A Double-blind, Randomized and Controlled Multicenter Prospective Trial to Compare the Oncological Benefit of Deep Neuromuscular Block in Gastric Cancer Obesity Patient
Phase: PHASE3
Conditions: Gastric Cancer, Obesity
Sponsor: Korea University Anam Hospital

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
 
 
 
Requirements for Submitting a Full Proposal 
Section #1 - MISP Protocol Identification 
Study Title: 
A double-blind, randomized and controlled multicenter prospective trial to 
compare the oncological benefit of deep neuromuscular block in gastric cancer 
obesity  patient  
Request Date: 
3rd August 2016 
Last update date:  
8th May 2020 
Institution Name 
Korea University College of Medicine 
Investigator Contact 
Information: 
- Full address  
- Phone No. 
- Fax  No. 
- E-mail  
 
Sungsoo Park 
Addr, Department of Surgery, 73, Inchon-ro, Seongbuk-gu, Seoul, 
Korea 02841 
Tel, +82 29206772 
Fax, +82 29281631 
Email, kugspss@korea.ac.kr 
 
 
 
Registered in www.clinicaltrials.gov as NCT03196791 
 

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
Section #2- Core Protocol 
2.1 Objectives & 
Hypotheses  
2.1 List the objectives.  
The present randomized study is designed to evaluate the impact of muscle 
relaxation during laparoscopic gastrectomy on oncological benefit, especially 
with obese patients over BMI 25. Because surgeons still find that 
laparoscopic surgery for obese patients is challenging. The retrieval of lymph 
nodes (LNs) is difficult because they are embedded in thick fat tissue and are 
hard to distinguish with surrounding fat so that, the operative time should be 
prolonged. Studies have revealed that the association between obesity and 
longer operative outcomes than normal body weight patients.  Therefore we 
assumed deep neuromuscular block was associated more adequate 
lymphadenectomy, smaller intraoperative bleeding, shorter operative time.  
2.1.1 List the clinical hypotheses.  
The primary endpoint is number of harvested lymph node that is critical point 
regarding quality of surgery in gastric cancer treatment. The secondary 
endpoint is intraoperative bleeding, surgeons’ satisfaction. 
2.2 Background 
& Rationale, 
Significance of 
Selected Topic 
& Preliminary 
Data  
Administraion of muscle relaxation is essential in a variety of procedures as it 
causes an improvement of surgical conditions. Until recently, intraoperative 
deep neuromuscular block was eschewed because of concerns about 
recovery at the end of surgery. Since 2009, many studies have confirmed the 
rapid efficacy and better safety of sugammadex for reversing moderate and 
deep neuromuscular blockades induced by steroidal muscle relaxants than 
standard reversing agents,but most of studies have been focused only on 
surgical condition or concerns from the view points from anesthesiologists.  
2.3 Study 
Design 
Prospective, Randomized, double blind controlled trial 
Multicenter trial : 9 centers 

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
2.4 Study 
Flowchart 
    
 
 
Enrolled patients (n=196) 
 
 
 
   
 
 
 
   
 
Group DB (n=98) 
train of our counts 0 
post tetanic counts 1-2 
Neuromuscular block  
Rocuronium bromide 
0.5-1.0 mg/kg/hr 
continuous infusion 
 
 
Group MB (n=98) 
train of our counts 1-2 
Neuromuscular block 
Rocuronium bromide 0.1-
0.5 mg/kg/hr continuous 
infusion 
  
 
 
 
  
 
Intraoperative measurement  
Total anesthesia time 
Total operation time  
Time of surgeon complain 
Surgical rating score  
Amount of bleeding  
Wasting (Interrupted) event, time d/t poor relaxation 
  
 
 
 
  
 
Reversal agent 
Sugammadex 4mg/kg 
(Bridion®, (MSD)) 
 
 
Reversal agent  
Sugammadex 2mg/kg 
(Bridion®, (MSD)) 
  
 
 
 
  
 
Postoperative measurement 
Sedation score 
Pain score using the VAS 
Count of rescure medication 
Number of harvested lymph node 
Postoperative complication  

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
2.5 Study 
Procedures 
Inclusion criteria 
1. 
Patient with obtaining written informed consent 
2. American Society of Anesthesiologists Physical status I or III, Aged 
19 to 75 yr   
3. Underwent elective laparoscopic distal gastrectomy  
4. Body mass index (BMI) > 25 kg/m2 
5. CStage l, ll  
Exclusion criteria 
1. End stage renal disease (ESRD) patient 
2. A (family) history of malignant hyperthermia; significant renal or 
hepatic dysfunction; known or suspected neuromuscular disorders; 
allergies to narcotics or muscle relaxants; known previous 
abdominal surgeries 
 
Anesthetic protocol 
1. The patients were randomly assigned to two groups using a computer-
generated randomization table:  
1) Deep neuromuscular block group  
the ‘post-tetanic counts 1-2’ (PTC1-2) 
2) Moderate neuromuscular group  
the ‘train-of-four counts 1-2’ (TOF count1-2)  
2. Premedication : None 
3. Standard monitoring included electrocardiogram, noninvasive blood 
pressure and pulse oximetry at OR 
4. Anesthesia is induced and maintained with propofol and remifentanil (BP 
within ± 20% of preinduction values)  
– TIVA TCI (target controlled infusion using effect-site concentration) 
5. After loss of consciousness is confirmed, neuromuscular activity 
monitoring via acceleromyography is initiated. 
-Neuromuscular monitoring was performed using a TOF-Watch SX®  
(Organon; Roseland, NJ, USA) at the adductor pollicis muscle. 
-The ulnar nerve was supramaximally stimulated near the wrist with square 
pulses of 0.2 ms duration, delivered as TOF pulses of 2 Hz at 15-second 
intervals. The resulting contractions of the adductor pollicis muscle were 
quantified using an acceleromyographic monitor.  
-The acceleromyograph was calibrated with 50 Hz tetanic stimulation for 5 s 
and train-of-four (TOF) stimulation for 3 min 
6. Muscle relaxation is induced rocuronium bromide (0.6 mg/kg)  
7. Mechanical ventilation was initiated. 
(Tidal volume : Ideal body weitht (IBW) *8, Respiratory rate (RR) : EtCO2 35-
45 유지) 
8. Hypnotic depth was kept in the range of 45 to 60 using BIS VISTA® 
(Aspect Medical Systems, Inc., Norwood, MA, USA). 
 
9. Neuromuscular blocking agent protocol 
 
Neuromuscular assessment 
Neuromuscular monitoring was performed using a TOF-Watch®. The ulnar 
nerve was supramaximally stimulated near the wrist with square pulses of 
0.2 ms duration, delivered as TOF pulses of 2 Hz at 15-second intervals. The 
resulting contractions of the adductor pollicis muscle were quantified using 
an acceleromyographic monitor. TOF stimulation and PTCstimulation were 
repeated every 15 s and twomin, respectively.  
 
In Moderate neuromuscular group  

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
If TOF count 1-2, rocuronium bromide 0.1-0.5 mg/kg/hr continusous infusion 
with TOF monitoring 
 
In Deep neuromuscular group  
followed by a continuous infusion of 0.5–1.0 mg/kg/hr (IBW) with TOF 
monitoring  
 
10. Additionally, if the surgeon asked the anesthesiologist for deeper NMB to 
achieve an adequate surgical field, rocuronium bolus 0.15 mg/kg was 
administered. 
11. rocuronium infusion stop at end of Laparoscope 
 
12. Reversal agent & Dose protocol 
-In Moderate neuromuscular group (second twitch appeared at TOF) 
Sugammadex 2mg/kg (Bridion®, (MSD)) 
-In Deep neuromuscular group (end of surgery) 
Sugammadex (Bridion®, Merck Sharp and Dohme (MSD), Oss, The 
Netherlands) 4 mg/kg 
13. When the TOF ratio recovered to 0.9 and spontaneous breath, opening 
of the eyes to verbal commands, extubation will be done. 
14. Insufflation pressure: 12mmHg 
 
Evaluation method 
At OR : Anesthesiologists 
Total anesthesia time 
Total surgical time (Incision – dressing) 
The time from the end of the operation to the administration of the reversal 
agent 
Total fluid 
Total rocuronium dose 
Hemodynamic parameter  
systolic,diastolic,mean BP 
-HR 
-EtCO2 
-Temperature 
-Peak inspiration pressure  
 
Sedation score(MOAA/S) 
 
0 
does not respond to pain 
1 
does not respond to mild prodding or shaking 
2 
responds only after mild prodding or shaking 
3 
responds only after name is called loudly and/or 
repeatedly 
4 
lethargic response to name spoken in normal tone 
5 
responds readily to name spoken in normal tone 
 
Surgeon 
Report of surgeon’s specific complains 
The wasting operative time due to poor neuromuscular relaxation 
Patient motion  
Surgical rating score :  consists of individual 4 parts of critical lymph node 
dissection areas - 
during lymph node dissection at 4sb, 6, supraduodenal area and 
suprapancreatic area  

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
 
 
Ward  
Pain score using the VAS until postoperative 48 hours 
PONV  
Count of rescue medication 
First flatus time 
Postoperative complication until POD 30 
2.6 Study 
Duration 
2 years after IRB approval 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
Statistical analyses were performed with IBM SPSS 20 software. 
Quantitative variables were expressed as means (  standard deviation) and 
were compared by Mann-Whitney and Wilcoxon nonparametric tests. 
Qualitative variables were described by numbers and percentages and 95% 
confidence intervals. The various parameters were compared by Pearson’s 
and Fisher’s Chi-squared tests. For all statistical tests, a P value < 0.05 was 
considered significant 
The major objective of this study is to estimate the number dissected lymph 
nodes. Based upon a sample size of n=89 patients per group, this study has 
80% power to detect a 6.3 difference between groups in harvested lymph 
nodes; this calculation is based on a between subject standard deviation of 
change of 15  for harvested lymph node (reference for where this variability 
statement originated). The calculations are the customary ones based on 
normal distributions –estimation of sample size and power for comparing two 
means in Bernard Rosner’s fundamentals of biostatistics. After considering 
10% of follow—up loss, a total of 196 patients will be needed. 
Regarding increasing effect of BMI on surgery, we will process it as 
continuous variable when we analyze data and if there is significance, we 
could decide a cut off value of BMI for specific anesthetic indication. 
In addition, to control the surgeons’ factors impacting results, we will 
perform surgeon stratified randomization. And if there is a serious surgeon’s 
technical problems being able to distort objective data when interim 
analysis, we would drop the surgeon out of this study.  

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
2.8 Specific 
Drug Supply 
Requirements  
N/A 
2.9 Adverse 
Experience 
Reporting 
Reporting Procedures for Exchange of Adverse Event Information. 
 
(i) For purposes of this Agreement the below terms shall be defined as 
follows: 
 
 “Adverse Event” or “AE” shall mean any untoward medical occurrence in a 
Study subject who is administered the Study Drug regardless of whether or 
not a causal relationship with the Study Drug exists.  By way of example and 
without limitation, an AE can be any unfavorable and unintended sign (for 
example, an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the Study Drug.  
 
 “Device Deficiency” shall mean inadequacy of a Study Drug device related 
to its identity, quality, durability, reliability, safety or performance, such as 
malfunction, misuse or use error and inadequate labeling. 
 
 “Incident” shall mean any malfunction or deterioration in the characteristics 
and/or performance of a Study Drug device, as well as any inadequacy in the 
labeling or the instructions for use which, directly or indirectly, might lead to 
or might have led to the death of a patient, or user, or of other persons or to 
a serious deterioration in the state of health. 
 
 “Medical Device Event” shall mean any malfunction or deterioration in the 
characteristics and/or the performance of a Study Drug device, as well as 
any inadequacy in the labeling or the instructions for use which led to or 
could have led to an untoward event for the user or any other person. 
 
 “Serious Adverse Event” or “SAE” shall mean any untoward medical 
occurrence in a Study subject who is administered the Study Drug that 
results in death, a life-threatening drug experience, requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent 
or significant disability/incapacity, or is a congenital anomaly/birth defect, 
cancer, or is a new cancer if the cancer is the condition of the study, or 
overdose.  Other important medical events that may jeopardize the patient or 
may require intervention to prevent one of the outcomes listed previously 
should also be considered “serious”. 
             
 “Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean 
any Serious Adverse Event, the nature, severity or frequency of which is not 
consistent with information in the most current investigator’s brochure, or 
with respect to a marketed product the most current Summary of Product 
Characteristics (SPC) or Package Insert. 
 

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
(ii) 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) within two (2) business days 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. 
 
(iii) MSD may define certain Non-Serious Events of Interest.  If any Non-
Serious Events of Interest are defined, Merck will provide such information in 
writing to Principal Investigator at the time of Protocol approval, execution of 
this Agreement or anytime thereafter.  Reporting of any defined Non-Serious 
Events of Interest will be handled in the same manner as SAEs unless 
mutually agreed otherwise in writing by the parties.   
 
(iv) All reports of Study Drug exposure during pregnancy or lactation 
(including a female partner of a male Study subject using the Study Drug), 
whether associated with an AE or not, must be reported to MSD GS in 
accordance with the timelines and contact information for an SAE.  Principal 
Investigator shall follow pregnancies to term to obtain the outcome of the 
pregnancy.  The outcome of the pregnancy shall be forwarded to MSD GS. 
 
(v)  Institution and Principal Investigator shall fully comply with all of their 
respective reporting obligations to the applicable regulatory authorities with 
respect to any AE, SAE or SUSAR that arises from the Study. 
 
(vi) SAE reports and any other relevant safety information are to be 
forwarded to MSD GS facsimile number:  215-993-1220 
2.10 Itemized 
Study Budget  
Annexed sheet 
2.11 References 
MH Kim, KY Lee, KY Lee et al., Maintaining Optimal Surgical Conditions 
With Low Insufflation Pressures is Possible With Deep Neuromuscular 
Blockade During Laparoscopic Colorectal Surgery. Medicine, 95 : 9: March 
2016 
M. V. Mads en , A. K. Staehr-Rye , C. Claudius et al.  Is deep neurom 
uscular block ade beneficial in laparoscopic surgery? Yes , probably. Acta 
Anaesthesiologica Scandinavica. 60 (2016) 710–716 

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
Aaron F. Kopman, Mohamed Naguib et al. Is deep neurom uscular block 
beneficial in laparoscopic surgery ? No , probably not., Acta 
Anaesthesiologica Scandinavica. 60 (2016) 717–722 
Anne K. Staehr-Rye,  Lars S. Rasmussen, Jacob Rosenberg etal., Surgical 
Space Conditions During Low-Pressure Laparoscopic Cholecystectomy with 
Deep Versus Moderate Neuromuscular Blockade: A Randomized Clinical 
Study.Anesthesia & Analgesia November 2014 • Volume 119 • Number 5 
Rachid Badaoui, Aure´lie Cabaret, Youssef Alami et al. Reversal of 
neuromuscular blockade by sugammadex in laparoscopic bariatric surgery: 
In support of dose reduction. Anaesth Crit Care Pain Med 35 (2016) 25–29 
Y. Caesar,  I. Sidlovskaja,  A. Lindqvist et al. Intraabdominal Pressure and 
Postoperative Discomfort in Laparoscopic Roux-en-Y Gastric Bypass 
(RYGB) Surgery: a Randomized Study OBES SURG DOI 10.1007/s11695-
016-2091-6 
Hemanga K., Bhattac harjee, Azarudeen Jalaludeen et al. Impact of 
standard-pressure  and low-pressure pneumoperitoneum on shoulder pain 
following laparoscopic cholecystectomy: a randomised controlled tria. Surg 
Endosc (2016) DOI 10.1007/s00464-016-5108-2 
Bon-Wook Koo, Ah-Young Oh, Kwang-Suk Seo et al., Randomized Clinical 
Trial of Moderate Versus Deep Neuromuscular Block for Low-Pressure 
Pneumoperitoneum During Laparoscopic Cholecystectomy World J Surg 
DOI 10.1007/s00268-016-3633-8 
Martini CH, Boon M., Bevers R.F., et al. Evaluation of surgical conditions 
during laparoscopic surgery in patients with moderate vs deep neuromuscular 
block Br J Anaesth 2013 1-8 
Boon M, Martini CH, Aarts LP, Effect of variations in depth of neuromuscular 
blockade on rating of surgical conditions by surgeon and anesthesiologist in 
patients undergoing laparoscopic renal or prostatic surgery (BLISS trial): 
study protocol for a randomized controlled trial Trials 2013, 14:63 
Lee JH, Paik YH, Lee JS, Ryu KW, Kim CG, Park SR, et al. Abdominal 
shape of gastric cancer patients influences short-term surgical outcomes. 
Ann Surg Oncol 2007;14:1288–1294. 
Shim JH, Song KY, Kim SN, Park CH. Laparoscopy-assisted distal 
gastrectomy for overweight patients in the Asian population. Surg Today 
2009;39:481–486. 
Kim KH, Kim MC, Jung GJ, Kim HH. The impact of obesity on LADG for early 
gastric cancer. Gastric Cancer 2006;9:303–307. 
Seo HS, Lee HH. Short-Term Outcomes of Three-Port Totally Laparoscopic 
Distal Gastrectomy in the Treatment of Gastric Cancer: Comparison with a 
Four-Port Approach Using a Propensity Score Matching Analysis. J 
Laparoendoscopic & Advanced Surgical Techniques 2016;26:531-535. 
Lee HJ, Kim YS, Park I. Calculation of sample size in clinical trials. CISE 
2013;16:53-57. 
2.12 Publication 
Plan 
Expected number of papers published with this trial: 1 paper –to make a high 
impact result, we are going to incorporate all surgical and anesthetic 
variables altogether. But if we could make collateral data, there would be 
more. 
Target journal: Annals of Surgery 
Abtracts: 2 to 3 

  
GMA KR 04.501_Att 004_Version 4.3                                                                                     Effective Date: 08-May-2020 
Scientific meetings considered with this study results: SAGES and ACS, and 
Korean International Surgical Meetings including KINGCA and KSELS.  
2.13 Curriculum 
Vitae 
Annexed sheet 
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
U.S. protocols should be submitted by US investigators directly or through 
the Global Research Specialist at  www.merckiisp.com   
Non U.S. protocols should be submitted to the MSD office by the 
investigators.