Clinical trial NCT03138967
Conditions: Malignant Neoplasms of Urinary Tract Bladder Cancer
Keywords: Malignant neoplasms of urinary tract Bladder cancer Outpatient bladder procedures Outpatient cystoscopy procedure Transurethral resection of the bladder TURB Rocuronium Rocuronium Bromide Zemuron Sugammadex Neostigmine Glycopyrrolate
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-09-18; Completion date: 2019-11-24
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to determine whether using sugammadex, given with a standard muscle relaxation drug during bladder surgeries, improves anesthesia conditions and recovery time.

During some bladder operations, your muscles must be completely relaxed. Muscle relaxation drugs cause the muscles to relax, including the respiratory muscles, and as a result artificial ventilation is needed to help you breathe. Sugammadex and other standard drugs reverse the effect of the muscle relaxation drugs, allowing you to breathe on your own after the operation.

Study Groups:

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

* If you are in Group 1, you will receive sugammadex to reverse the muscle relaxation.
* If you are in Group 2, you will receive the standard of care (neostigmine/glycopyrrolate) to reverse the muscle relaxation.

You and the surgeon will not know which group you have been assigned to. However, the anesthesiologist and study staff will know.

Length of Study:

You will be on study for up to 1 week after the cystoscopy. If you are unable to have the procedure performed, you may be taken off study early.

This is an investigational study. Sugammadex and neostigmine/glycopyrrolate are all FDA approved and commercially available to reverse muscle relaxation. The comparison of these drugs is investigational.

Up to 50 participants will take part in this study. All will be enrolled at MD Anderson.

Detailed description:
Study Procedures:

Before the cystoscopy, we will collect your basic information and medical history. We will take your vital signs and the anesthesiologist will perform routine assessments. This will take about 30-60 minutes to complete.

Before the cystoscopy, you will be given rocuronium to relax your muscles. After the procedure, you will receive either sugammadex or the standard of care to reverse the relaxation.

After you are extubated (the tube is removed from your throat), we will assess how fast the relaxation drugs the anesthesiologist gave you wear off (stop working), using a small monitoring device that will be attached to your wrist. This is the only research test that will be done right after surgery.

If you are still in the hospital 1 day after the cystoscopy, a member of the staff will ask you the series of questions. If you have been sent home, you will be called and you will complete them by phone.

Researchers will also collect information about your cystoscopy procedure and recovery from your medical record. This collection will continue for up to 1 week after surgery.

Arms: arm 1: Participants to have cystoscopy with bladder tumor resection.

Rocuronium used to induce the neuromuscular blockade and given in a rapid sequence for endotracheal intubation at a dose of 0.45 mg/kg of Ideal Body Weight. If maintenance is needed for continued relaxation then a dose of 0.15 mg/kg of Ideal Body Weight repeated as necessary.

Sugammadex administered as a single bolus, intravenous injection. The amount used is based on the patient's weight. A dose of 4 mg/kg used if recovery has reached at least 1-2 post-tetanic counts (PTC) following Rocuronium induced blockade. arm 2: Participants to have cystoscopy with bladder tumor resection.

Rocuronium used to induce the neuromuscular blockade and given in a rapid sequence for endotracheal intubation at a dose of 0.45 mg/kg of Ideal Body Weight. If maintenance is needed for continued relaxation then a dose of 0.15 mg/kg of Ideal Body Weight repeated as necessary.

Neostigmine/Glycopyrrolate administered as a single bolus, intravenous injection. The amount used is based on the patient's weight. Once T1 is at 10% or greater, a dose of 70 mcg/kg of Neostigmine with 14 mcg/kg Glycopyrrolate administered simultaneously over a period of one minute up to 5 mg.
Interventions: intervention 1: Rocuronium intervention 2: Sugammadex intervention 3: Neostigmine intervention 4: Glycopyrrolate
Intervention descriptions: intervention 1: Experimental: Sugammadex Participants to have cystoscopy with bladder tumor resection. Rocuronium used to induce the neuromuscular blockade and given in a rapid sequence for endotracheal intubation at a dose of 0.45 mg/kg of Ideal Body Weight. If maintenance is needed for continued relaxation then a dose of 0.15 mg/kg of Ideal Body Weight repeated as necessary. intervention 2: Sugammadex administered as a single bolus, intravenous injection. The amount used is based on the patient's weight. A dose of 4 mg/kg used if recovery has reached at least 1-2 post-tetanic counts (PTC) following Rocuronium induced blockade. intervention 3: 70 mcg/kg by vein to reverse the muscle relaxation. intervention 4: 14 mcg/kg by vein to reverse the muscle relaxation.

Protocol documents:
Prot_SAP_000.pdf: 
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      MISP Template: Protocol 
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M
Meerrcckk  IInnvveessttiiggaattoorr  SSttuuddiieess  PPrrooggrraam
m  ((M
MIISSPP))  
PPrroottooccooll  TTeem
mppllaattee  
 
Requirements for Submitting a Full Proposal 
 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
  
A phase IV Investigation of Sugammadex in outpatient urological procedures  
Request Date: 
 
May 18, 2015 
Institution Name 
The University of Texas MD Anderson Cancer Center 
Investigator 
Contact 
Information: 
- Full address  
- Phone No. 
- Fax  No. 
- e-mail address 
Farzin Goravanchi, DO 
1515 Holcombe Blvd, Unit 1243 
Houston, TX 77030-4009 
Phone: 713-291-1163  
Fax: 713-745-2956 
Email: fgoravan@mdanderson.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A phase IV Investigation of Sugammadex in outpatient urological procedures 
2015-1007 
 
Principal Investigator: Dr. Farzin Goravanchi1 
Co-Investigator: Dr. Ashish M. Kamat2 
 
Collaborators: Dr. Alicia M. Kowalski1, Dr. Elizabeth Rebello1, Dr. Jeffrey Cerny1, Dr. Katy E. French1, Dr. 
Linh T. Nguyen1, Dr. Spencer Kee1, Dr. Neema Navai2, Lei Feng3 
 
1 Department of Anesthesiology & Perioperative Medicine 
2 Department of Urology 
3 Department of Biostatistics 
 
 
 
Contents 
2.1  
Objectives & Hypotheses 
2.2  
Background & Rationale, Significance of Selected Topic & Preliminary Data 
2.3  
Study Design 
2.4  
Study Flowchart 
2.5  
Study Procedures 
2.6  
Study Duration 
2.7  
Statistical Analysis and Sample Size Justification 
2.8  
Specific Drug Supply Requirements 
2.9  
Adverse Experience Reporting 
2.10  
Itemized Study Budget 
2.11  
References 
2.12  
Publication Plan 
2.13  
Curriculum Vitae 
2.14  
Protocol Submission for Investigator-Initiated Studies 
 


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Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
 
2.1.  List Objectives  
 
2.1.1  Primary: To determine if Sugammadex can improve muscle recovery time, 
measured  by time from administration of neuromuscular blockade reversal to train-
of-four ratio of 0.9, for outpatient bladder procedures. 
 
2.1.2  Secondary: To determine if Sugammadex can improve post-operative 
complications for outpatient bladder procedures; such as bladder perforation, 
nausea, vomiting, post-operative intubation and hospital admittance secondary to 
respiratory complications. 
 
To determine if Sugammadex can improve overall recovery time, measured by time 
from end of surgery to train-of-four of 0.9, for outpatient bladder procedures. 
 
2.1.3  List the clinical hypotheses.  
Using Sugammadex in conjunction with a standard paralytic agent during bladder 
surgeries improves anesthesia conditions and recovery time. 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
 
Background: 
Bladder cancer is the 8th most common cancer in the US affecting 563,000 men and 
women annually. There are approximately 72,000 new cases diagnosed each year 
and roughly 16,000 patients die each year as a result of bladder cancer [1].  Many of 
these patients are diagnosed with the cancer confined to the bladder. These patients 
often come to the operating room for an initial screening, biopsy(s), and/or 
resection(s). They require frequent tumor resections which may have invaded the 
bladder muscle wall. This would require a deep level of anesthesia with muscle 
relaxation for safe and adequate tumor resection. This study will evaluate the use of 
a unique muscle relaxation reversal agent and its effect on the surgical condition, 
anesthetic provided, decrease of provider variability, as well as hospital utilization. 
 
Sugammadex, a selective relaxant binding agent, is used to speed up recovery of 
muscles after anesthesia. During some operations, your muscles must be completely 
relaxed.  This is often required by the surgeon in order to perform the operation. 
Muscle relaxation medications cause the muscles to relax; the general anesthetic 
includes muscle relaxants such as Esmeron and Norcuron. Since respiratory 
muscles also become relaxed, artificial ventilation is required. Sugammadex 
reverses the effect of the muscle relaxation medications. After the operation 
spontaneous breathing is achieved [2]. 
 
This study will involve the use of Sugammadex which was recently approved by the 
FDA.  Sugammadex has been used in Europe as Bridion since 2008 and the specific 
drug information has been attached as an appendix item. [3] 
 
Rationale for this Study 
Bladder cancer affects about 72,000 patients each year and the first step for the 
diagnosis and treatment involves a transurethral resection of the bladder (TURB) 
tumor. This is a highly skilled procedure due to the complexity of resecting a tumor 
from within the lumen of a thin, hollow organ: the bladder [4]. 
Subclinical perforation of the bladder with extravasation of urine has been reported in 


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as many as 58% of cases, when evaluation with immediate post TURB cystogram is 
used [5]. Clinically detected perforation of the bladder has been reported in up to 
10% of cases and this can be a serious complication resulting in leakage and 
systemic absorption of irrigation fluid and by bleeding, vascular or bowel injury [6].  
While extraperitoneal perforations can often be managed conservatively, large, 
intraperitoneal bladder perforations may require immediate treatment to prevent 
complications. In addition, perforations have been linked to reports suggesting that 
extravesical growth of tumor can occur in some patients when this happens [7]. 
 
There are approximately 1050 surgical cases of cystoscopy performed per year at 
the UT MD Anderson Cancer Center operating rooms. These procedures are 
performed on patients who have a history of bladder cancer or other type of 
abdominal cancer which has affected the bladder. Due to a large number of 
anesthesia providers, there is a large variability of intra-operative management of 
these patients. The surgeon will often ask for a short period of complete muscle 
relaxation when electro cautery is used, in order to decrease spontaneous 
movement. 
 
Because 
of 
the 
long 
duration 
of 
reversal 
with 
neostigmine/glycopyrrolate, patients are usually given lower doses of muscle 
relaxant, which increases the risk for bladder perforation. By using Sugammadex, 
the anesthesiologist expects to improve the surgical condition by providing a deeper 
level of muscle relaxation with a standardized dose of muscle relaxant. A more 
predictable reversal of muscle relaxation will be provided, while minimizing post-
operative side effects. Neostigmine/glycopyrrolate usually is not administered 
immediately after the end of surgery and, for a profound block, takes a considerable 
amount of time for reversal. Sugammadex may be administered much earlier and is 
expected to complete the reversal in several minutes. There has not been a study 
which provides an outcome in outpatient surgical or urological patients. Due to the 
high comorbidity of this population, maintenance of patient safety needs to be 
studied.  Therefore, this study will focus on the use of Sugammadex as a reversal 
agent for muscle relaxation during bladder surgery to improve the patient’s ease of 
recovery [8,9]. 
 
Rationale for Endpoints  
Patients who receive muscle relaxation reversal by use of neostigmine/ 
glycopyrrolate experience more post-operative nausea and vomiting than patients 
who don’t receive neostigmine. Patients also experience oral secretion and 
salivation, bradycardia, and tachycardia. These anesthetic complications may 
prolong PACU stay, prolong recovery, or result in hospital admission; effecting and 
increasing hospital utilization [10].  Variability of response to Rocuronium as 
measured by quality and duration of muscle relaxation has resulted in a variability of 
doses given during outpatient surgery. By use of a standard dose of Rocuronium, an 
improved recovery should be expected by use of Sugammadex. 
 
Train of Four 
 
An Acceleromyograph (e.g. TOF-Watch SX) is a neuromuscular monitoring device 
which can objectively measure neuromuscular blockade reversal. Electrodes are 
placed over the ulnar nerve near the wrist, and a transducer is placed on the thumb. 
The ulnar nerve is stimulated and the response of the adductor pollicis muscle is 
recorded. 
 
The train-of-four (TOF) is a method that assesses the depth of neuromuscular 
blockade. In 15-second cycles, with a 10-second gap between cycles, the ulnar 
nerve is stimulated four times within two seconds and the twitch responses (T1-T4) 


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are recorded. The height of T4 relative to T1 is known as the TOF ratio (TOFR). After 
administration of neuromuscular blockade, there is a fade in the latter twitch 
responses. As the blockade deepens, the nerve stimulation will stop producing 
responses, starting with T4. The loss of T4, T3, T2, and T1 represents a blockade of 
80%, 85%, 90%, and 100% respectively. Once there are no twitch responses, the 
device switches to post-tetanic count (PTC) mode automatically. Once in PTC mode, 
the nerve is stimulated at 1 Hz over fifteen seconds. If there are no responses, there 
is five seconds of tetanic stimulation at 50 Hz. After a pause of three seconds, there 
are stimulations at 1 Hz over fifteen seconds. The number of responses during this 
fifteen second cycle constitutes the PTC. After reversal of neuromuscular blockade, 
the PTC will gradually increase. Once there are more than five consecutive 
responses, the device automatically goes back to TOF mode [11]. Once TOFR 
reaches 0.9, the patient has recovered from the neuromuscular blockade and may 
be extubated. TOFR of 0.9 is considered the standard for neuromuscular blockade 
reversal, greatly reducing the risk of residual blockade [12]. 
 
2.3 Study Design 
 
 
This is a Phase IV, single center, open-label, randomized, parallel study in patients 
scheduled for outpatient bladder surgery at The University of Texas MD Anderson 
Cancer Center - Mays Clinic (ACB).  Patients will be treated with Sugammadex 
administered 
intravenously 
at 
4 
mg/kg 
for 
deep 
muscle 
relaxation 
or 
Neostigmine/Glycopyrrolate, which will be administered intravenously at 70 mcg/kg 
of neostigmine with 14 mcg/kg glycopyrrolate following Rocuronium induced 
blockade as per manufacturer package insert. 
 
Patients who have been scheduled for cystoscopy with suspected diagnosis of 
bladder tumor. In this Phase IV study, up to approximately 50 eligible patients will be 
enrolled.  It is anticipated that full accrual to this study will take approximately 10 
months. 
 
Inclusion  Criteria 
 
Is scheduled to undergo cystoscopy with bladder tumor resection procedure 
under general anesthesia requiring neuromuscular relaxation using 
Rocuronium bromide to secure airway and requiring neuromuscular reversal 
at The University of Texas MD Anderson Cancer Center – Mays Clinic (ACB-
outpatient)   
 
Male or Females who are >= 18 years of age 
 
Classified by the American Society of Anesthesiologists (ASA) as Class I-IV 
 
Candidate for use of laryngeal mask airway (LMA) 
 
Able to give consent 
 
Exclusion Criteria 
 
severe renal impairment as measured by eGFR less than 30 per institutional 
laboratory. 
 
Females who are pregnant or might be pregnant or are breast-feeding  
 
Females who have been diagnosed with breast cancer and currently taking 
Toremifene 
 
is known or suspected to have significant hepatic dysfunction, with AST & 
ALT 3 times above UNL per institutional laboratory. 
 
is known or suspected to have a (family) history of malignant hyperthermia 
 
is known or suspected to have an allergy to opioids, muscle relaxants or 
other medications used during general anesthesia 
 
is known or suspected to have neuromuscular disorders (ex: myasthenia 
gravis). 
 


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Subject Recruitment Plans and Consent Process 
 
Recruitment Plans: 
All patients who are scheduled to have an outpatient cystoscopy procedure including 
transurethral resection of the bladder (TURB) at the outpatient Mays Clinic Surgical 
Center in Houston Texas will be pre-screened to see if they meet the enrollment 
criteria.  If so, the patient will be approached by a member of the research study 
team.   
 
Informed Consent: 
Patients who are eligible to participate in the study will be approached by a member 
of the study team and informed about the trial.  Patients will be encouraged to 
discuss participation in the study with their family and given the opportunity to have 
any questions answered before written informed consent is sought. 
 
Randomization Assignments and Results with be mailed out to the subjects after 
publication.  
 
Randomization Method  
 
Once eligibility criteria have been confirmed patients will be randomized (1:1) to one 
of two groups using an automated on-line randomization scheme.  After assignment 
to one of the two treatment groups, a unique study number will be assigned.  Only 
one unique study number will be assigned per patient. 
 
This will be a double-blind study in that the Surgeon and patient will be blinded to the 
randomization. Note: The Anesthesiologist and study personnel will not be blinded. 
 
Risks and Benefits 
 
The risks to participating in this study are minimal.  The patient may experience 
increased bradycardia.  Adequate safety measures, vigilance, and awareness will be 
taken by the anesthesia team.   By participating in this study the patient is not 
exposed to any additional risks than they would otherwise experience under the 
standard practice for this procedure.   
 
The benefits to utilizing Sugammadex as a reversal agent for a neuromuscular 
blockade may include improved quality of recovery and decreased time for recovery 
when compared to the current (Neostigmine/Glycopyrrolate). 
 
Duration of Study or Criteria for Terminating Participation in the Study 
 
Patients will be removed from study if the patient elects to withdraw from the study 
prior to general anesthesia.  The reason for study removal and the date the patient 
was removed must be documented in the Case Report Form.  Additionally, if there is 
a change in the patient’s health status or if the patient requires an alternative 
anesthesia plan that would contradict the use of muscle relaxation, such as regional 
anesthesia or sedation. 
 
Data Collection and Follow-up for Withdrawn Subjects 
 
Data that has already been collected prior to notifying the PI of the patient’s wish to 
withdraw from the study will remain in the study database. No additional information 
will be collected past this time point.  
 


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STUDY DRUG 
 
Rationale for Dose Regimen 
 
The dose used for the following medications are the standard doses from the 
manufacturers: Sugammadex, Rocuronium, Neostigmine/Glycopyrrolate. 
 
Typical Dosing: 
Rocuronium will be used to induce the neuromuscular blockade and will be given in 
a rapid sequence for endotracheal intubation at a dose of 0.45 mg/kg of Ideal Body 
Weight. If maintenance is needed for continued relaxation then a dose of 0.15 mg/kg 
of Ideal Body Weight will be repeated as necessary. 
 
Treatment Group: Sugammadex will be administered as a single bolus, 
intravenous injection. The amount used is based on the patient’s weight.  A dose 
of 4 mg/kg will be used if recovery has reached at least 1-2 post-tetanic counts 
(PTC) following Rocuronium induced blockade.   
 
Standard of Care: Neostigmine/Glycopyrrolate will be administered as a single 
bolus, intravenous injection.  The amount used is based on the patient’s weight. 
Once T1 is at 10% or greater, a dose of 70mcg/kg of neostigmine with 14 mcg/kg 
glycopyrrolate will be administered simultaneously over a period of one minute 
up to 5 mg.  
 
2.4 Study Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Operative 
Screen for patient eligibility: 
Patients undergoing cystoscopy with bladder resection procedure under GA + 
neuromuscular relaxation using Rocuronium and requires reversal with Sugammadex. 
Age ≥18  
ASA physical status I-IV 
LMA candidate 
Outpatient – Mays Clinic (ACB)
Informed Consent 
Preoperative Data Collection  
Randomization – Day of Surgery
Intra-Operative 
Induction of GA and secure airway with Rocuronium bromide 
0.45 of IBW mg/kg IV  
Neuromuscular Reversal: 
Sugammadex 
4.0 mg/kg (profound blockade or 1-2 PTC) 
 
Intra-operative Data Collection 
Standard of Care Reversal:  
Neostigmine / Glycopyrrolate 
70 mcg/kg of neostigmine  
+ 14 mcg/kg glycopyrrolate, at T1 > 10% 


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2.5 Study 
Procedures 
 
Screening Period  
 
Screening period will be defined as the time up until consent has been signed. 
Confirmation of diagnosis of cancer or abdominal disease either in the electronic 
medical records or prior to scheduling of surgery and enrollment into the study. 
Inclusion/Exclusion criteria will be confirmed. 
 
Baseline Period (Perioperative) 
 
Baseline will be defined as the period after consent has been received and will 
include the perioperative period prior to surgery.  Randomization will occur during 
this time frame.  
Recordings: 
 
Patient demographics and medical history 
 
Height, Weight, BMI, Age, and Temperature 
 
ASA Classification 
 
Treatment Period (Intraoperative) 
 
This will be a parallel study.  Anesthesia will be provided as standard routine practice 
for cystoscopy with bladder tumor resection. Patient will receive General Anesthesia; 
they will be induced with intravenous Propofol and Fentanyl, Rocuronium will be 
administered as relaxant agent during Induction. They will be maintained with volatile 
agents and Fentanyl. Neuromuscular blockage will be monitored with an 
Acceleromyograph.   Neuromuscular reversal will be performed using either 
treatment group; Sugammadex or Neostigmine/Glycopyrrolate at the conclusion of 
surgery. Patient will be extubated after recovery from General Anesthesia and a 
TOFR of 0.9 has been reached.   
 
Treatment will be defined as the intra-operative period until the conclusion of the 
surgical procedure or prior to patient being moved to PACU. 
Recordings: 
 
Duration of Reversal (administration of reversal agent to TOFR 0.9) 
 
Time of extubation 
 
Duration of surgery 
 
Doses for neuromuscular block and reversal (Rocuronium, Sugammadex, 
and Neostigmine/Glycopyrrolate) 
 
 
Post-Operative 
PACU Data Collection: 
Ease of Recovery  
Postoperative Complications 
Follow-Up Data Collection 
Short-term follow up on Day 1 
Phone follow up on Day 7 (1 week) 
Follow-Up 


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Recovery Period - PACU 
 
Recovery will be defined as the time the patient is sent to PACU until he/she is 
discharged.  
Recordings: 
 
Whether anti-nausea meds were given as a parameter of ease of recovery 
 
Length of Time for patient to meet PACU discharge criteria  
 
Post-op complications will be documented based on event occurrence  
 
Follow Up Period  
 
Patients will be followed for 1 day post discharge from PACU or until death, 
whichever occurs first. Follow up will be face-to-face if the patient is still in the 
hospital; otherwise it will be conducted via telephone after the patient has been 
discharged.  Upon discharge from the hospital, the patient will be sent home with 
diagrams necessary to complete the assessments over the phone. A final Phone 
Follow-Up will be conducted a week post procedure, on Day 7. 
 
Recordings: 
 
Post-op complications such as bladder perforation, nausea, vomiting, post-
operative intubation and hospital admittance secondary to respiratory 
complications, will be documented based on event occurrence. 
 
Patient re-admission within one week post procedure for any other cause. 
 
2.6 Study Duration 
 
Patients will be followed for 1 day post discharge from PACU or until death, 
whichever occurs first, then on Day 7 for a final follow up. Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event. 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
 
Sample Size Justification 
 
This is a randomized, double-blinded trial designed to evaluate the reversal effect of 
the muscle relaxation medications using Sugammadex comparing to the standard of 
care (SOC) using Neostigmine/Glycopyrrolate on patients undergoing cystoscopy 
with bladder tumor resection procedure.  The primary objective is to determine if 
Sugammadex can improve muscle recovery comparing to the SOC, measured by 
time from administration of neuromuscular blockade reversal to train-of-four ratio of 
0.9.  Fifty-six patients will be randomized with a 1:1 ratio to receive either 
Sugammadex or Neostigmine/Glycopyrrolate.  
 
With a sample size of 25 in each group, the trial will have 80% power to detect an 
effect size of 0.809 in mean of the time from administration of neuromuscular 
blockade 
reversal 
to 
train-of-four 
ratio 
of 
0.9 
between 
the 
Neostigmine/Glycopyrrolate arm and Sugammadex arm.  The two-sided Type I error 
rate was 0.05, and the test statistic used was the two group t-test (nQuery Advisor 
7.0) Considering that 10% of the enrolled patients will be inevaluable, the trial need 
to enroll a total of 56 patients.  Patients are considered to be inevaluable if they 
have protocol violations or do not have the measurement on the primary endpoint. 
 
Patients will be randomized through CORe at MDACC.  There will not be any 
stratification factors. 


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Analysis Plans 
 
The analysis will be performed on evaluable patients.  Patients are considered to be 
evaluable if they don’t have any protocol violations and have the measurement on 
the primary endpoint. Patients’ demographic information at baseline will be analyzed, 
with data summarized in tables listing the number of subjects per treatment arm in 
order to assess comparability. We will summarize the distribution of time from 
administration of neuromuscular blockade reversal to train-of-four ratio of 0.9 and 
overall recovery time by each treatment. We will use the student t-test or the 
Wilcoxon rank sum test to compare continuous variables between two different 
patient groups.  The Fisher’s exact test will be applied to assess the association 
between two categorical variables.  Linear regression may be utilized to assess the 
effects of patient prognostic factors on time from administration of neuromuscular 
blockade reversal to train-of-four ratio of 0.9. 
 
Toxicity data will be summarized by frequency tables.  The association between the 
types and severity of toxicity and the treatment groups will be evaluated.  No formal 
statistical testing will be performed on these summary data. 
 
The dosage of Rocuronium has been reduced from 0.6 mg/kg to 0.45mg/kg after 
enrolling two patients (one on each treatment arm). The Rocuronium dosage may 
impact the evaluation of the primary endpoint which is the time of recovery from 
neuromuscular block.  We will perform a sensitivity analysis to evaluate the impact of 
including these two patients in the analysis. 
 
2.8 Specific Drug 
Supply 
Requirements  
 
Patient or insurance provider is responsible for all costs of surgery, including 
anesthesia and hospitalization. This includes all drugs involved in the study including 
Rocuronium, which is used as a neuromuscular blocking agent. 
 
The study/treatment drugs Sugammadex, Neostigmine and Glycopyrrolate will be 
covered by the Sponsor and not billed to the patient.  Other drugs utilized in this 
study will be used as per standard routine care.  The site institution’s research 
pharmacy department will maintain study supplies and record documentation.  
Additionally, they will also be responsible for the destruction of the supplies at the 
end of the study as per ICH/GCP guidelines, local regulations, and institutional 
policies.  Supply should be shipped in marked vials to allow for non-blinded 
administration by the anesthesiologist.  
 
Note: At conclusion of the study or upon drug expiration, the Merck GRS will be 
responsible for issuing a Drug Disposition Letter to the investigator for US based 
studies.   
 
2.9 Adverse 
Experience 
Reporting 
 
We will follow specific requirements outlined in the study agreement for adverse 
experience reporting.  For clinical protocols, specific adverse experience reporting 
requirements must be identified in the protocol if the Model Study Agreement is not 
used (in general, this would apply to non-US. studies whose local requirements may 
prohibit the use of the agreement). 
 


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2.10 Itemized Study 
Budget  
 
This is a preliminary study budget that represents an initial cost estimate based on 
the proposed protocol and cannot be finalized until a final protocol has been 
submitted to the IRB.  This is based on an anticipated enrollment of 50 patients.  We 
have budgeted on the high side.  However, when the statistical plan has been 
completed and the sample size confirmed, the budget will be adjusted accordingly. 
 
Please note there are fixed costs that MD Anderson charges for all prospective 
studies and these cannot be negotiated.  A description of these costs is listed in the 
justification below.  
 
Direct 
Indirect (25%) 
IRB Fee: Fixed Cost 
 $         5,000  
n/a  
Translation of Informed Consent Document 
$         1,000 
n/a 
Investigational Pharmacy Admin Fee: Fixed Cost 
 $         1,500  
n/a 
Department Administration Fee 
 $         3,000  
n/a 
CORe/PDMS User Fee: Fixed rate $250/patient 
 $       12,500  
 $      3,125  
Investigational Pharmacy Fee: Fixed rate 
$150/patient 
 $         7,500  
 $      1,875  
Data Manager (3% effort) 
 $         2,184  
 $         546  
Study Coordinators (1 @ 50% effort each) 
 $       30,913  
 $      7,728  
Statistician (3% effort) 
 $         3,450  
 $         863  
Principal Investigator (1% effort) 
 $         4,278 
 $      1,070 
Fringe (28%) 
 $       11,431  
 $      2,858  
SOC drug cost: Neostigmine/Glycopyrrolate  
$         2,665 
n/a 
Office Supplies 
$            500 
 $          125  
Subtotal  $       85,921 
 $    18,189 
Total Project  $     104,110 
Per Patient Cost  $    2,082.21  
 
Budget Justification 
 
IRB Fee:  This is a fixed cost for the submission of the protocol to the IRB.  This fee 
also includes the initial translation of the informed consent document into any 
language.  Depending on the complexity of the ICD, an additional charge may be 
required but is not anticipated. There will not be any additional IRB fees for 
amendments or protocol revisions.  
Investigational Pharmacy Administration Fee:  This is a required institutional fee for 
the start-up of investigational pharmacy.  This is a fixed rate at $1,500 per study.  An 
additional per patient fee is required and described below. 
Department Administration Fee:  This is reimbursement for the protocol review, 
entry, and management of the study prior to study activation.  This is not a fixed rate. 
PDMS/CORe User Fee: Required institutional fee for patient registration in the 
Protocol Data Management System (PDMS), which is a computer-based information 


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management system that maintains and processes patient information through data 
collection and management, tracking mechanisms and analysis; IRB mandates the 
use of PDMS for regulatory compliance issues, and since the PDMS system is 
supported by our NCI core grant. This is a fixed rate of $250 per patient registration.  
Investigational Pharmacy Fee:  This is a required institutional fee for each patient 
enrolled in the study.  Investigational Pharmacy will be responsible for randomizing 
each patient to the treatment arm and maintain all compliance documentation 
required per federal guidelines regarding shipping, disposal, returning of study drug 
to sponsor, etc.  This is a fixed rate of $150 per patient.  
 
2.11 References 
 
1.   American Society of Cancer. What are the key statistics about bladder cancer? 
Bladder Cancer 2015; 
http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-
statistics, 2015. 
2. Merck Sharp & Dohme Limited. Bridion 100 mg/ml solution for injection. 
European Medicines Agency 2014; https://www.medicines.org.uk/emc/print-
document?documentId=21299. 
3.   Merck Sharp & Dohme (Australia) Pty Limited. Bridion Product Compound 2008; 
Available at: 
http://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkpbridi. 
4.   Golan S, Baniel J, Lask D, Livne PM, Yossepowitch O. Transurethral resection of 
bladder tumour complicated by perforation requiring open surgical repair - clinical 
characteristics and oncological outcomes. BJU Int. 2011;107(7):1065-1068. 
5.   Balbay MD, Cimentepe E, Unsal A, Bayrak O, Koc A, Akbulut Z. The actual 
incidence of bladder perforation following transurethral bladder surgery. J Urol. 
2005;174(6):2260-2262, discussion 2262-2263. 
6.   Collado A, Chechile GE, Salvador J, Vicente J. Early complications of 
endoscopic treatment for superficial bladder tumors. J Urol. 2000;164(5):1529-
1532. 
7.   Herkommer K, Hofer C, Gschwend JE, Kron M, Treiber U. Gender and body 
mass index as risk factors for bladder perforation during primary transurethral 
resection of bladder tumors. J Urol. 2012;187(5):1566-1570. 
8.   Castro DS, Jr., Leao P, Borges S, Gomes L, Pacheco M, Figueiredo P. 
Sugammadex reduces postoperative pain after laparoscopic bariatric surgery: a 
randomized trial. Surgical laparoscopy, endoscopy & percutaneous techniques. 
2014;24(5):420-423. 
9.   Caldwell J. Reversal of residual neuromuscular block with neostigmine at one to 
four hours after a single intubating dose of vecuronium. Anesthesia and 
analgesia. 1995;80(6):1168-1174. 
10.  an TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the 
management of postoperative nausea and vomiting. Anesthesia and analgesia. 
2014;118(1):85-113. 
11. Organon (Ireland) Ltd., Drynam Road, Swords, Co. Dublin, Ireland, TOF-Watch 
Operator Manual, 
http://www.mainlinemedical.com/mm/manuals/bluestar_tof_watch_instruction_m
anual.pdf 
12. Fuchs-Buder, T., Claudius, C., Skovgaard, L. T., Eriksson, L. I., Mirakhur, R. K. 
and Viby-Mogensen, J. (2007), Good clinical research practice in 
pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm 
revision. Acta Anaesthesiologica Scandinavica, 51: 789–808. doi: 
10.1111/j.1399-6576.2007.01352.x 
13. Royse CF, Newman S, Chung F, et al. Development and feasibility of a scale to 
assess postoperative recovery: the post-operative quality recovery scale. 
Anesthesiology. 2010;113(4):892-905. 


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2.12 Publication 
Plan 
Generally, a publication plan is discussed between the investigator and Merck /MSD 
during time when the protocol is under development.  Details of the publication and 
the obligations to Merck/MSD are outlined in the study agreement.   
 
There are plans to publish data and findings.   
 
Additionally, the PI will present the data at one of the following conferences: ASA, 
SAMBA, Texas Society of Anesthesiology. 
2.13 Curriculum 
Vitae 
 
Investigator should provide curriculum vitae in English and a listing of references to 
Merck/MSD. 
2.14 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.