relationship of the likely patient risk to benefit relied upon to approve the protocol; 
 
scientific soundness of the investigational plan, or; 
 
rights, safety, or welfare of the human patients involved in the investigation. 
8.4. Emergency Actions 
Merck, Inc. accepts the right of the Investigator to deviate from the protocol in an emergency 
and/or break study drug blinding when necessary to safeguard the life or the physical well-being 
of a study patient. If a patient is displaying signs and/or symptoms of residual neuromuscular 
blockade that jeopardizes the safety of the patient, the anesthesiologist may decide to 
administer an additional amount of Sugammadex.  In such an event, the patient will remain in 
the intention to treat group but will be excluded from the analysis between the two treatment 
groups.  The Investigator must give notice of any emergency deviations and justification for the 
deviation to Merck and the IRB as quickly as possible after the episode, in any event no later 
than 24 hours after the emergency. 
8.5. Protocol Deviations 
A protocol deviation is defined as an event where the Clinical Investigator or site personnel did 
not conduct the study according to the protocol. Investigators shall be required to obtain prior 
approval from Merck, Inc clinical study management before initiating deviations from the 
protocol, except where necessary to protect the life or physical well-being of a patient in an 
emergency. Such approval shall be documented in writing and maintained in clinical study 
management and Investigator files. Prior approval is generally not expected in situations where 
unforeseen circumstances are beyond the Investigator’s control, (e.g. patient was not available 
for scheduled follow-up office visit, blood sample lost by laboratory, etc.); however, the event is 
still considered a deviation and will be reported via the appropriate CRF. 
Deviations will be reported to Merck, Inc. regardless of whether medically justifiable, pre-
approved by Merck, Inc. or taken to protect the patient in an emergency. Patient specific 
deviations will be reported on the Protocol Deviation case report form. The investigators will also 
adhere to procedures for reporting study deviations to their IRB in accordance with their specific 
IRB reporting policies and procedures. 
Regulations require that Investigators maintain accurate, complete and current records, 
including documents showing the dates of and reasons for each deviation from the protocol. 
8.6. Coverage of Expenses 
The treated patients will not be reimbursed or compensated for participating in the Study. 


Protocol 2017-0046 
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Page 15 of 20 
Patient or insurance provider is responsible for all costs of surgery, including anesthesia and 
hospitalization. This includes all drugs involved in the study including Rocuronium, which is 
used as a neuromuscular blocking agent. 
The study/treatment drugs Sugammadex and Neostigmine will be covered by the Sponsor and 
not billed to the patient.  Other drugs utilized in this study will be used as per standard routine 
care.  The site institution’s research pharmacy department will maintain study supplies and 
record documentation.  Additionally, they will also be responsible for the destruction of the 
supplies at the end of the study as per ICH/GCP guidelines, local regulations, and institutional 
policies.  Supply should be shipped in marked vials to allow for non-blinded administration by 
the anesthesiologist.  
Note: At conclusion of the study or upon drug expiration, the Merck GRS will be responsible for 
issuing a Drug Disposition Letter to the investigator for US based studies.  
8.7. Confidentiality 
Confidentiality of patients will be maintained throughout the study. A unique identification 
number will be assigned to each patient participating in this study. 
8.8. Documentation 
The Principal Investigator must maintain detailed source documents on all study patients who 
are enrolled in the study or who undergo screening. Source documents include patient medical 
records, hospital charts, clinic charts, Investigator’s patient Study files, as well as the results of 
diagnostic tests (e.g., laboratory tests). 
The following minimum information should be recorded in the patient’s medical records: 
 
The date the patient entered the Study and the patient number 
 
The Study protocol number 
 
The date that informed consent was obtained 
 
Evidence that the patient meets Study eligibility requirements (e.g.,medical history, 
Study procedures and/or evaluations) 
 
Evidence that required procedures and/or evaluations were completed 
 
Use of any concurrent medications 
 
Documentation of specific device used, if any 
 
All lab reports taken for this study 
 
Occurrence and status of any Adverse Events 
 
The date the patient exited the Study, and a notation as to whether the patient 
completed the Study or was discontinued, including the reason for discontinuation. 
8.9. Record Retention 
The Investigator will maintain all essential Study documents and source documentation, in 
original format, that support the data collected on the study patients in compliance with the 
ICH/GCP guidelines. Following publication study data will be archived in REDCap. Since study 
data may be useful for future research studies performed under separate IRB approved 
protocols, study data will be archived indefinitely in REDCap. Since REDCap is a secure 
electronic database with controlled access, and because patient identifiers may be needed to 
link study data to data from other sources under future IRB approved protocols, patient 
identifying information will be retained in the archived database. 
8.10. Criteria for Terminating Study 


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The Investigators reserve the right to terminate the study but intends only to exercise this right 
for valid scientific or administrative reasons and reasons related to protection of patients. 
Possible reasons for study termination include:  
 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study.  
 
A decision on the part of Merck to suspend or discontinue development of 
Sugammadex. 
8.11. Investigator Responsibilities 
 
Be willing to perform and be capable of performing treatment procedures as outlined in 
this protocol 
 
Comply with all required elements of this protocol (e.g., perform testing and follow-up as 
specified, especially during personnel transitions) and supply material suitable for 
quantitative analysis 
 
Agree to obtain written Informed Consent before any study specific procedures are 
performed in accordance with GCP 
 
Complete all CRFs 
8.12. Publication Policy 
The information in this document and regarding this Study might contain commercially sensitive 
information that is confidential and may not be disclosed unless such disclosure is required by 
regional or national law or regulations. Patient to the foregoing, this information may be 
disclosed only to those persons involved in the Study who have a need to know, but all such 
persons must be instructed not to further disseminate this information to others. These 
restrictions of disclosure will apply equally to all future information provided that is indicated as 
confidential. All manuscripts associated with the data collected on this study are not to be 
submitted for publication without the written consent of the MD Anderson Principal 
Investigator. 
9. Regulatory Considerations 
9.1. Role of Investigator and collaborators 
The Investigator has the overall responsibility for the conduct of the study, including assurance 
that the study meets the regulatory requirements of the Food and Drug Administration (FDA). 
Investigators or collaborators are responsible for obtaining IRB approvals prior to start of the 
study. The Investigator is required to obtain signed study agreements, to provide the 
Investigators with the information necessary to conduct the study and adequate on-site training 
to conduct the Study, to ensure proper clinical site monitoring, and to provide the required 
reports to the Investigators, and IRBs. 
The investigator will be responsible for providing quality data that satisfies publication 
requirements and informing of serious unanticipated adverse events and deviations from the 
protocol. 
9.2. Monitoring 
The Investigator will review significant new information, including unanticipated serious adverse 
events and ensure that such information is provided to the IRB. 
9.3. Maintaining Records 


Protocol 2017-0046 
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The Investigator will maintain copies of correspondence, data, shipment of devices, serious 
adverse device effects and other records related to the clinical Study. The Investigator will 
maintain records related to the signed Investigator Agreements. 
9.4. Informed Consent & Institutional Review Board (IRB) 
All patients must provide written informed consent / Assent in accordance with the MD 
Anderson Cancer Center IRB. All Protected Health Information (PHI) to be collected in the study 
will be described in the informed consent form, and all study data will be managed in 
accordance with the Privacy Law (HIPAA). 
 
 


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