A Double-blind, Randomized, Parallel Design to Compare the Effectiveness of Deep Versus Moderate Neuromuscular Blockade With Standard-pressure Pneumoperitoneum During Laparoscopic Gastrectomy on Postoperative Pain in Surgical Patients
Phase: NA
Conditions: Neuromuscular Blockade
Sponsor: Asan Medical Center

               
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Clinical Trial Protocol 
 
 
Title of Study 
A double-blind, randomized, parallel design to compare the effectiveness of deep versus 
moderate neuromuscular blockade with standard-pressure pneumoperitoneum during 
laparoscopic gastrectomy on postoperative pain in surgical patients 
 
Principle Investigator of Clinical Study 
Byung-Moon Choi, Associate professor, Department of Anesthesiology and Pain Medicine, Asan 
Medical Center 
 
Name and location of the clinical trial institution 
Name 
Asan Medical Center 
Location 
88, Olympic-ro 43-gil, Songpa-gu, Seoul, Korea 
 
NCT Number 
NCT03266419 
 
Date of the Document 
Aug-18, 2017 
 
 
Version: 1.4 
Protocol No.: 2018_sugammadex 
 
 

               
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Table of Contents 
1. Synopsis ......................................................................................................................................................... 3 
2. List of Abbreviation and Definition Structures ............................................................................... 8 
3. Introduction ............................................................................................................................................... 10 
4. A pilot study for pivotal study ............................................................................................................. 10 
4.1. Sample size calculation .............................................................................................................................. 13 
5. Study aims .................................................................................................................................................. 14 
6. Study design ............................................................................................................................................... 14 
7. Study population ...................................................................................................................................... 16 
8. Eligibility ..................................................................................................................................................... 16 
8.1. Inclusion criteria ........................................................................................................................................... 16 
8.2. Exclusion criteria .......................................................................................................................................... 16 
9. Study procedures ..................................................................................................................................... 17 
10. Study endpoints ..................................................................................................................................... 21 
10.1. Primary endpoint ....................................................................................................................................... 21 
10.2. Secondary endpoints ................................................................................................................................ 21 
10.3. Additional endpoints ............................................................................................................................... 21 
11. Statistical analysis ................................................................................................................................. 21 
12. Study Management ............................................................................................................................... 21 
12.1. Regulatory and Ethical Considerations ......................................................................................... 21 
12.1.1. Regulatory Guidelines .................................................................................................................... 21 
12.1.2. Institutional Review Board or Independent Ethics Committees ............................ 21 
12.1.3. Informed Consent .............................................................................................................................. 22 
12.1.4. Data Collection and Study Documentation ......................................................................... 22 
12.2. Disclosure and Confidentiality ........................................................................................................... 23 
13. Procedures for Reporting Adverse Events and Unanticipated Problems ......................... 23 
13.1. Clinical Adverse Events ........................................................................................................................... 23 
13.2. Unanticipated problems ........................................................................................................................ 24 
13.3. Serious Adverse Events (SAE) ............................................................................................................. 24 
13.4. Time Frame for Reporting Unanticipated Problems.............................................................. 25 
14. Reference.................................................................................................................................................. 27 
Appnedix.1 Rhodes index of nausea, vomiting and retching (RINVR): Korean version ..... 29 
 

               
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1. Synopsis 
Title 
A double-blind, randomized, parallel design to compare the 
effectiveness of deep versus moderate neuromuscular blockade with 
standard-pressure 
pneumoperitoneum 
during 
laparoscopic 
gastrectomy on postoperative pain in surgical patients 
Investigational 
site 
Asan medical center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, 
Korea 
Investigators 
Byung-Moon Choi, M.D. & Ph.D. 
Sponsor 
Merck Sharp & Dohme (MSD) 
Representatives 
Byung-Moon Choi, M.D. & Ph.D. 
Objectives 
The aim of this study is to evaluate the influence of depth of 
neuromuscular 
blockade 
during 
laparoscopic 
gastrectomy 
on 
postoperative pain in surgical patients allocated randomly to either 
deep or moderate neuromuscular blockade group with standard-
pressure pneumoperitoneum of 13 mmHg. 
Study design 
This study is investigator-initiated, randomized, double blinded clinical 
trial. 
 

               
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NMB: neuromuscular blockade, PTC: post-tetanic count, TOF: train of 
four, PnP: pneumoperitoneum, IV: intravenous, PCA: patient controlled 
analgesia, BIS: bispectral index, PACU: postanesthesia care unit, MEAD: 
minimum effective analgesic dose, BW: body weight, PONV: 
postoperative nausea and vomiting, RINVR: Rhodes index of nausea, 
vomiting and retching, VAS: visual analogue scale 
Patients 
Patients (n=114) scheduled for elective laparoscopic gastrectomy will 

               
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be randomly assigned to deep or moderate NMB groups at a ratio of 1:1. 
Inclusion criteria 
− Patients 20 to 65 years old 
− American Society of Anesthesiologist Physical Status 1 or 2 or 3   
− Patients undergoing laparoscopic gastrectomy 
− Patients who signed a written informed consent form 
Exclusion criteria  
− Pregnant or nursing (lactating) women, where pregnancy is defined 
as the state of a female after conception and until the termination of 
gestation, confirmed by a positive urine pregnancy test 
− Patients with known hypersensitivity to rocuronium or sugammadex 
− Patient with VAS score of at least 1 before surgery 
− Patients with liver cirrhosis confirmed by abdominal CT 
− Patients with neuromuscular disease that may interfere with 
neuromuscular data (ex. Duchenne muscular dystrophy, myasthenia 
gravis) 
− Clinically significant impairment of cardiovascular function, defined 
by ejection fraction < 50% 
− Clinically significant impairment of renal function, defined by 
estimated GFR < 60 ml/min or need for hemodialysis 
− Clinically significant impairment of liver function, defined by alanine 
aminotransferase > 100 IU/L 
− Indication for rapid sequence induction 
− Use of opioids within the 7 days prior to surgery 
− History of abdominal surgery 
− History of chronic obstructive pulmonary disease 
− Body mass index (BMI) ≥ 35 kg/m2 
− Body weight < 50 kg  
− Conversion to laparotomy 
− Family history of malignant hyperthermia 
− Patients who are considered by the investigator to be unsuitable to 
participate in the study for any other reason not mentioned in the 

               
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inclusion and exclusion criteria 
Duration of study 
From the IRB approval date to February 28, 2019 
Study endpoints 
Primary endpoint 
− MEAD of oxycodone at PACU 
Secondary endpoints 
− Mean VAS score for wound pain at PACU 
− Area under the curve of VAS score for wound pain over time at PACU 
− VAS score for wound pain at 6 h after the end of surgery 
− VAS score for wound pain at 24 h after the end of surgery 
− Frequency and amount of rescue analgesics at ward 
− Surgical rating score  
Additional endpoints 
− VAS score for should pain at 6 and 24 h after the end of surgery 
− Incidence and severity of PONV assessed by Rhodes index for nausea, 
vomiting and retching (Korean version of the RINVR, appendix 1) at 
1, 6 and 24 h after the end of surgery 
− Incidence of other adverse events 
Sample size 
A preliminary study to determine the appropriate sample size was 
conducted by measuring the MEAD of oxycodone in 13 patients. The 
mean (SD) values were 9.00 (3.96) for deep NMB group and 13.33 
(7.97) for moderate NMB group, respectively. The equality test was 
performed using these results. 
 
2
2
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5 7.97
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On the basis of this observation, a sample size of 50 patients per 
treatment arm was calculated to be sufficient to allow a detection of 4 
mg difference in MEAD with 90% power at an alpha of 0.05. 
Statistical analysis 
All statistical analyses were conducted using R (version 3.3.2, R 
Foundation for Statistical Computing, Vienna, Austria) or SigmaStat 3.5 
for Windows (Systat Software, Chicago, IL, USA). Normally distributed 

               
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continuous variables are expressed as mean (SD), non-normally 
distributed variables as median (range), and categorical variables as 
counts and percentages. A P value less than 0.05 was considered 
statistically significant. 
 
 

               
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2. List of Abbreviation and Definition Structures 
AE 
Adverse event 
ASA PS 
American Society of Anesthesiologists Physical Status 
AUC 
Area under the curve 
AUCVAS 
Area under the curve of visual analogue scale 
BIS 
Bispectral index 
BMI 
Body mass index 
BW: 
Body weight 
CT 
Computed tomography 
eCRF 
Electronic case report forms 
GCP 
Good Clinical Practices  
GFR 
Glomerular filtration rate 
HR 
Heart rate 
ICH 
International conference on harmonization  
IEC 
Independent ethics committees 
IRB 
Institutional review board 
ITT 
Intention-to-treat 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
MAP 
Mean arterial blood pressure 
MEAD: 
Minimum effective analgesic dose 
ml 
Milliliter 
NMB 
Neuromuscular blockade 
NIBP 
Non-invasive blood pressure 
PACU 
Postanesthesia care unit 

               
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PCA 
Patient controlled analgesia 
PnP 
Pneumoperitoneum 
PONV 
Postoperative nausea and vomiting 
PTC 
Post-tetanic count 
RINVR 
Rhodes index of nausea, vomiting and retching 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reaction 
TOF 
Train of four 
VAS 
Visual analogue scale 
 
 
 

               
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3. Introduction 
Administration of neuromuscular blockade (NMB) is essential for laparoscopic surgeries because 
it causes an improvement of surgical conditions. Previous studies have suggested that deep NMB 
(post-tetanic count 1–2) results in an improved quality of surgical conditions compared with 
moderate NMB (train-of-four 1–2) during laparoscopic surgeries (Madsen, Staehr-Rye, Claudius, 
& Gatke, 2016; Martini, Boon, Bevers, Aarts, & Dahan, 2014; Staehr-Rye et al., 2014; Veelo et al., 
2015). However, in review articles written by Kopman and Naguib, there are little objective data 
to support the proposition that deep NMB contributes to better patient outcome or improves 
surgical operating conditions, when compared with moderate block (Kopman & Naguib, 2015, 
2016). The usefulness of deep NMB does not seem to be concluded yet. 
In laparoscopic surgery, low-pressure pneumoperitoneum is facilitated by the use of deep NMB. 
The most important benefit of low-pressure pneumoperitoneum is lower postoperative pain 
scores, which is supported by previous studies including meta analyses (Hua, Gong, Yao, Zhou, & 
Song, 2014; Ozdemir-van Brunschot et al., 2016). Recently, there is a randomized controlled trial 
to evaluate the effect of deep NMB and low-pressure pneumoperitoneum in laparoscopic 
hysterectomy (Madsen, Istre, et al., 2016). The authors concluded that deep NMB and low-
pressure pneumoperitoneum (8 mmHg) reduced the incidence of postoperative shoulder pain as 
compared to standard-pressure pneumoperitoneum (12 mmHg) with standard NMB (Madsen, 
Istre, et al., 2016). However, we could not determine whether the deep NMB had an effect on 
postoperative shoulder pain due to the combination of the two interventions in this study. 
Theoretically, there is a possibility that the deep NMB may have an analgesic effect because deep 
NMB facilitates maximum stretching of abdominal wall muscle fibers during laparoscopic surgery. 
This leads to an increased abdominal wall compliance that may reduce pressure-related 
postoperative pain. However, the question of whether the use of deep NMB influences 
postoperative pain scores after laparoscopic surgery remains unanswered. 
The aim of this study is to evaluate the influence of depth of neuromuscular blockade during 
laparoscopic gastrectomy on postoperative pain in surgical patients allocated randomly to either 
deep or moderate neuromuscular blockade group with standard-pressure pneumoperitoneum of 
12 mmHg 
 
4. A pilot study for pivotal study 
A preliminary study to determine the appropriate sample size was conducted by measuring the 
minimum effective analgesic dose (MEAD) of oxycodone in 13 patients undergoing laparoscopic 

               
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gastrectomy. Patients allocated to deep or moderate NMB groups received a bolus dose of 
rocuronium of 1.0 mg/kg or 0.5 mg/kg, followed by a continuous infusion of rocuronium of 1.0 
mg/kg/h or 0.3 mg/kg/h for maintaining deep NMB (post tetanic count 12) or moderate NMB 
(train of four 12) during operation, respectively (Martini et al., 2014). For both groups, an 
abdominal pressure of 13 mmHg was maintained during the laparoscopic surgery. The patients 
were administered a bolus dose of oxycodone of 0.05 mg/kg at the end of pneumoperitoneum. 
After the end of surgery, patients were taken to the postoperative anesthesia care unit (PACU), 
and assessed for pain every 10 min using a visual analogue scale (VAS) (0=no pain; 10=the most 
severe pain). Pain was measured at rest and when the wound areas were compressed with a force 
of 20 N (i.e., 2 kg of pressure imposed by three fingers on a 10 cm2 area). The wound compression 
was performed by a blinded researcher who were trained with an algometer (Commander 
Algometer, J Tech Medical Industries, Midvale, UT, USA) to apply this force consistently. The 
patient was administered intravenous oxycodone 2 mg (body weight <80 kg) or 3 mg (>80 kg) 
every 10 min until the VAS assessments showed that the pain intensity had decreased to <3 at rest 
and <5 on wound compression. At this point, MEAD of oxycodone was determined (Choi et al., 
2016). Demographics of these patients are summarized in Table 1. 
 
Table 1. Demographics of patients enrolled in a preliminary study. 
 
Deep NMB group (n=7) 
Moderate NMB group (n=6) 
Age, yr 
51.1  8.0 
50.3  10.8 
Weight, kg 
69.0  11.0 
68.4  11.5 
Height, cm 
168.5  3.5 
166.7  8.8 
Male / Female 
6/1 
4/2 
ASA PS I/II 
3/4 
3/3 
Data are expressed as mean  SD or count as appropriate. Patient characteristics were compared 
using the two-sample t-test. No significant differences between deep NMB and moderate NMB 
groups were found between any of the observations., NMB: neuromuscular blockade, ASA PS: 
American Society of Anesthesiologists Physical Status. 
 
 

               
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The distribution of MEAD of oxycodone is shown in Figure 1.  
 
 
 
Fig. 1. The distribution of minimum effective analgesic dose (MEAD) of oxycodone in patients 
undergoing laparoscopic gastrectomy. The mean (SD) values of MEAD were 9.00 (3.96) for 
deep neuromuscular blockade group and 13.33 (7.97) for moderate neuromuscular blockade 
group, respectively. The red solid horizontal lines and whiskers represent mean and standard 
deviation of MEAD.  
 
The VAS for pain over time at PACU is shown in Figure 2. 
 
 
 
Fig. 2. Visual analogue scale for over time at postanesthesia care unit in patients assigned to 

               
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deep neuromuscular blockade group (A) or moderate neuromuscular blockade group (B).  
 
The area under the VAS-time curve (AUCVAS) at PACU was calculated using WinNonlin 6.3 
(Pharsight, a Certara Company, St. Louis, MO, USA). The distribution of AUCVAS is shown in Figure 
3.  
 
 
 
Fig. 3. The distribution of the area under the curve of visual analogue scale (AUCvas) in patients 
assigned to deep or moderate neuromuscular blockade (NMB) group. The mean (SD) values 
of AUCvas were 2509.3 (1398.4) for deep NMB group and 4524.1 (3116.3) for moderate NMB 
group, respectively. The red solid horizontal lines and whiskers represent mean and standard 
deviation of AUCvas.  
 
4.1. Sample size calculation 
A preliminary study to determine the appropriate sample size was conducted by measuring the 
MEAD of oxycodone in 13 patients. The mean (SD) values were 9.00 (3.96) for deep NMB group 
and 13.33 (7.97) for moderate NMB group, respectively. The equality test was performed using 
these results. 
 
2
2
2
2
2
2/
2
6 3.96
5 7.97
(1.96 1.28)
(1 1/1)
(
)
(1 1/ )
11
49.1
(
)
4
t
t
c
Z
Z
k
n








+ 
+
+


+
+


=
=
=
−
 

               
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On the basis of this observation, a sample size of 50 patients per treatment arm was calculated to 
be sufficient to allow a detection of 4 mg difference in MEAD with 90% power at an alpha of 0.05. 
 
5. Study aims 
The aim of this study is to evaluate the influence of depth of neuromuscular blockade during 
laparoscopic gastrectomy on postoperative pain in surgical patients allocated randomly to either 
deep or moderate neuromuscular blockade group with standard-pressure pneumoperitoneum of 
12 mmHg. 
 
6. Study design 
The study flow diagram is shown in Figure 4.  
 

               
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Fig 4. Study flow diagram. NMB: neuromuscular blockade, PTC: post-tetanic count, TOF: train 
of four, PnP: pneumoperitoneum, IV: intravenous, PCA: patient controlled analgesia, BIS: 
bispectral index, PACU: postanesthesia care unit, MEAD: minimum effective analgesic dose, BW: 
body weight, PONV: postoperative nausea and vomiting, RINVR: Rhodes index of nausea, 
vomiting and retching, VAS: visual analogue scale. 
 

               
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7. Study population 
Patients (n=100) scheduled for elective laparoscopic gastrectomy will be randomly assigned to 
deep or moderate NMB group at a ratio of 1:1. 
− Deep NMB group (n=50): The abdomen is insufflated to 13 mmHg pneumoperitoneum with 
deep NMB (post tetanic count 12) during operation 
− Moderate NMB group (n=50): The abdomen is insufflated to 13 mmHg pneumoperitoneum with 
moderate NMB (train of four 12) during operation  
 
8. Eligibility  
8.1. Inclusion criteria 
− Patients 20 to 65 years old 
− American Society of Anesthesiologist Physical Status 1, 2 or 3   
− Patients undergoing laparoscopic gastrectomy 
− Patients who signed a written informed consent form 
 
8.2. Exclusion criteria 
−  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive urine pregnancy 
test 
−  Patients with known hypersensitivity to rocuronium or sugammadex 
−  Patient with VAS score (0=no pain; 114=the most severe pain) of at least 10 before surgery 
−  Patients with liver cirrhosis confirmed by abdominal CT 
−  Patients with neuromuscular disease that may interfere with neuromuscular data (ex. 
Duchenne muscular dystrophy, myasthenia gravis) 
−  Clinically significant impairment of cardiovascular function, defined by ejection fraction < 50% 
−  Clinically significant impairment of renal function, defined by estimated GFR < 60 ml/min or 
need for hemodialysis 
−  Clinically significant impairment of liver function, defined by alanine aminotransferase > 100 
IU/L 
−  Indication for rapid sequence induction 
−  Use of opioids within the 7 days prior to surgery 
−  History of abdominal surgery 

               
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−  History of chronic obstructive pulmonary disease 
−  Body mass index (BMI) ≥ 35 kg/m2 
− Body weight < 50 kg 
−  Conversion to laparotomy 
−  Family history of malignant hyperthermia 
− Patients who are considered by the investigator to be unsuitable to participate in the study for 
any other reason not mentioned in the inclusion and exclusion criteria 
 
9. Study procedures 
− All patients were fasted from midnight without premedication 
− Once in the operating room, the patients were monitored using electrocardiography, pulse 
oximetry, end-tidal carbon dioxide partial pressure, non-invasive blood pressure, and bispectral 
index (Aspect 2000; Aspect Medical Systems, Inc., Newton, MA, USA) measurements. 
− Neuromuscular transmission was monitored using the M-NMT® module at the adductor 
pollicis muscle (Carescape® B850, GE Healthcare, Milwaukee, WI, USA). 
− Throughout the surgery, these data were continuously downloaded to personal computers by 
using RS232C cables. 
− Following pre-oxygenation with 100% O2, anesthesia was induced with propofol and 
remifentanil, which were administered using a target effect-site concentration-controlled 
infusion pump (Perfusor® Space, B. Braun Melsungen, Germany) by using the models 
suggested by Schnider et al. and Minto et al (Minto et al., 1997; Schnider et al., 1998). 
− Tracheal intubation was facilitated with rocuronium 0.6 mg/kg. 
− After tracheal intubation, the lungs of the patients were then ventilated with oxygen in air (1:1) 
and the ventilation rate was adjusted to maintain the end-tidal carbon dioxide partial pressure 
between 35 and 45 mmHg. 
− For deep NMB group, an intravenous bolus of rocuronium (0.7 mg/kg) was given 2 minutes 
after intubation, followed by a continuous infusion of rocuronium of 0.81.2 mg/kg/h for 
maintaining deep NMB (post tetanic count 12) during operation. PTC was measured every 
5 minutes. In the case of deviations from the target PTC, the pump speed could be increased 
or decreased or a bolus dose (10 mg) could be given. 
− For moderate NMB group, no further loading dose of rocuronium was given. An intravenous 
infusion with rocuronium (0.4–0.6 mg/kg/h) was started at a TOF count of 1 for maintaining 

               
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moderate NMB (train of four 12) during operation. TOF was measured every 5 minutes. In 
the case of deviations from the target TOF, the pump speed could be increased or decreased 
or a bolus dose (10 mg) could be given. 
− The target effect-site concentrations of propofol were adjusted within a range of 2.53 μg/ml 
to maintain the bispectral index values at less than 60 during the induction and maintenance 
of anesthesia. 
− The target effect-site concentrations of remifentanil were titrated to prevent signs of 
inadequate anesthesia and to maintain stable hemodynamics (SBP > 80 mmHg and HR > 45 
beats/min).  
• Signs of inadequate anesthesia: systemic arterial blood pressure increased to greater than 
15 mm Hg higher than the patient's normal value; heart rate exceeding 90 beats/min in the 
absence of hypovolemia; somatic responses, such as body movements (minimal muscle 
paralysis allowed physical movement), swallowing, coughing, grimacing, or opening of the 
eyes; and autonomic signs of inadequate anesthesia (Ausems, Vuyk, Hug, & Stanski, 1988) 
− If necessary, ephedrine or atropine is administered to maintain systolic blood pressure above 
80 mmHg and heart rate above 45 beats/min during anesthesia. 
− An abdominal pressure of 13 mmHg was maintained during the laparoscopic surgery. 
− When the surgeon asks for muscle relaxation due to the inability to obtain a visible 
laparoscopic field, additional bolus dose of rocuronium (10 mg) should be given. 
− All patients were administered a bolus dose of oxycodone of 0.05 mg/kg at the end of 
pneumoperitoneum. 
− IV PCA with oxycodone is started after the administration of loading dose. A semi-electronic 
pump (Automed 3200; Ace Medical, Seoul, South Korea) is used for PCA with demand bolus 
of 1 ml, background infusion of 1 ml/h and lock-out time of 15 min. The concentration of 
oxycodone in IV PCA bag is 1 mg/ml, and the volume of oxycodone-normal saline mixture 
delivered to patients for approximately 4 days is 200 ml.  
− Rocuronium infusions are discontinued after deflation of CO2. 
− After the end of surgery, a single intravenous bolus dose of sugammadex 2 or 4 mg/kg was 
administered for reversal of moderate and deep NMB, respectively.  
− After the end of surgery, patients were taken to the PACU, and assessed for pain every 10 
min using a VAS (0=no pain; 10=the most severe pain).  

               
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−  Researchers who evaluate postoperative pain will be blinded to the patient’s allocation 
− Pain was measured at rest and when the wound areas were compressed with a force of 20 N 
(i.e., 2 kg of pressure imposed by three fingers on a 10 cm2 area). The wound compression 
was performed by a blinded researcher who was trained with an algometer (Commander 
Algometer, J Tech Medical Industries, Midvale, UT, USA) to apply this force consistently.  
− The patient was administered intravenous oxycodone 2 mg (body weight <80 kg) or 3 mg 
(>80 kg) every 10 min until the VAS assessments showed that the pain intensity had 
decreased to <3 at rest and <5 on wound compression. At this point, MEAD of oxycodone 
was determined.  
− VAS for wound and shoulder pain were also assessed at 6 and 24 h after the end of surgery. 
− Postoperative nausea and vomiting were evaluated using the Rhodes index of nausea 
vomiting retching (RINVR) at 6 and 24 h after the end of surgery (Lee et al., 2016).  
− After the end of surgery, the surgeon scored the surgical working conditions according to a five-
point ordinal scale ranging from 1 (extremely poor conditions) to 5 (optimal conditions) (Table 
2) (Martini et al., 2014).  
− If the surgeon requests blind cessation for patient safety reasons, blindness is lifted. 
 
Table 2. The surgical rating scale. 
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 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 

               
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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. 
 
 
 

               
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10. Study endpoints 
10.1. Primary endpoint 
− MEAD of oxycodone at PACU 
10.2. Secondary endpoints 
− Mean VAS score for wound pain at PACU 
− Area under the curve of VAS score for wound pain over time at PACU 
− VAS score for wound pain at 6 h after the end of surgery 
− VAS score for wound pain at 24 h after the end of surgery 
− Frequency and amount of rescue analgesics at ward 
− Surgical rating score  
10.3. Additional endpoints 
− VAS score for should pain at 6 and 24 h after the end of surgery 
− Incidence and severity of PONV assessed by Rhodes index for nausea, vomiting and retching 
(Korean version of the RINVR, appendix 1) at 1, 6 and 24 h after the end of surgery 
− Incidence of other adverse events 
 
11. Statistical analysis 
All statistical analyses were conducted using R (version 3.3.2, R Foundation for Statistical 
Computing, Vienna, Austria) or SigmaStat 3.5 for Windows (Systat Software, Chicago, IL, USA). 
Normally distributed continuous variables are expressed as mean (SD), non-normally distributed 
variables as median (range), and categorical variables as counts and percentages. A P value less 
than 0.05 was considered statistically significant. The area under the curve of visual analogue 
scale for wound pain was calculated by non-compartmental methods (WinNonlin Professional 
6.3; Pharsight, St. Louis, MO). 
 
12. Study Management  
12.1. Regulatory and Ethical Considerations  
12.1.1. Regulatory Guidelines  
This study is to be performed in full compliance with International Conference on Harmonization 
(ICH) and all applicable local Good Clinical Practices (GCP) and regulations. All required study 
documentation will be archived by the investigator as required by regulatory authorities.  
12.1.2. Institutional Review Board or Independent Ethics Committees 

               
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The protocol, informed consent, and appropriate related documents must be reviewed and 
approved by an Institutional Review Board (IRB) or Independent Ethics Committees (IEC) 
constituted and functioning in accordance with ICH E6, Section 3.  
A signed letter of study approval from the IRB/IEC Chairman must be sent to the PI prior to study 
start. Study progress is to be reported to IRB/IECs annually (or as required) by the Investigator, 
depending on local regulatory obligations. Serious Adverse Events (SAEs) should be reported to 
the IRB/IEC in accord with local regulatory requirements. In the case of early 
Termination/temporary halt of the study, the Investigator should notify the IEC within 15 days 
and a detailed written explanation of the reasons for the Termination/halt should be given.  
12.1.3. Informed Consent  
It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable 
by local regulations), to obtain signed and dated informed consent from each subject prior to 
participating in this study. As part of administering the informed consent document, the 
Investigator must explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, and any compensation 
or potential discomfort. Each subject must be informed that participation in the study is voluntary 
and that subject may withdraw from the study at any time and that withdrawal of consent will not 
affect subsequent medical treatment or relationship with the treating physician. This informed 
consent should be given by means of a standard written statement, written in non-technical 
language. The subject should understand the statement before signing and dating it and will be 
given a copy of the signed document after adequate explanation of the aims, methods, objectives 
and potential hazards of the study.  
12.1.4. Data Collection and Study Documentation  
OpenClinica, a secure web-based application, will be used for electronic data acquisition and 
storage. OpenClinica will provide electronic case report forms (eCRFs) for transfer of all research 
data from data source documentation to a computer data base. Each responsible person will have 
user access to OpenClinica through his/her unique username and password, with permissions 
providing each person his/her needed access. Two data monitoring persons will verify all data 
against its source. Monitoring will be enhanced by computer assisted data management 
identifying missing or possibly erroneous data. This approach will allow initial monitoring, and 
communication between data monitoring persons and study personnel before and between data 
monitoring, and will expedite data review and cleaning. Missing data and identified data errors 
(or possible errors) will be communicated by the data monitoring persons to study investigators 

               
Ver 1.4  
23 
 
using OpenClinica for correction or acknowledgement that data is correct as entered. OpenClinica 
and all study data are housed in a secure computing environment. OpenClinica further provides a 
real-time data entry validation (e.g. for data types and range checks), and audit trail of all data 
entry. 
For accurate, complete, and legible source documentation, the following criteria are to be 
maintained:  
− All entries are to be completed using a black ink ballpoint pen.  
− There are to be no erasers, write-overs, use of correction fluid or tape, and the original entry 
must remain legible. 
− Errors are to be corrected by placing one line through the error: The correct entry should 
appear next to the error, dated, and initialed by the responsible person making the change; the 
name of anyone making corrections must appear on the Signature Log collected at the beginning 
of the study and as study assignments change throughout the conduct of the study; each error 
is to be corrected separately.  
− The Investigator must sign and date the source documents where noted; a signature stamp may 
not be used. 
− Changes that have been previously signed by the Investigator must be initialed and dated by the 
Investigator after the change is made; changes made to electronic CRFs via data clarification 
forms issued by the Sponsor must likewise be signed by the Investigator.  
− Subject’s name is not to appear on documents in order to maintain confidentiality.  
12.2. Disclosure and Confidentiality  
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the Investigators, the Investigator’s staff, and IRB, and will not 
be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the consent of the Principal Investigator. No data collected as part 
of this study will be utilized in any written work, including publications, without the consent of 
the Principal Investigator. Collected data should be kept for up to 5 years after the end of the study 
and discarded thereafter. 
13. Procedures for Reporting Adverse Events and Unanticipated Problems  
13.1. Clinical Adverse Events 
A human subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s participation 
in the research, whether or not considered related to the subject’s participation in the research” 

               
Ver 1.4  
24 
 
(modified from the definition of adverse events in the 1996 International Conference on 
Harmonization E-6 Guidelines for Good Clinical Practice). All clinical AEs encountered during the 
clinical study will be reported on the AE page of the CRF. Relationship of the AE to the treatment 
should also be assessed. Pre-existing conditions that worsen during a study are to be reported as 
AEs.  
13.2. Unanticipated problems  
In general, unanticipated problems include any incident, experience, or outcome that meets all of 
the following criteria:  
− Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the subject population being 
studied;  
− Related or possibly related to participation in the research (in this guidance document, 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 
− Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
Only when a particular adverse event or series of adverse events is determined to meet the criteria 
for an unanticipated problem should a report of the adverse event(s) be submitted to the IEC or 
IRB. It is the responsibility of the Investigator or Sub investigator(s) to perform periodic and 
special assessments for unanticipated problems and submit reports to their respective IRBs. Any 
distributed reports shall include: (1) a clear explanation of why the adverse event or series of 
adverse events has been determined to be an unanticipated problem; and (2) a description of any 
proposed protocol changes or other corrective actions to be taken by the investigators in response 
to the unanticipated problem.  
13.3. Serious Adverse Events (SAE) 
The following definition of SAE will be used for this study: A SAE is any experience that suggests 
a significant hazard, contraindication, side effect or precaution. An SAE must fulfill at least one of 
the following criteria:  
− is fatal (results in the outcome death*)  
− is life-threatening  
− required in-patient hospitalization or  
− prolongation of existing hospitalization  

               
Ver 1.4  
25 
 
− results in persistent or significant disability/incapacity is a congenital anomaly/birth defect  
− is medically significant or requires intervention to prevent one or other of the outcomes listed 
above.  
 
An AE that is serious or potentially serious requires detailed reports and follow-up and should be 
recorded in the CRF. The content of these detailed reports should address the Investigator’s 
estimate of causality, and outcome of the AE.  
13.4. Time Frame for Reporting Unanticipated Problems  
The investigator must comply with the applicable local requirements related to the reporting of 
SAEs or unanticipated events involving his/her subjects to the IEC that approved the study. In 
particular, all deaths must be promptly reported to the IEC that approved the study. Unless clearly 
defined otherwise by national or site-specific regulations and duly documented, the Investigator 
must promptly notify the concerned IEC of safety reports.  
The purpose of prompt reporting is to ensure that appropriate steps are taken in a timely manner 
to protect other subjects from avoidable harm. The appropriate time frame for satisfying the 
requirement for prompt reporting will vary depending on the specific nature of the unanticipated 
problem, the nature of the research associated with the problem, and the entity to which reports 
are to be submitted. For example, an unanticipated problem that resulted in a subject’s death or 
was potentially life-threatening generally should be reported to the IRB within a shorter time 
frame than other unanticipated problems that were not life-threatening. Therefore, the following 
guidelines are recommended in order to satisfy the requirement for prompt reporting:  
− Unanticipated problems that are serious adverse events should be reported to the IRB within 1 
week of the investigator becoming aware of the event.  
− Any other unanticipated problem should be reported to the IRB within 2 weeks of the 
investigator becoming aware of the problem.  
− Serious Adverse Event and Suspected Unexpected Serious Adverse Reaction, Medical Device 
Event, Potential Incident, Device Deficiency or Incident Reporting:  Principal Investigator shall 
forward to MSD’s Global Safety (“MSD GS”) group, any SAE and SUSAR, Medical Device Event, 
Device Deficiency or Incident information, including, but not limited to, all initial and follow-up 
information involving any Study subject in the Study.  Notification shall be in the form of a 
completed CIOMS I/MedWatch (or other mutually agreed upon format) immediately but no 
later than 1 business day of learning of the information. If learned during a weekend or holiday, 
report within one business day or no later than three (3) calendar days (whichever is 

               
Ver 1.4  
26 
 
shorter)from the day of learning of the information. This information shall be transmitted to 
MSD GS using the contact information provided below or such other modified contact 
information as provided by MSD in writing.  All information shall be transmitted in the English 
language and contain the reporter’s name and the Study subject identifier code. SUSAR 
information will be reported unblinded if the Study Drug has been blinded in the Study.  
Randomization codes for all other SAEs will be provided to MSD GS at end of Study if the Study 
Drug has been blinded in the Study. 
 
 

               
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27 
 
14. Reference 
Ausems, M. E., Vuyk, J., Hug, C. C., Jr., & Stanski, D. R. (1988). Comparison of a computer-assisted 
infusion versus intermittent bolus administration of alfentanil as a supplement to nitrous 
oxide for lower abdominal surgery. Anesthesiology, 68(6), 851-861.  
Choi, B. M., Lee, Y. H., An, S. M., Lee, S. H., Lee, E. K., & Noh, G. J. (2016). Population pharmacokinetics 
and analgesic potency of oxycodone. Br J Clin Pharmacol. doi:10.1111/bcp.13101 
Hua, J., Gong, J., Yao, L., Zhou, B., & Song, Z. (2014). Low-pressure versus standard-pressure 
pneumoperitoneum for laparoscopic cholecystectomy: a systematic review and meta-
analysis. Am J Surg, 208(1), 143-150. doi:10.1016/j.amjsurg.2013.09.027 
Kopman, A. F., & Naguib, M. (2015). Laparoscopic surgery and muscle relaxants: is deep block 
helpful? Anesth Analg, 120(1), 51-58. doi:10.1213/ANE.0000000000000471 
Kopman, A. F., & Naguib, M. (2016). Is deep neuromuscular block beneficial in laparoscopic 
surgery? 
No, 
probably 
not. 
Acta 
Anaesthesiol 
Scand, 
60(6), 
717-722. 
doi:10.1111/aas.12699 
Lee, Y. H., Seo, J. H., Min, K. T., Lim, Y. J., Jeong, S. W., Lee, E. K., . . . Noh, G. J. (2016). Population 
pharmacokinetics and prophylactic anti-emetic efficacy of ramosetron in surgical patients. 
Br J Clin Pharmacol, 82(3), 762-772. doi:10.1111/bcp.13010 
Madsen, M. V., Istre, O., Staehr-Rye, A. K., Springborg, H. H., Rosenberg, J., Lund, J., & Gatke, M. R. 
(2016). Postoperative shoulder pain after laparoscopic hysterectomy with deep 
neuromuscular blockade and low-pressure pneumoperitoneum: A randomised controlled 
trial. Eur J Anaesthesiol, 33(5), 341-347. doi:10.1097/EJA.0000000000000360 
Madsen, M. V., Staehr-Rye, A. K., Claudius, C., & Gatke, M. R. (2016). Is deep neuromuscular 
blockade beneficial in laparoscopic surgery? Yes, probably. Acta Anaesthesiol Scand, 60(6), 
710-716. doi:10.1111/aas.12698 
Martini, C. H., Boon, M., Bevers, R. F., Aarts, L. P., & Dahan, A. (2014). Evaluation of surgical 
conditions during laparoscopic surgery in patients with moderate vs deep neuromuscular 
block. Br J Anaesth, 112(3), 498-505. doi:10.1093/bja/aet377 
Minto, C. F., Schnider, T. W., Egan, T. D., Youngs, E., Lemmens, H. J., Gambus, P. L., . . . Shafer, S. L. 
(1997). Influence of age and gender on the pharmacokinetics and pharmacodynamics of 
remifentanil. I. Model development. Anesthesiology, 86(1), 10-23.  
Ozdemir-van Brunschot, D. M., van Laarhoven, K. C., Scheffer, G. J., Pouwels, S., Wever, K. E., & Warle, 
M. C. (2016). What is the evidence for the use of low-pressure pneumoperitoneum? A 
systematic review. Surg Endosc, 30(5), 2049-2065. doi:10.1007/s00464-015-4454-9 

               
Ver 1.4  
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Schnider, T. W., Minto, C. F., Gambus, P. L., Andresen, C., Goodale, D. B., Shafer, S. L., & Youngs, E. J. 
(1998). The influence of method of administration and covariates on the 
pharmacokinetics of propofol in adult volunteers. Anesthesiology, 88(5), 1170-1182.  
Staehr-Rye, A. K., Rasmussen, L. S., Rosenberg, J., Juul, P., Lindekaer, A. L., Riber, C., & Gatke, M. R. 
(2014). Surgical space conditions during low-pressure laparoscopic cholecystectomy with 
deep versus moderate neuromuscular blockade: a randomized clinical study. Anesth Analg, 
119(5), 1084-1092. doi:10.1213/ANE.0000000000000316 
Veelo, D. P., Gisbertz, S. S., Hannivoort, R. A., van Dieren, S., Geerts, B. F., van Berge Henegouwen, M. 
I., & Hollmann, M. W. (2015). The effect of on-demand vs deep neuromuscular relaxation 
on rating of surgical and anaesthesiologic conditions in patients undergoing 
thoracolaparoscopic esophagectomy (DEPTH trial): study protocol for a randomized 
controlled trial. Trials, 16, 331. doi:10.1186/s13063-015-0849-0 
 
 
 

               
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29 
 
Appnedix.1 Rhodes index of nausea, vomiting and retching (RINVR): Korean version 
1. 수술이 끝난 후 X시간 
동안 (   )번 토했다.  
7번 이상 
 5  6번  
3  4번 
1  2번 
 토하지 
않았다.  
2. 수술이 끝난 후 X시간 
동안 헛구역질 때문에 (    
) 고생하였다.  
전혀 고생 
하지 
않았다.  
 경미하게 중간 정도로 
많이 
못 견딜 
정도로 
3. 수술이 끝난 후 X시간 
동안 토하는 것 때문에 (    
) 고생하였다.  
 못 견딜 
정도로 
많이  
중간 정도로 
경미하
게 
전혀 
고생하
지 
않았다 
4. 수술이 끝난 후 X시간 
동안 (    )시간 동안 
메스꺼웠다.  
전혀 
메스껍지 
않았다.  
1시간 
이하. 
2  3시간  
4  
6시간 
6시간 
이상 
5. 수술이 끝난 후 X시간 
동안 메스꺼움 때문에 (    
) 고생하였다.  
전혀 
고생하지 
않았다. 
경미하게 
중간 정도로 
많이 
못 견딜 
정도로 
6. 수술이 끝난 후 X시간 
동안 한번 토할 때 마다 (   
) 토했다. 
매우 많이 
(3 컵 
이상) 
많이 
(2 컵 
이상 3컵 
미만) 
중간 정도로 
(반 컵에서 
 2 컵 미만) 
적게 
(반 
컵까지) 
토하지 
않았다.  
7. 수술이 끝난 후 X시간 
동안 (    )번 메스꺼웠다. 
7번 이상 
5  6번 
3  4번 
1  2번 
0번 
8. 수술이 끝난 후 X시간 
동안 토하지는 않았으나 (   
)번 헛구역질은 하였다.  
0번 
1  2번 
3  4번 
5  6번 
7번 
이상 
X: 1, 6 혹은 24. 

               
Ver 1.4  
30 
 
Scoring system for RINVR 
Directions for Use 
Complete Rhodes INVR Scale at 6 and 24 h after the end of surgery. 
Directions for Use 
To score the Rhodes INVR, reverse items 1, 3, 6 and 7. Assign a numeric value to each 
response from 0, the least amount of distress, to 4, the most distress. Total symptom 
experience from nausea and vomiting is calculated by summing the patient's responses to 
each of the eight items on the Rhodes INV. The potential range of scores is from a low of 0 
to a maximum of 32. Subscale scores also can be obtained from the Rhodes INVR for the 
following. 
Calculation of Subscale Scores 
Subscales for Symptom Experience 
Items on Scale  
Potential Range of Scores 
  Nausea experience 
4, 5, 7 
0-12 
  Vomiting experience 
1, 3, 6 
0-12 
  Retching experience 
2, 8 
0-8 
  Total experience score 
All items 
0-32 
Subscales for Symptom Occurrence 
Items on Scale  
Potential Range of Scores 
  Nausea occurrence 
4, 7 
0-8 
  Vomiting occurrence 
1, 6 
0-8 
  Retching occurrence 
8 
0-4 
  Total occurrence score 
All items 
0-20 
Subscales for Symptom Distress 
Items on Scale  
Potential Range of Scores 
  Nausea distress 
5 
0-4 
  Vomiting distress 
3 
0-4 
  Retching distress 
2 
0-4 
  Total distress score 
All items 
0-12 
 
Rhodes index of nausea, vomiting and retching (RINVR): English version 
1. In the last X hours, I threw up (   ) 
times. 
7 or more 5-6 times 3-4 times 1-2 times 
I did not 
throw up 
2. In the last X hours, from reteching 
or dry heaves have felt (   ) distress. 
no 
mild 
moderate 
great 
severe 

               
Ver 1.4  
31 
 
3. In the last X hours, from vomiting or 
throwing up, I have felt (   ) distress. 
severe 
great 
moderate 
mild 
no 
4. In the last X hours, I have felt 
nauseated or sick at my stomach (   
). 
not at all 
1 hour or 
less 
2-3 hours 4-6 hours 
more 
than 6 
hours 
5. In the last X hours, from 
nausea/sickness at my stomch, I have 
felt (   ) distress. 
no 
mild 
moderate 
great 
severe 
6. In the last X hours, each time I 
threw up I produced a (    ) amount. 
very large 
(3 cups or 
more) 
large (2-3 
cups) 
moderate 
(1/2-2 
cups) 
small (up 
to 1/2 
cup) 
I did not 
throw up 
7. In the last X hours, I have felt 
nauseated or sick at my stomach (   ) 
times. 
7 or more 5-6 times 3-4 times 1-2 times 
no 
8. In the last X hours, I have had 
periods of reteching or dry heaves 
without bringing anything up (   ) 
times. 
no 
1-2 times 3-4 times 5-6 times 7 or more 
X: 1, 6 or 24.