Clinical trial NCT04638881
Conditions: Esophageal Spasm
Sponsor: Stanford University
Start date: 2020-12-28; Completion date: 2023-04-13
Enrollment: 92 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Postoperative pain after peroral endoscopic myotomy occurs due to involuntary esophageal smooth muscle spasms. Magnesium has antispasmodic properties as a smooth muscle relaxant. This study hypothesizes that among patients having peroral endoscopic myotomy, magnesium will decrease postoperative esophgeal pain as measured by the esophageal symptoms questionnaire, while decreasing perioperative opioid requirements.

Detailed description:

Arms: arm 1: Bolus to be administered at start of mucosal incision, followed by infusion. Infusion to be terminated at extubation. arm 2: Bolus to be administered at start of mucosal incision, followed by infusion. Infusion to be terminated at extubation.
Interventions: intervention 1: Magnesium sulfate intervention 2: Normal Saline
Intervention descriptions: intervention 1: Magnesium infusion 50 mg/kg bolus over 15 minutes and 25 mg/kg/hr infusion, both administered intraoperatively under general anesthesia. intervention 2: Placebo. Bolus and infusion administered similarly under general anesthesia.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and the property of Stanford University School of Medicine. 
 
 
 
 
 
 
A prospective, randomized, double-blind, placebo-controlled trial of the 
effects of magnesium sulfate on postoperative esophageal spasm-
associated pain following peroral endoscopic myotomy 
 
 
 
 
 
 
Protocol Number 
58859 
 
Clinicaltrials.gov Number 
04638881 
 
 
 
 
Version 1.0 
 
 
Date 
International date format: 12 November 2020 
 
 
 
 
 


 
 
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Regulatory Sponsor: 
Richard K. Kim, MD MSc 
Department of Anesthesiology, Perioperative and Pain 
Medicine 
Stanford University 
300 Pasteur Drive, H3580 
Stanford, CA 
347-586-9661 
Funding Sponsor: 
Stanford University 
300 Pasteur Drive, H3580 
Stanford, CA 
Study Product: 
Magnesium Sulfate 
 
 


 
 
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Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 1 
1 
INTRODUCTION .............................................................................................................................................. 2 
1.1 
BACKGROUND ............................................................................................................................................. 2 
1.2 
INVESTIGATIONAL AGENT ........................................................................................................................... 2 
1.3 
PRECLINICAL DATA ..................................................................................................................................... 2 
1.4 
CLINICAL DATA TO DATE............................................................................................................................ 3 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ....................................................................................................... 3 
2 
STUDY OBJECTIVES ...................................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................................ 3 
3.1 
GENERAL DESIGN........................................................................................................................................ 3 
3.2 
PRIMARY STUDY ENDPOINTS ...................................................................................................................... 3 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................................. 4 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................. ERROR! BOOKMARK NOT DEFINED. 
4 
SUBJECT SELECTION AND WITHDRAWAL............................................................................................ 4 
4.1 
INCLUSION CRITERIA ................................................................................................................................... 4 
4.2 
EXCLUSION CRITERIA ................................................................................................................................. 4 
4.3 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................... 4 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................................ 4 
4.4.1 
When and How to Withdraw Subjects .................................................................................................... 4 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ....................................................................... 5 
5 
STUDY DRUG ................................................................................................................................................... 5 
5.1 
DESCRIPTION ............................................................................................................................................... 5 
5.2 
TREATMENT REGIMEN ................................................................................................................................ 5 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................................................... 5 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG .............................................................................. 5 
5.5 
SUBJECT COMPLIANCE MONITORING .......................................................................................................... 6 
5.6 
PRIOR AND CONCOMITANT THERAPY .......................................................................................................... 6 
5.7 
PACKAGING ................................................................................................................................................. 6 
5.8 
BLINDING OF STUDY DRUG ......................................................................................................................... 6 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ....................................................................................... 6 
5.9.1 
Receipt of Drug Supplies ....................................................................................................................... 6 
5.9.2 
Storage ................................................................................................................................................... 6 
5.9.3 
Dispensing of Study Drug ...................................................................................................................... 6 
5.9.4 
Return or Destruction of Study Drug ..................................................................................................... 7 
6 
STUDY PROCEDURES .................................................................................................................................... 7 
6.1 
VISIT 1 ................................................................................................ ERROR! BOOKMARK NOT DEFINED. 
6.2 
VISIT 2 ................................................................................................ ERROR! BOOKMARK NOT DEFINED. 
6.3 
ETC. ..................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN ....................................................................................................................................... 8 
7.1 
SAMPLE SIZE DETERMINATION ................................................................................................................... 8 
7.2 
STATISTICAL METHODS............................................................................................................................... 8 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS .................................................................................................... 9 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................... 9 
8.1 
DEFINITIONS ................................................................................................................................................ 9 
8.2 
RECORDING OF ADVERSE EVENTS............................................................................................................. 11 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................... 11 


 
 
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8.3.1 
Study Sponsor Notification by Investigator ......................................................................................... 11 
8.3.2 
EC/IRB Notification by Investigator .................................................................................................... 12 
8.3.3 
FDA Notification by Sponsor ............................................................................................................... 12 
8.4 
UNBLINDING PROCEDURES........................................................................................................................ 12 
8.5 
STOPPING RULES ................................................................................. ERROR! BOOKMARK NOT DEFINED. 
8.6 
MEDICAL MONITORING ............................................................................................................................. 12 
8.6.1 
Internal Data and Safety Monitoring Board .......................................... Error! Bookmark not defined. 
8.6.2 
Independent Data and Safety Monitoring Board ................................... Error! Bookmark not defined. 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 12 
9.1 
CONFIDENTIALITY ..................................................................................................................................... 12 
9.2 
SOURCE DOCUMENTS ................................................................................................................................ 13 
9.3 
CASE REPORT FORMS ................................................................................................................................ 13 
9.4 
RECORDS RETENTION ................................................................................................................................ 13 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 13 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 13 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 14 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 14 
12 
STUDY FINANCES ......................................................................................................................................... 14 
12.1 
FUNDING SOURCE ..................................................................................................................................... 14 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 15 
12.3 
SUBJECT STIPENDS OR PAYMENTS ...................................................... ERROR! BOOKMARK NOT DEFINED. 
13 
PUBLICATION PLAN .................................................................................................................................... 15 
14 
REFERENCES ................................................................................................................................................. 15 
15 
ATTACHMENTS ............................................................................................................................................ 15 
 


 
 
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List of Abbreviations 
 
ESQ – Esophageal symptoms questionnaire 
NMDA - N-methyl-D-aspartate  
POEM - Peroral endoscopic myotomy 
SHC – Stanford Hospital & Clinics


 
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Study Summary 
Title 
A prospective, randomized, double-blind, placebo-controlled trial of the 
effects of magnesium sulfate on postoperative esophageal spasm-
associated pain following peroral endoscopic myotomy 
Short Title 
MgPOEM 
Protocol Number 
58859   
Methodology 
Randomized, double-blind, placebo-controlled prospective trial  
Study Duration 
2 years 
Study Center(s) 
Single-center  
Objectives 
This study hypothesizes that among patients having peroral endoscopic 
myotomy, intraoperative magnesium sulfate infusion will reduce the 
severity of postoperative pain while decreasing perioperative opioid 
requirements. 
Number of Subjects 
100 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis: Esophageal motility disorder, including achalasia  
Main Inclusion Criteria: Patient undergoing peroral endoscopic 
myotomy  
Study Product, Dose, 
Route, Regimen 
Magnesium sulfate. 50 mg/kg (based on lean body weight) intravenous 
over 15 minutes at start of mucosal incision, followed by 25 mg/kg/hr 
infusion that is turned off at patient extubation 
Duration of 
administration 
Only limited to surgery duration, from start of mucosal incision to 
patient extubation 
Reference therapy 
Reference is placebo (normal saline) 
Statistical 
Methodology 
Chi-square test to compare primary outcome (postoperative pain) 
Chi-square test, Fisher’s exact test, or Mann-Whitney U test to compare 
secondary outcomes (intraoperative opioid usage, postoperative opioid 
usage, pain at 24 hours, esophageal symptoms questionnaire results) 
 


 
 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 Background 
Since its initial description in 2010, POEM has been suggested to be a safe and effective surgery 
for achalasia and other esophageal motility disorders.1,2 Compared to patients who undergo the 
traditional laparoscopic Heller myotomy, patients managed with POEM experience shorter 
procedure times, longer myotomies, lower adverse events, and improved functional outcomes.3 
However, postoperative retrosternal pain and regurgitation due to residual carbon dioxide and/or 
increased intraoperative esophageal exposure to gastric acid remain common. Dual innervation 
of the esophagus by vagal and spinal afferent fibers is present along the entire length of the 
esophagus, accounting for patients' reports of vague discomforts and localized retrosternal 
sensations, respectively.4 Pain management has largely been based on opioids, which may 
contribute to worsened symptoms associated with achalasia.5 Postoperatively, most patients 
typically experience mild to moderate pain requiring modest doses of opioids.6  
1.2 Investigational Agent 
We recently published a case report on opioid-free anesthesia for POEM surgery utilizing 
magnesium not only for its analgesic,7 but also antispasmodic properties.8,9 Magnesium has 
been recognized as an antinociceptive agent since 1916, but its mechanism of action remains 
poorly elucidated. Two of its functions were considered for this anesthetic plan. First, 
magnesium is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that can 
decrease visceral hyperalgesia.7 Second, magnesium induces smooth muscle relaxation by 
decreasing intracellular calcium concentrations in both smooth muscle and the adrenal gland, the 
latter causing a decrease in circulating catecholamines.10 Magnesium has been well 
characterized in obstetrical management of preeclampsia.8. The antispasmodic potential of 
magnesium was recently studied in the context of bladder surgery, where intraoperative 
magnesium administration was associated with decreased catheter-related bladder discomfort 
and improved patient satisfaction.9 In POEM procedures, insufflation with carbon dioxide for 
visualization can lead to postoperative subcutaneous or mediastinal emphysema. Residual carbon 
dioxide along the esophagus can also lead to referred pain that translates as postoperative 
esophageal spasm and regurgitation. Magnesium may adequately relax esophageal smooth 
muscle and desensitize afferent nerve endings to decrease these symptoms. In other words, the 
mechanisms underlying magnesium provide a physiologically and anatomically targeted therapy 
for esophageal pain. 
1.3 Preclinical Data 
None 


 
 
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1.4 Clinical Data to Date 
Magnesium has been extensively studied for its nonopioid analgesic properties across multiple 
different types of surgeries and procedures in the anesthesia literature.11 Its smooth muscle 
relaxant properties have been also documented in the context of preeclampsia management in 
obstetrics.12 We also recently published a case report that highlighted the role of magnesium in 
decreasing postoperative pain specific to esophageal spasms and reflux.13 
1.5 Dose Rationale and Risk/Benefits 
The magnesium bolus dosing of 50 mg/kg emulates the dose used in a recent urologic study that 
explored the effect of magnesium to decrease bladder catheter-associated discomfort.9 
Furthermore, this bolus dose and the infusion rate are the most frequently reported dose/rate in a 
meta-analysis of 20 randomized controlled trials.12 The aforementioned meta-analysis found no 
major adverse events associated with magnesium toxicity, whilst finding a statistically and 
clinically significant decrease in postoperative pain. The medication is administered 
intravenously as part of the intraoperative anesthetic regimen. The POEM surgery lasts on 
average 1 to 2 hours, which is the maximum duration of the magnesium infusion. This will limit 
the risk of magnesium toxicity. Hence, the study will be safely investigating a nonopioid 
analgesic that has been shown to be efficacious in similar populations undergoing a diverse range 
of surgeries, with the hope of clarifying the antispasmodic potential of magnesium. 
2 Study Objectives 
Primary Objective 
To assess the efficacy of magnesium sulfate on decreasing esophageal spasm-associated pain as 
measured by subjective pain scores and the esophageal symptoms questionnaire score.14 
 
Secondary Objective 
To assess the efficacy of magnesium sulfate on decreasing intraoperative opioid usage. 
To assess the efficacy of magnesium sulfate on decreasing postoperative opioid consumption. 
To assess the efficacy of magnesium sulfate on decreasing discharge opioid prescription. 
To assess the efficacy of magnesium sulfate on decreasing postoperative pain as measured by the 
esophageal symptoms questionnaire score at 24 hours.  
3 Study Design 
3.1 General Design 
• Prospective randomized, double-blind, placebo-controlled trial 
• Expected duration of subject participation: 2 days   
3.2 Primary Study Endpoints 
This study will evaluate the efficacy of magnesium sulfate on decreasing esophageal spasm-
associated pain as measured by subjective pain scores and the esophageal symptoms 
questionnaire score. 


 
 
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3.3 Secondary Study Endpoints 
This study will assess the efficacy of magnesium sulfate on decreasing intraoperative opioid 
usage, postoperative opioid consumption, discharge opioid prescription, and on decreasing 
postoperative pain as measured by the esophageal symptoms questionnaire score at 24 hours.  
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
i) 
Ages 18 and over 
ii) 
Subjects capable of giving informed consent, or have an acceptable surrogate 
capable of giving consent on the subject’s behalf  
iii) 
Planned peroral endoscopic myotomy 
4.2 Exclusion Criteria 
i) cannot give consent  
ii) patients who are clinically unstable and/or require urgent/emergent intervention  
iii) previous esophageal myotomy  
iv) preexisting hypermagnesemia  
v) end-stage renal disease  
vi) neuromuscular disease, including but not limited to Guillain-Barre syndrome, myasthenia 
gravis, congenital myopathy, and muscular dystrophy  
vii) preexisting heart failure  
viii) 
severe ventricular systolic dysfunction (left or right ventricle) 
4.3 Subject Recruitment and Screening 
No patient health information will be collected prior to enrollment. When possible, the primary 
endoscopist/surgeon or other health care provider(e.g. nurse practitioner, nursing staff) will 
inform eligible participants of the study. If the patient expresses interest they will be approached 
by research study personnel. If they decline they will not receive any further information about 
the study. In cases where it is not feasible for an endoscopist to inform the patients of the study, 
or the patient has not yet met the endoscopist, a research personnel will screen for eligibility 
using chart review. Eligible patients will be approached about the study if history review reveals 
a potential candidate for the study. If the family expresses interest, the research personnel will 
proceed with consent and protocol. If patient decline interest, we will respect their decision and 
will not pursue the family any further for this study. Participants will be asked if they are 
participating in other studies. They will be allowed to participate in more than one study if it can 
be determined that this poses no increased risk to the participants or the integrity of the data 
collected for either study. 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Patients will be informed that they may withdraw from the study at any time, for any reason, 
with no consequences for withdrawing, and the standard clinical care and procedures will 
continue as normal.  


 
 
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4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
All data will be de-identified and stored in Stanford-secured encrypted devices, only accessible 
to research personnel. For withdrawn subjects, we will attempt to seek permission for 
magnesium levels drawn during the defined follow-up period (postoperative days 0 and 1). This 
is related to the safety profile of the study drug. Otherwise, all other data related to the 
withdrawn subject will be destroyed, and no further follow-up information will be collected. 
5 Study Drug  
5.1 Description 
Magnesium sulfate is the second most plentiful electrolyte in human intracellular fluids. It has 
NMDA antagonist and smooth muscle relaxant properties. The medication will appear as 
magnesium sulfate USP 50%, a sterile, concentrated solution of magnesium sulfate in water. In 
the vial, each milliliter contains 500 mg magnesium sulfate heptahydrate.  
5.2 Treatment Regimen 
A loading dose of 50 mg/kg (based on lean body weight) will be administered intravenously over 
15 minutes at start of mucosal incision, followed by 25 mg/kg/hr infusion intravenously that is 
turned off at patient extubation. The expected treatment duration is 1 to 2 hours. 
5.3 Method for Assigning Subjects to Treatment Groups 
Randomization codes will be generated using web-based randomization software (RStudio) with 
block sizes of four and an allocation ratio of 1:1 for either intravenous magnesium sulfate 
(magnesium group) or intravenous normal saline as control (control group). These randomization 
codes will be enclosed in sequentially numbered, identical, opaque, and sealed envelopes. They 
will be kept in a closed box during the entire study period. The envelopes will be provided in 
sequence to the anesthesia team. 
5.4 Preparation and Administration of Study Drug 
The anesthesia team will prepare the study treatment based on the instructions within the 
envelope. Specifically, the anesthesia team will be instructed to draw up 10 g (20 ml) of the 
study drug within a 20 ml syringe, or to draw up 20 ml of normal saline within a 20 ml syringe. 
Although both medications are colorless and transparent, and thus are indistinguishable to the 
endoscopist, the syringes will be labeled as “study” to minimize drug error during the 
intraoperative anesthetic management. These medications will be administered using a syringe 
pump (Alaris; Becton, Dickinson and Company, New Jersey, USA) available in all SHC 
operating rooms. Instructions to manually program the syringe pump will be provided. 
Specifically, the anesthesia team will be instructed to enter 10 g of the study drug in 20 ml of 
volume, and to enter the patient’s lean body weight. The team will enter the infusion rate as 25 
mg/kg/hr, and save these settings. 
When the endoscopist announces that she/he will start the mucosal incision, the syringe pump 
will be programmed to bolus 50 mg/kg over 15 minutes. After the bolus is administered, the 
syringe pump will default to the infusion rate of 25 mg/kg/hr. The anesthesia team will stop the 
infusion at extubation.  


 
 
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5.5 Subject Compliance Monitoring 
The anesthesia team will be documenting the drugs in the intraoperative anesthesia medication 
record. The research staff will review the records to ensure compliance with administration of 
the study drug. There is no compliance monitoring necessary for the study participant as they 
will not be administering the drug to or by themselves.  
5.6 Prior and Concomitant Therapy 
Information on their preoperative medications will be collected, including use of multivitamins, 
herbal supplements, or magnesium-containing supplements, and use of acid-reducing 
medications such as H2-receptor antagonists or proton pump inhibitors.  
During the study, the patients will be expected to receive standard anesthetic care including 
hypnotics, narcotics, neuromuscular blockers (e.g. succinylcholine/rocuronium), antiemetics, 
vasopressors, antihypertensives, and anesthetics as needed at the anesthesia team’s discretion. 
In the rare case of magnesium toxicity, all healthcare providers will have access to calcium 
chloride/gluconate therapy to reverse the cardiorespiratory and musculoskeletal effects. 
5.7 Packaging 
As described above, the magnesium sulfate is packaged in 2 ml vials, each containing 1 g (500 
mg/ml). Multiple vials are already available in the anesthesia medication carts in every operating 
room. In addition, the normal saline vials are packaged in 10 ml vials. 
5.8 Blinding of Study Drug 
The study drug will be blinded to the endoscopist and patient. While the study or control drug is 
being prepared by the anesthesia team, the endoscopist will not be present in the operating room 
environment. The 20 ml syringe in which the drug is prepared will be labeled as “study” for the 
purpose of minimizing drug error during the course of intraoperative management.  
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
The magnesium sulfate and normal saline are already available for use in the anesthesia 
drug carts. 
5.9.2 Storage 
The drugs are maintained at room temperature with no particular light protection 
requirements in every anesthesia drug cart. The special handling requirements are 
necessary.  
5.9.3 Dispensing of Study Drug 
The anesthesia team will follow instructions provided to them to prepare the study drug, 
using multiple vials of the drug already available for use in the anesthesia drug cart. 


 
 
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5.9.4 Return or Destruction of Study Drug 
By the completion of the anesthetic, the drug’s bolus and infusion will be documented in 
the electronic anesthetic record. The usused study drug remaining in the syringe will be 
wasted and destroyed.  
6 Study Procedures 
6.1 24 to 72 hours prior to scheduled surgery  
6.1.1 Patients undergoing per-oral endoscopic myotomy (POEM) in the SHC operating rooms 
will be identified, and screened by phone whether or not they agree to the study. 
6.2 Day of surgery  
6.2.1 In the preoperative holding area, all enrolled patients will have preoperative plasma 
calcium and magnesium levels drawn and complete the esophageal symptoms 
questionnaire (ESQ), a validated survey to assess symptoms of dysphagia, globus, and 
reflux.  
6.2.2 The patient will proceed to the OR for anesthetic care.  
6.2.2.1 Patients will undergo rapid sequence induction of general anesthesia. In the control 
group, the anesthesia team will use ketamine, propofol, succinylcholine, and esmolol 
and/or opioids at their discretion. In the treatment arm, the anesthesia team will use 
ketamine and propofol using lean body weight (LBW) dosing, and succinylcholine at 
total body weight (TBW) dosing. After endotracheal tube placement and confirmation, 
sevoflurane in air and oxygen will be used for maintenance of general anesthesia. The 
anesthesiologist will ensure adequate neuromuscular relaxation throughout the case.  
6.2.2.2 In the treatment arm, the anesthesia team will prepare a magnesium sulfate infusion 
within a 20 ml syringe. Patients will receive a magnesium sulfate bolus of 50 mg/kg 
lean body weight over 15 minutes, followed by a magnesium sulfate infusion at 25 
mg/kg/hr when the endoscopist begins mucosal incision. In addition, the patients will 
receive dexamethasone 0.1-0.2 mg/kg at the start of case, and ondansetron 4 mg at the 
end of case. The magnesium infusion will be discontinued at extubation. After surgery, 
patients will be admitted to the postanesthesia care unit. For mild pain reported as a 
numeric score ranging from 1 to 3, acetaminophen 1000 mg IV will be offered. For pain 
greater than a score of 3, opioids (fentanyl and hydromorphone) will be available. For 
nausea and vomiting, prochlorperazine and haloperidol will be provided. Calcium 
gluconate and a code cart with emergency drugs and airway equipment will be made 
available in case of symptoms concerning for magnesium toxicity. 
6.2.2.3 In the control arm, the anesthesia team will prepare a normal saline infusion within a 20 
ml syringe. Patients will receive a normal saline bolus of 50 mg/kg lean body weight 
over 15 minutes, followed by a normal saline infusion at 25 mg/kg/hr when the 
endoscopist begins mucosal incision. Opioids (fentanyl and hydromorphone) will be 
administered for analgesia at the discretion of the anesthesia team. In addition, patients 


 
 
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will receive dexamethasone and ondansetron in the aforementioned doses. After 
surgery, patients will be admitted to the postanesthesia care unit, where opioids 
(fentanyl and hydromorphone) and antiemetics (anesthesia team's discretion) will be 
available for further pain and nausea management.  
6.3 
All study participants will repeat the ESQ in the PACU when the nursing team deems the 
patient's recovery appropriate enough to participate.  
6.4 Postoperative Day 1  
6.4.1 The ESQ and serum calcium/magnesium levels will be reobtained in the morning of 
POD1. 
7 Statistical Plan 
7.1 Sample Size Determination 
Unpublished data at our institution reveals an 60% incidence of esophageal spasm-related pain. 
We assume that magnesium might decrease the incidence of esophageal spasm-related pain by 
30%. Based on this assumption, our calculation show that 45 patients in each group would be 
necessary to acquire statistical significance, with a two-sided α = 0.05 and β = 0.20. Considering 
a 10% dropout rate, 50 patients are necessary for each group.  
7.2 Statistical Methods 
Data will be expressed as means ± SD, number (proportion), relative risk, 95% CI, absolute risk 
reduction, or number needed to treat.  
The primary outcome is the incidence of esophageal spasm-related pain at 0 h postoperatively, 
compared using the chi-square test.  
The secondary outcomes of the incidence of esophageal spasm-related pain at 24 hours 
postoperatively, intraoperative opioid usage, postoperative opioid consumption, and discharge 
opioid prescription will be compared using the chi-square test or Fisher’s exact test as 
appropriate. Continuous variables will be compared using the Mann–Whitney U test. Categorical 
variables will be compared using the chi-square test or Fisher’s exact test as appropriate.  
Post hoc subgroup analyses will be conducted regarding the incidence of esophageal spasm-
related pain according to achalasia type (e.g. type 1, 2, or 3), preoperative H2-receptor antagonist 
use, preoperative proton pump inhibitor use, and intraoperative opioid usage. Post hoc subgroup 
analysis will be further conducted on postoperative magnesium levels and the incidence of 
esophageal spasm-related pain at 24 hours. 
All P values will be two-sided, and a value of P < 0.05 will be considered statistically 
significant.  
Comparisons of postoperative pain between the two groups at time 0 h and time 24 h will be 
analyzed using the Mann–Whitney U test and performed using an adjusted significance level of 
0.0125 (0.05/4) after post hoc analysis using the Bonferroni method.  
Statistical analyses will be performed using R version 4.0.3. 
  


 
 
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7.3 Subject Population(s) for Analysis 
Enrollment will cease when the target sample size is obtained. Analyses will be performed on an 
intention-to-treat basis. All patients who are enrolled and randomly allocated for treatment will 
be included in the analysis. 
8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment follow-
up.  For this study, the study treatment follow-up is defined as 30 days following the last 
administration of study treatment.  
Preexisting Condition 


 
 
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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  The investigator should notify the study 
sponsor of any death or adverse event occurring at any time after a subject has discontinued 
or terminated study participation that may reasonably be related to this study.  The sponsor 
should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that 
has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise 
in this protocol.  Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 


 
 
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• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events 
8.3.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to the study sponsor by telephone within 24 
hours of the event.  A Serious Adverse Event (SAE) form must be completed by the 
investigator and faxed to the study sponsor within 24 hours.  The investigator will keep a 
copy of this SAE form on file at the study site.  Report serious adverse events by phone 
and secure email to: 
 
Richard K. Kim, MD 
347-586-9661 
rkwkim@stanford.edu 
 
At the time of the initial report, the following information should be provided: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was 
discontinued 
• The reason why the event is 
classified as serious 
• Investigator assessment of the 
association between the event and 
study treatment 
 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event in the form of a written narrative.  This should include a copy of the 
completed Serious Adverse Event form, and any other diagnostic information that will 
assist the understanding of the event.  Significant new information on ongoing serious 
adverse events should be provided promptly to the study sponsor 


 
 
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8.3.2 EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the EC/IRB within 10 working days.  Copies of each report and 
documentation of EC/IRB notification and receipt will be kept in the Clinical 
Investigator’s binder. 
8.3.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the drug as soon 
as possible but no later than 7 calendar days from the sponsor’s original receipt of the 
information. Other serious, unexpected adverse events associated with the use of study 
drug shall be reported to the FDA no later than 15 calendar days from the sponsors’ 
original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found to fit 
the criteria for reporting, the study sponsor will submit the adverse event in a written 
report to the FDA as soon as possible, but no later than 15 calendar days from the time 
the determination is made. 
8.4 Unblinding Procedures 
Postoperative magnesium levels evaluated after surgery will reveal those among study 
participants who received magnesium or normal saline. If a study participant experiences a 
serious adverse event postoperatively, including cardiorespiratory arrest, unblinding will occur to 
ensure the patient’s safety by evaluating if the patient would benefit from administration of 
calcium chloride therapy. The patient’s randomization envelope contents will be shared with the 
care team. Documentation of this will be indicated in our data collection spreadsheets. The 
sponsor will be notified of each participant who was unblinded within 24 hours by phone or 
email, followed by a written narrative of the event within 48 hours.   
8.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 


 
 
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• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Attachment ___.  The 
investigator will allocate adequate time for such monitoring activities.  The Investigator will also 


 
 
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ensure that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  See Attachment ___ for a copy of the Subject Informed Consent Form.  This consent 
form will be submitted with the protocol for review and approval by the EC/IRB for the study.  
The formal consent of a subject, using the EC/IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
12 Study Finances 
12.1 Funding Source 
This study is financed solely through divisional and departmental funds from the Division of 
Regional Anesthesia and Acute Pain Medicine of the Department of Anesthesiology, 
Perioperative and Pain Medicine at Stanford University School of Medicine, and the Division of 
Gastroenterology and Hepatology of the Department of Medicine at Stanford University School 
of Medicine.  


 
 
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12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All Stanford University investigators will follow the 
University conflict of interest policy. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
14 References 
1. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM) for esophageal 
achalasia. Endoscopy. 2010;42(4):265-271. 
2. Von Renteln D, Fuchs KH, Fockens P, et al. Peroral endoscopic myotomy for the treatment of 
achalasia: an international prospective multicenter study. Gastroenterology. 
2013;145(2):309-311.e301-303. 
3. Kumbhari V, Tieu AH, Onimaru M, et al. Peroral endoscopic myotomy (POEM) vs 
laparoscopic Heller myotomy (LHM) for the treatment of Type III achalasia in 75 
patients: a multicenter comparative study. Endoscopy international open. 
2015;3(3):E195-201. 
4. Sengupta JN. An overview of esophageal sensory receptors. The American journal of 
medicine. 2000;108 Suppl 4a:87s-89s. 
5. González ES, Bellver VO, Jaime FC, Cortés JA, Gil VG. Opioid-induced Lower Esophageal 
Sphincter Dysfunction. Journal of neurogastroenterology and motility. 2015;21(4):618-
620. 
6. Misra L, Fukami N, Nikolic K, Trentman TL. Peroral endoscopic myotomy: procedural 
complications and pain management for the perioperative clinician. Medical devices 
(Auckland, NZ). 2017;10:53-59. 
7. McRoberts JA, Coutinho SV, Marvizón JC, et al. Role of peripheral N-methyl-D-aspartate 
(NMDA) receptors in visceral nociception in rats. Gastroenterology. 2001;120(7):1737-
1748. 
8. Riemer RK, Heymann MA. Regulation of uterine smooth muscle function during gestation. 
Pediatric research. 1998;44(5):615-627. 
9. Park JY, Hong JH, Kim DH, Yu J, Hwang JH, Kim YK. Magnesium and Bladder Discomfort 
after Transurethral Resection of Bladder Tumor: A Randomized, Double-blind, Placebo-
controlled Study. Anesthesiology. 2020;133(1):64-77. 
10. Herroeder S, Schönherr ME, De Hert SG, Hollmann MW. Magnesium--essentials for 
anesthesiologists. Anesthesiology. 2011;114(4):971-993. 
11. Tramer MR, Schneider J, Marti R-A, Rifat K. Role of Magnesium Sulfate in Postoperative 
Analgesia. Anesthesiology. 1996;84(2):340-347. 


 
 
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12. Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other 
anticonvulsants for women with pre-eclampsia. The Cochrane database of systematic 
reviews. 2010;2010(11):Cd000025. 
13. Kim RK, Hwang JH, Tsui BCH. Utilization of Magnesium in Opioid-Free Anesthesia for 
Peroral Endoscopic Myotomy: A Case Report. A&A Practice. 2020. In Press. 
14. Kwiatek MA, Kiebles JL, Taft TH, et al. Esophageal Symptoms Questionnaire for the 
assessment of dysphagia, globus, and reflux symptoms: initial development and 
validation. Diseases of the Esophagus. 2011;24(8):550-559. 
 
15 Attachments 
• Sample Consent Form 
• Sample Protocol for Magnesium Treatment Group 
• Sample Esophageal Symptoms Questionnaire