Use of Perioperative Pain Blocks In Urological Surgery: A Phase III Randomized Single Blind Single Center Three Arm Non-inferiority Trial
Phase: PHASE3
Conditions: Pain, Postoperative, Nerve Block, Robotic Surgical Procedures
Sponsor: Icahn School of Medicine at Mount Sinai

Use Of Perioperative Pain Blocks In Urological Surgery 
A Phase III Randomized single blind single center three arm non-inferiority trial 
PI: Reza Mehrazin, MD
NCT04426500
Document Date: 1/7/2020

 
 
 
 
 
 
Use Of Perioperative Pain Blocks In Urological Surgery  
A Phase III Randomized single blind single center three arm non-inferiority trial  
 
 
Principal Investigator:  
Reza Mehrazin, MD 
 
 
 
 
Icahn School of Medicine at Mount Sinai 
 
 
 
 
1468 Madison Ave 
 
 
 
 
(Phone) 212 241 3091 
 
 
 
 
Reza.mehrazin@mountsinai.org 
 
Sub-Investigator(s): 
 
Alan Sim 
 
 
 
 
Ashutosh Tewari 
 
 
 
 
Ketan K. Badani 
 
 
 
 
Michael Palese 
 
 
 
 
Jared Winoker 
 
 
 
 
Daniel C. Rosen 
 
 
 
 
Greg Mullen  
 
 
 
 
Alexander Small 
 
 
 
 
Prachee Pathak 
 
 
 
 
Vinayak Wagaskar 
 
 
 
 
Zach Dovey 
 
 
 
 
Alp Tuna Beksac 
 
 
 
 
 
Biostatistician: 
 
Erin Moshier 
 
 
 
 
TCI Biostatistics Shared Resource Facility 
 
 
 
 
Department of Population Health Science & Policy 
 
 
 
 
 
 
Icahn School of Medicine at Mount Sinai 
 
 
 
 
1425 Madison Avenue, 
 
 
 
 
 
 
New York, NY 10029 
 
 
 
 
Phone: 212 659 9208 
 
 
 
 
Email: erin.moshier@mountsinai.org 
 
 
Study Drug: 
 
 
None 
 
IND Number: 
 
 
N/A 
 
IND Holder Name: 
 
N/A 
Funding Source:  
 
 
Initial version:  
 
8/7/18 
 
Amended: 
 
 
01/7/2020 
BDW Approved: 
 
01/14/2019 
Version: 
 
 
1.6 
 
 
 

 
 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................1 
STUDY SCHEMA..............................................................................................................2 
STUDY SUMMARY ..........................................................................................................2 
1.0 
BACKGROUND AND RATIONALE ...................................................................4 
1.1 
Disease Background........................................................................................................ 4 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 4 
1.3 
Other Agents .................................................................................................................... 4 
1.4 
Rationale .......................................................................................................................... 4 
1.5 
Correlative Studies .......................................................................................................... 5 
2.0 
STUDY OBJECTIVES...........................................................................................5 
2.1 
Primary Objectives ........................................................................................................... 5 
2.2 
Secondary Objectives ...................................................................................................... 5 
2.3 
Exploratory Objectives ..................................................................................................... 5 
2.4 
Endpoints ......................................................................................................................... 5 
3.0 
PATIENT ELIGIBILITY .........................................................................................6 
3.1 
Inclusion Criteria .............................................................................................................. 6 
3.2 
Exclusion Criteria ............................................................................................................. 6 
4.0 
TREATMENT PLAN ..............................................................................................6 
4.1 
Treatment Dosage and Administration ............................................................................ 6 
4.2 
Toxicities and Dosing Delays/Dose Modifications ........................................................... 7 
4.3 
Concomitant Medications/Treatments ............................................................................. 7 
4.4 
Other Modalities or Procedures ....................................................................................... 7 
4.5 
Duration of Therapy ......................................................................................................... 7 

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4.6 
Duration of Follow Up ...................................................................................................... 8 
4.7 
Removal of Patients from Protocol Therapy .................................................................... 8 
4.8 
Patient Replacement ....................................................................................................... 8 
5.0 
STUDY PROCEDURES ........................................................................................8 
5.1 
Screening/Baseline Procedures ...................................................................................... 8 
5.2 
Procedures During Treatment ......................................................................................... 9 
5.3 
Follow-up Procedures ...................................................................................................... 9 
5.4 
Time and Events Table .................................................................................................... 9 
5.5 
Removal of Subjects from Study ..................................................................................... 9 
6.0 
Measurement of Effect ......................................................................................10 
6.1 
Antitumor Effect- Solid Tumors ........................................ Error! Bookmark not defined. 
6.2 
Antitumor Effect- Hematologic Tumors ............................ Error! Bookmark not defined. 
6.3 
Safety/tolerability ............................................................. Error! Bookmark not defined. 
7.0 
DRUG INFORMATION .......................................................................................14 
7.1 
Bupivicaine 0.25% ........................................................... Error! Bookmark not defined. 
8.0 
CORRELATIVES/SPECIAL STUDIES ............................................................15 
8.1 
Sample Collection Guidelines .......................................... Error! Bookmark not defined. 
8.2 
Assay Methodology ......................................................... Error! Bookmark not defined. 
8.3 
Specimen Banking ........................................................... Error! Bookmark not defined. 
9.0 
STATISTICAL CONSIDERATIONS .............................................................15 
9.1 
Study Design/Study Endpoints ...................................................................................... 15 
9.2 
Sample Size and Accrual .............................................................................................. 16 
9.3 
Data Analyses Plans...................................................................................................... 18 
10.0 
STUDY MANAGEMENT .................................................................................20 
10.1 
Conflict of Interest .......................................................................................................... 21 

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10.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 21 
10.3 
Data Management and Monitoring/Auditing .................................................................. 21 
10.4 
Adherence to the Protocol ............................................................................................. 22 
10.5 
Amendments to the Protocol ......................................................................................... 23 
10.6 
Record Retention ........................................................................................................... 23 
10.7 
Obligations of Investigators ........................................................................................... 23 

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LIST OF ABBREVIATIONS 
 
TAP 
Transversus abdominis plane 
 
US 
Ultrasound 
UTAP 
ultrasound-guided transversus abdominis plane 
LTAP 
laparoscopic-guided transversus abdominis plane 
SD 
Standard deviation 
VAS 
Visual Analog Scale 
PCAS 
Patient-controlled analgesia system 
NRS 
Numeric Rating Scale 
 
 

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STUDY SCHEMA 
 
 
 
 
 
STUDY SUMMARY 
Title 
Use of perioperative pain blocks in urological surgery 
Short Title 
Use of perioperative pain blocks in urological surgery 
Protocol Number 
IF2449510 
Phase 
Phase III 
Methodology 
Single Blind, Stratified Randomization, Three Arm Non-inferiority 
Study Duration 
One Year  
Study Center(s) 
Single Center 
Objectives 
Primary Objectives 
 
To verify assay sensitivity by demonstrating that UTAP (the active 
reference) is superior than local bupivicaine at controlling 24 hour 
postoperative pain. 
 
To demonstrate non-inferiority of LTAP (the experimental approach) 
to UTAP (the active reference) with respect to 24 hour postoperative 
pain control.  
 
Secondary Objectives  
 
To determine the efficacy of regional blocks on postoperative pain 
control. 
 
To determine whether the LTAP ability of regional blocks to reduces 
narcotic 24 hour cumulative postoperative opioid analgesic 
requirement usage in the perioperative period compared to UTAP 
and Placebo. 
 
To determine the rate of antiemetic medication use during 
postoperative course in UTAP, LTAP, and Placebo groups. 
 
To determine the days to return of bowel function in the UTAP, LTAP, 
and Placebo groups. 
 
To determine the length of hospital stay in the UTAP, LTAP and 
Placebo groups. 
 
To determine the time taken to complete the surgical block, operating 
room time, and surgical time in the UTAP, LTAP and Placebo groups.  
 
To determine whether determine the efficacy of LTAP is non-inferior 
to UTAP ultrasound and laparoscopic regional blocks in obese 
patients. 
 
To determine procedure related complications and adverse events 
including bleeding or injection of anesthetic intravascular 
 
Number of Subjects 
235 (94 LTAP, 94 UTAP, 47 Placebo) 
Diagnosis and Main 
Inclusion Criteria 
Robotic Prostatectomy and Partial nephrectomy patients 
Study Product(s), Dose, 
Route, Regimen 
None 
 
235 Robotic Urologic Surgery Patients 
94 US guided 
blocks 
94 Laparoscopic guided 
blocks 
47 Placebo 
(Local) 

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Duration of administration 
None  
Reference therapy 
None  
Statistical Methodology 
 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Currently, ultrasound-guided transversus abdominis plane (UTAP) blocks 
(regional anesthetic blocks) are being employed for the care of urological surgery 
patients. Local and regional anesthesia is commonly used throughout surgical fields. 
However, ultrasound-guidance can be challenging, particularly in larger, obese patients. 
It is unknown how such techniques compare to laparoscopic-guided blockade, with 
respect to time to perform, learning curve, and postoperative analgesia. The transversus 
abdominis plane lies deep within the abdominal wall, potentially allowing for greater 
ease of access from a laparoscopic approach from within than the ultrasound guided 
percutaneous approach.  
 
Prior randomized studies have been completed comparing UTAP and Placebo. In 
2012 Hosgood et al. compared UTAP and placebo (UTAP w/ saline) in 46 live-donor 
laparoscopic nephrectomy patients (24 UTAP vs. 22 placebo).  Pain control (measured 
using the 0-10 VAS scale) was greater on post-operative day (POD) 1 in patients 
receiving UTAP than in controls, 19 (15) vs. 37 (20) (presented as mean (SD)), 
respectively.1  A similar randomized study in 2014 compared UTAP and placebo (UTAP 
w/saline) in 21 hand assisted laparoscopic nephrectomy patients (10 UTAP vs. 11 
placebo). The study was initially powered for 50 patients but with decreased accrual 
secondary to a surgeon taking a leave of absence during the study period. Pain scores 
were recorded using the 0-10 VAS score.  Postoperatively at 24 hours (median (IQR)) 
UTAP patients demonstrated decreased postoperative pain than placebo patients (1 (0-2) 
vs. 4 (2-6)) on the VAS score, respectively.2  
 
A larger study, done in 2016, with 80 randomized patients undergoing 
retroperitoneal laparoscopic urologic surgery compared UTAP (40) and saline UTAP 
(40). Pain scores were assessed using the 0-100 VAS score scale. On POD1, UTAP 
group had lower pain scores (mean (SD)) of 8.4 (5.9) vs. placebo 28.3 (12.2).3   
 
The most recent study, done in 2018, examined 100 randomized patients 
undergoing robotic-assisted laparoscopic prostatectomies.  Fifty patients were given 
UTAP blocks while the others received no block.  A Numerical Rating Scale (assumed to 
range from 0-10 as not otherwise specified) was used to assess pain.  Patients receiving 
the block at 24 hours had better pain control (mean (SD)) (1.8 (0.82) vs. 3.57 (0.64)).4 
 
While all of these studies point to potential efficacy of UTAP, no data has been 
published to date comparing laparoscopic administration of the TAP block (LTAP) to 
ultrasound guided administration. While these regional anesthetic blocks carry a 
theoretical risk of hematoma or damage to surrounding structures, none of the above 
studies report any complications with the injections.   
1.2 
Study Agent(s) Background and Associated Known Toxicities 
N/A 
1.3 
Other Agents 
N/A 

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1.4 
Rationale 
We aim to prospectively compare Placebo (local administration), UTAP, and LTAP 
blocks in patients undergoing surgery of the prostate and kidney.  We expect to be able to 
equally efficiently administer the blocks using direct visualization and ultrasound 
guidance. We expect that a negative result would obviate the need for longer operative 
time by eliminating the need for the separate ultrasound guided block while a positive 
result would demonstrate the increased utility of preoperative ultrasound blocks in 
managing postoperative pain. 
1.5 
Correlative Studies 
None 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 To verify assay sensitivity by demonstrating that UTAP (the active 
reference) is superior to placebo (local administration) at controlling 24 
hour postoperative pain. 
2.1.2  To demonstrate non-inferiority of LTAP (the experimental approach) to 
UTAP (the active reference) with respect to 24 hour postoperative pain 
control. 
 
2.2 Secondary Objectives  
 
2.2.1 To determine whether LTAP reduces 24 hour cumulative postoperative 
opioid analgesic requirement in the perioperative period compared to 
UTAP and Placebo. 
2.2.2  To determine the rate of antiemetic medication use during postoperative 
course in UTAP, LTAP, and Placebo groups. 
2.2.3 To determine the days to return of bowel function in the UTAP, LTAP, 
and Placebo groups. 
2.2.4 To determine the length of hospital stay in the UTAP, LTAP and Placebo 
groups. 
2.2.4 To determine the time taken to complete the surgical block, operating 
room time, and surgical time in the UTAP, LTAP and Placebo groups.  
2.2.5 To determine whether LTAP is non-inferior to UTAP in obese patients. 
2.2.6 To determine procedure related complications and adverse events 
including bleeding or injection of anesthetic intravascular 
2.3 Exploratory Objectives 
2.4 Endpoints 
Primary:  
The primary endpoint is 24 hour postoperative pain scores recorded using the visual 
analog scale (VAS) described in section 6.1.1.  

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Secondary:  
The secondary endpoints include: 
 The 24-hour cumulative postoperative opioid analgesic requirement described in 
Section 6.2. 
 Use of antiemetic medications during the postoperative course 
 Days to return of bowel function 
 Length of hospital stay 
 Intraoperative time taken to complete surgical blocks 
 Operating Room time 
 Surgical Time 
 Procedure related complications and adverse events including bleeding or injection of 
anesthetic intravascular will be determined according to Common Terminology 
Criteria for Adverse Events (CTCAE v 4.0) 
 
3.0 
PATIENT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and 
exclusion criteria to be registered to the study. Study treatment may not begin until a 
subject is registered. 
3.1 
Inclusion Criteria 
 
3.1.1 Aged 18 years or older 
3.1.2 Undergoing Robotic Assisted Laparoscopic Partial Nephrectomy or 
Robotic Assisted Laparoscopic Prostatectomy 
3.1.3 Ability to understand and the willingness to sign a written informed 
consent. 
3.2 
Exclusion Criteria 
 
3.2.1 Prior Partial Nephrectomy or Subtotal Prostatectomy Surgery (organ 
specific) 
3.2.2 Conversion to open surgery 
3.2.3 History of chronic pain  
3.2.4 History of opiate or alcohol dependence 
3.2.5 Allergies to local anesthetic 
3.2.6 Retroperitoneal surgery 
3.2.7 Single Port Surgery 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 30mL of 0.25% bupivacaine will be administered to bilateral TAP using 
ultrasound or laparoscopic guidance in prostatectomies. 40ml 0.25% 

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bupivacaine unilateral will be administered in nephrectomy patients 
(weight based dosage permitting). Placebo groups will receive direct 
injection of bupivacaine into surgical wounds. 
 
4.1.2 The anesthesia protocol will be at the discretion of the anesthesiologist, 
including premedication, induction of anesthesia, endotracheal intubation, 
and maintenance of sedation and neuromuscular blockade. Similarly, all 
patients will undergo standardized procedure for obtaining 
pneumoperitoneum and insertion of laparoscopic ports.  
 
 
Patients in the UTAP group will receive abdominal wall nerve block by 
the anesthesia team with 30 cc of 0.25% Bupivacaine in bilateral TAP 
regions under ultrasound guidance (percutaneously) after obtaining 
general anesthesia. (unilateral 40ml for nephrectomies) Conversely, 
patients in the LTAP group will undergo bilateral nerve blocks by the 
surgical team under direct vision from an intraabdominal access after 
creating pneumoperitoneum and inserting the laparoscope. Patients in the 
Placebo will receive injection of bupivicaine directly into the surgical 
wound. 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. 
Each patient will be assessed for the development of toxicity according to the 
Time and Events table. Toxicity will be assessed according to the NCI Common 
Toxicity Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments 
should be made according to the system showing the greatest degree of toxicity.  
 
N/A 
4.3 
Concomitant Medications/Treatments 
Pain medication will be given according to the level of pain expressed by the 
patient. 1 tab of Percocet (325-5mg acetaminophen-oxycodone) will be given for 
moderate pain, 2 tabs of Percocet for severe pain. For breakthrough pain 4mg of 
morphine sulfate will be given.  
4.4 
Other Modalities or Procedures 
In the laparoscopic arm, administration of the block will take place through a 
laparoscopic port after pneumoperitoneum has been established.  
4.5 
Duration of Therapy 
The block will be administered in the perioperative period.  Bupivacaine is 
expected to last up to 8 hours.  

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4.6 
Duration of Follow Up 
The patient will be followed while an inpatient postoperatively, as well as at the 
first postop visit at which time the protocol will conclude.  
4.7 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 
5.5 apply. Notify the Principal Investigator, and document the reason for study 
removal and the date the patient was removed in the Case Report Form. The 
patient should be followed-up per protocol.  
4.8 
Patient Replacement 
If any patient expires, is converted to open surgery, or requires a return to the 
operating room they will be removed from the study.  
5.0 
STUDY PROCEDURES 
5.1 Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be 
done only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for 
baseline values even if the studies were done before informed consent was 
obtained. 
 
All screening procedures must be performed within 0 days prior to registration 
unless otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting. 

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5.1.8 Hematology 
5.1.9 Blood draw for correlative studies 
None 
5.1.10 
Serum chemistries 
 
5.1.11 
Pregnancy test (for females of child bearing potential) 
See section 3.1.6.1 for definition. Distinguish between blood and urine 
tests for pregnancy. If pregnancy test is completed at more than one visit, 
it should be detailed for each visit and include which type of test is being 
conducted (urine or blood).  
5.2 
Procedures during Treatment 
5.3 
Follow-up as in 5.4  
5.4 Time and Events Table 
 
 
Pre-
study 
Postop 4-
6 hours 
Postop 12 
hours 
Postop 
24 
hours 
Follow 
up Visit 
VAS Pain 
Assessment 
 
X 
X 
X 
 
Informed 
Consent 
X 
 
 
 
 
History and PE 
X 
 
 
X 
X 
Other required 
labs 
 
X 
 
 
X 
Narcotic Use  
X 
 
 
 
X 
Monitoring for 
Adverse Events 
 
X 
X 
X 
X 
 
5.5 Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 Patient voluntarily withdraws from treatment (follow-up permitted);  
5.5.2 Patient withdraws consent (termination of treatment and follow-up); 
5.5.3 Patient is unable to comply with protocol requirements; 

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6.0 
Measurement of Effect 
6.1 
Pain Scale 
6.1.1 
Definition 
 
Patient solicited pain scores will be assessed using the Visual Analogue Pain 
Scale (VAS-Pain). VAS is a pain rating scale where scores are based on self-
reported measures of symptoms that are recorded with a single handwritten mark 
placed at one point along the length of a 10-cm line that represents a continuum 
between the two ends of the scale—“no pain” on the left end (0 cm) of the scale 
and the “worst pain” on the right end of the scale (10 cm). Measurements from the 
starting point (left end) of the scale to the patients' marks are recorded in 
centimeters and are interpreted as their pain intensity. This will be administered 
by asking the patient to place a line perpendicular to the VAS line at the point that 
represents the pain intensity.  This pain scale is commonly used throughout the 
pain literature and takes <1 minute to complete.  
 
Further explanation may be found here: 
https://onlinelibrary.wiley.com/doi/full/10.1002/acr.20543 
 
6.2 
Cumulative Morphine Equivalent Dose Requirement  
6.2.1 
Definition 
The 24-hour cumulative postoperative opioid analgesic requirement will be 
calculated for each patient. The administered medications over the 24 hour period 
will be recorded in each patient's medication administration record, ensuring that 
all opiates used within the hospital stay are recorded. The only opiates the patients 
on this trial will receive are morphine and/or Percocet (oxycodone). The standard 
of care for these patients is 1 Percocet for moderate pain, 2 for severe pain, and 
4mg of morphine for breakthrough pain. Oxycodone 5mg is considered equivalent 
to morphine 7.5mg. Ideally, only morphine sulfate will be used for breakthrough 
pain. If another opioid is administered, we will convert the dose, using standard 
tables to morphine equivalents 
(https://www.oregonpainguidance.org/opioidmedcalculator). 
6.3         Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of Subjects enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  
 

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All patients experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or death. 
6.3.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
6.3.2 Definition of Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
The CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as 
follows: 
Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of 
the event. 
Fatal (grade 5): the event caused death. 
6.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any 
untoward medical occurrence that: 
6.3.3.1 Results in death. 
If death results from (progression of) the disease, the disease 
should be reported as event (SAE) itself. 

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6.3.3.2 Is life-threatening. 
(The patient was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused 
death if it were more severe). 
6.3.3.3 Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
6.3.3.4 Results in persistent or significant disability or incapacity. 
6.3.3.5 Is a congenital anomaly/birth defect 
6.3.3.6 Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for reporting 
as a serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of 
“Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
6.3.4 Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
 
Step 4:  
Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity of 
the event is not listed in: 
 the current known adverse events listed in the Agent Information Section 
of this protocol; 

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 the drug package insert; 
 the current Investigator’s Brochure 
6.3.5 Reporting Requirements for Adverse Events 
6.3.5.1 Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of 
learning of any serious adverse events, regardless of attribution, 
occurring during the study or within 30 days of the last administration 
of the study drug.  
 
 
The IRB/PPHS must be notified within 5 business days of “any 
unanticipated problems involving risk to subjects or others” 
(UPR/UPIRSO). 
The following events meet the definition of UPR 
a. Any new information that indicates a new or increased risk, 
or safety issue (e.g., interim analysis, safety monitoring 
report, publication, updated sponsor safety report), that 
indicates an unexpected change to the risk/benefit ratio for 
the research. 
b. An investigator brochure, package insert, or device labeling 
is revised to indicate an increase or magnitude of a 
previously known risk, or describes a new risk.  
c. Withdrawal, restriction, or modification of a marketed 
approval of a drug, device, or biologic used in research 
protocol 
d. Protocol deviation or violation that harmed subjects or 
others or that indicated subjects or others might be at 
increased risk of harm. 
e. Complaint of subject that indicates subjects or others might 
be at increased risk of harm or at risk of a new harm 
f. Any breach in confidentiality that may involve risk to the 
subject or others. 
g. Any harm experienced by a subject or other individual that 
in the opinion of the investigator is unexpected and at least 
probably related to the research procedures. 
6.3.5.2 Routine Reporting 
All other adverse events- such as those that are expected, or are 
unlikely or definitely not related to the study participation- are to be 
reported annually as part of regular data submission. 

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6.4 Unblinding Procedures 
Patients will be informed of their method of anesthetic administration if they 
request removal from the trial. 
6.5 Stopping Rules  
7.0 
As none of the prior trials report any complications with TAP procedures, an acceptable 
AE rate would need to be very low i.e. <5% and include theoretical complications such as 
bleeding, or injection of anesthetic intravascularly. Most recent randomized trials3,4 do 
not report any complications with these injections. This trial will be monitored by the 
DSMB on a biannual basis and if a TAP procedure related serious complication occurs 
then accrual will be halted for safety considerations and a DSMB meeting requested. 
8.0 
DRUG INFORMATION 
8.1 
0.25% Bupivacaine 
 
Other names for the drug(s): 
Marcaine 
 
Classification - type of agent: 
Anesthetic 
 
Mode of action: 
Sodium Channel blocker 
 
Storage and stability: Room Temperature 
 
 
Protocol dose: 30x2/40mL  
 
 
Preparation: None 
 
 
Route of administration for this study: Laparoscopic versus percutaneous 
versus local 
 
 
Incompatibilities:  
Allergy to local anesthetic  
 
Availability: Commercially available 
 
 
 
Side effects: Please refer to a complete list of side effects available from the 
manufacturer  
 
 
Nursing implications: 
8.1.1 
Return and Retention of Study Drug 
N/A 
 
7.1.2 Pain scale is asked as part of standard postoperative treatment and is used 
in order to treat patient’s pain.    

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9.0 
CORRELATIVES/SPECIAL STUDIES 
 
N/A 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
This is a single-center, single-blinded, (stratified) randomized placebo-controlled 
three-arm non-inferiority trial with 2:2:1 allocation ratio.  
 
Randomization: 
People who meet eligibility requirements and provide informed consent will be 
randomly allocated to 3 groups to receive either UTAP, LTAP or Placebo with a 
2:2:1 allocation ratio. The allocation sequence will be stratified by type of surgery 
(prostatectomy or partial nephrectomy) using stratified block randomization with 
randomly varying block sizes. Random permuted blocks sizes within stratification 
groups will be used to minimize the chance of selection bias. Investigators will be 
blinded to the size of each block with only the study statistician responsible for 
generating the randomization list knowing this information. A randomization 
service called Sealedenvelope.com available at 
https://www.sealedenvelope.com/simple-randomiser/v1/ will be used for 
allocation concealment to ensure that retrieval of the treatment group assignment 
is only revealed to appropriate team members on a real time basis after each new 
patient has been screened and consented. This service allows for allocation 
concealment that would not be possible if the entire randomization list was made 
available to team members at the beginning of the study. The security and 
integrity of the codes used by Sealedenvelope.com follows the Food and Drug 
Administration (FDA) standards for electronic records and follows the 
International Conference on Harmonisation Good Clinical Practice (ICH GCP) 
guidelines.  
 
The following is an overview of the randomization generation and management 
process. The trial coordinator will create an administrator account with 
sealedenvelope.com. Only the email address given when setting up the trial will 
be registered as the administrator email address and it can be used to change the 
password, delete the trial, or receive a list of all randomizations performed at any 
time. The study statistician will generate the randomization list in 
Sealedenvelope.com. Once the account for the trial has been opened and the 
randomization list generated; any designated user (designated by the account 
administrator) with the single password for the trial can carry out new 
randomizations. Online randomization is achieved by the user completing a form 
with the trial ID and password after providing a patient ID as well as surgical type 
for stratification purposes. An email notification is then generated displaying the 
next sequential treatment group assignment from the randomization list and sent 
to the email address given by the user randomizing and the administrator. Data 
and randomizations held by the sealed envelope randomization system cannot be 

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changed or edited by users. Sealed Envelope will not edit or delete any data held 
by the system. 
Participants will be blinded from the type of block given. Investigators cannot be 
blinded due to the nature of the intervention; however allocation concealment will 
be implemented by use of the sealed envelope service described above. 
 
Blinding: 
Participants will be blinded to group allocation throughout the study. Due to the 
nature of the intervention, it is not possible to blind the investigator to group 
allocation. 
 
 
10.2 
Sample Size and Accrual 
For two-arm non-inferiority trials, issues such as choice of non-inferiority margin, 
constancy assumption, and assay sensitivity have been debated for years, and the 
statistical methodology has been challenged. Three-arm trials including the 
experimental treatment, an active reference treatment and a placebo are 
recommended in the guidelines of the ICH5 and EMEA/CPMP6 as a useful 
approach to the assessment of assay sensitivity providing the trial with internal 
validation. The placebo group affords an opportunity to test for non-inferiority 
directly without use of a fixed pre-specified non-inferiority margin thereby 
making the constancy assumption an irrelevant point and allows for direct testing 
of assay sensitivity by comparing the active reference to the placebo. 
 
The objectives of this trial are two-fold: 1. to verify assay sensitivity by 
demonstrating that UTAP (the active reference) is superior to placebo at 
controlling 24 hour postoperative pain and 2. to demonstrate non-inferiority of 
LTAP (the experimental approach) to UTAP (the active reference) with respect to 
24 hour postoperative pain control. 
 
A step-down hierarchical hypothesis testing approach will be used to test the two 
hypotheses (co-primary endpoints). In the first step, to establish assay sensitivity, 
the alternative hypothesis that UTAP is superior to placebo will be tested: 
 
 
H01: µUTAP ≥ µPlacebo 
 
 
HA1: µUTAP < µPlacebo  
 
 
If and only if we reject the null hypothesis, H01, thereby establishing assay 
sensitivity will we proceed to the second step, to demonstrate non-inferiority of 
LTAP to UTAP.  
 
In the second step, to establish non-inferiority, the alternative hypothesis that 
LTAP is non-inferior to UTAP will be tested using the ‘fractional approach’ 

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introduced by Pigeot I et al (2003) where the effect estimate is based on the ratio 
of the differences in means between LTAP and placebo and UTAP and placebo7 : 
 
   
H02: 
µLTAP−µPlacebo
µUTAP−µPlacebo ≤𝜃 
 
 
HA2: 
µLTAP−µPlacebo
µUTAP−µPlacebo > 𝜃 
 
θ is a pre-specified fixed fraction of active reference effect (retention of effect). 
Koch and Tangen8 provide reasonable regions of θ for non-inferiority testing 
between 0.5 and 0.99.  
 
If the null hypothesis, H02 is rejected for a given θ, we will claim that LTAP (the 
experimental approach) retains more than θx100% efficacy of UTAP (the active 
reference) compared with the placebo, and non-inferiority of LTAP to UTAP will 
be declared. 
 
With a hierarchical step down closed testing procedure (which can occur when 
one has two or more endpoints for which demonstration of an effect on each is 
needed to support regulatory approval), the familywise type I error rate is 
controlled at the level α as there is only one way to succeed, however, the type II 
error rate is inflated thereby decreasing the overall power to show success on both 
endpoints. To account for inflation of the type II error rate, the sample size will be 
calculated to provide an overall power (to detect both endpoints) of 80% by 
setting the power for each hypothesis test at 90% (90%x90%=80%)9 
corresponding to β=0.10.  
 
The statistical methodology for a test problem based on the ratio of (differences 
in) population means was published by Koch et al. (1998).10 The null hypothesis 
H02, referred to above as our second hypothesis, can be rejected, if the lower limit 
of Fieller’s one-sided 100 (1-α)% confidence interval for the ratio of differences 
in means is greater than θ. Pigeot et al. (2003) investigated Fieller’s confidence 
interval and derived formulas for power and hence sample size calculation. The R 
package ‘ThreeArmedTrials’ developed by Tobias Muetze (2016)11 provides a 
collection of functions for statistical inference in three-arm trials using the 
formulas derived by Pigeot et al. for a normally distributed outcome. For a study 
assessing non-inferiority of an experimental approach compared to an active 
reference, tools to: determine optimal sample size allocation among groups 
(UTAP, LTAP, Placebo), compute total (and group) sample size required to detect 
a particular non-inferiority fraction θ at a particular power and alpha level, as well 
as analyze the final data set are provided. For a normally distributed endpoint the 
group means, variances as well as power, alpha, group allocation ratios and non-
inferiority fraction θ need to be specified for computation of sample size. It is 
recommended by Muetze to use estimates of means and variances from a random 
effects meta-analysis of the historical placebo-controlled trials comparing UTAP 
to placebo (presented in Section 1.1). Based on meta-analysis of the four 

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historical placebo-controlled trials with parameters listed in the table below and 
discussed in the introduction, the estimated pooled mean pain scores and (total 
variance) was 3.4 (1.50) in the placebo and 1.49 (1.77) in the UTAP groups. The 
random effects meta-analysis was conducted with the Comprehensive Meta-
Analysis Software Version 3.3.070 (2013).12 
 
Study name 
Treatment 
Mean 
SD 
Variance 
Sample size 
Hosgood (2012) 
Placebo 
3.70 
2.00 
4.00 
22 
Aniskevich (2014) 
Placebo 
4.00 
2.30 
5.29 
11 
Qu (2016) 
Placebo 
2.80 
1.20 
1.44 
40 
Fabrizio (2018) 
Placebo 
3.57 
0.64 
0.41 
50 
Random 
Placebo 
3.40 
 
1.50 
 
Hosgood (2012) 
UTAP 
1.90 
1.50 
2.25 
24 
Aniskevich (2014) 
UTAP 
1.50 
1.20 
1.44 
10 
Qu (2016) 
UTAP 
0.84 
0.59 
0.35 
40 
Fabrizio (2018) 
UTAP 
1.80 
0.82 
0.67 
50 
Random 
UTAP 
1.49 
 
1.77 
 
 
 
In accordance with ICH guidelines on statistical principles for clinical trials a type 
I                 error rate of 0.025 was used for this sample size calculation. Optimal 
sample size allocation was determined to follow a 2:2:1 ratio of 
LTAP:UTAP:Placebo. A total sample size of 235 is required with a 2:2:1 
allocation ratio (94 LTAP, 94 UTAP and 47 Placebo) to achieve 90% power to 
establish non-inferiority of LTAP to UTAP with a fixed fraction of 0.50 (LTAP 
has to achieve more than 50% of the effect of UTAP compared to placebo to 
claim as non-inferior) assuming means and variances of 1.49 (1.77), 1.49 (1.77) 
and 3.40 (1.50) in the LTAP, UTAP and Placebo groups, respectively. This 
sample size calculation was performed using the PowerRet function of the 
‘ThreeArmedTrials’ package with the following parameters: 
power_RET(experiment = c(1.49,1.77), reference = c(1.49,1.77), placebo =c( 
3.4,1.5),Delta = 0.7, sig_level = 0.025, power= 0.9,allocation = c(2,2,1) 
/5,distribution = "normal") 
 
The statistical evaluation will be performed in the first step by a two sample t-test 
for demonstrating superiority of UTAP over placebo. Group sample sizes of 94 
and 47 for UTAP and placebo groups achieve over 99% power to reject the null 
hypothesis of equal or worse means when the population VAS pain score means 
(SDs) in the UTAP and Placebo groups are 1.50 (1.33) and 3.4 (1.22), 
respectively, with a significance level of 0.025 using a one-sided two-sample 
unequal-variance t-test. The calculation was performed with PASS Version 15.   
 
10.3 
Data Analyses Plans 
Analysis of Co-Primary Endpoints: 

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The distribution of VAS pain scores in each group will be examined and assessed 
for normality and homoscedasticity, visually, by generating probability-
probability (P-P) plots, boxplots, stem-and-leaf plots and quantile-quantile (Q-Q) 
plots, and with the Shapiro-Wilk normality test. If necessary, a transformation of 
the data will be made to render appropriate for parametric testing. All analyses 
will be performed on patients who undergo surgery and have a 24 hour VAS pain 
score assessment. Balance on baseline characteristics (including gender, age at 
surgery, height, weight, BMI, and operative time) among the randomized groups 
will be assessed separately for each intervention, using the standardized 
difference. Any variable with an absolute standardized difference >0.52 (i.e., 1.96 
× 1/n1 + 1/n2) for either intervention will be adjusted for in secondary 
analyses.13,14 
 
A step-down hierarchical hypothesis testing approach will be used to test the two 
hypotheses (co-primary endpoints). In the first step, to establish assay sensitivity, 
the alternative hypothesis that the 24-hour post-operative mean VAS pain score in 
the UTAP group is superior to that in the placebo group will be tested by a one-
sided two sample t-test at the 0.025 level of significance (H01: µUTAP ≥ µPlacebo vs. 
HA1: µUTAP < µPlacebo).  
 
If assay sensitivity is demonstrated in the first step by rejecting the null 
hypothesis, H01, we will proceed to the second step of testing for non-inferiority 
of LTAP to UTAP. To establish non-inferiority, the alternative hypothesis that 
LTAP is non-inferior to UTAP will be tested using the ‘fractional approach’ 
introduced by Pigeot et al (2003) where the effect estimate is based on the ratio of 
the differences in means between LTAP and placebo and UTAP and placebo (H02: 
µLTAP−µPlacebo
µUTAP−µPlacebo ≤𝜃: vs. HA2: 
µLTAP−µPlacebo
µUTAP−µPlacebo > 𝜃). 
θ is pre-specified as the fixed fraction of active reference effect (retention of 
effect) of 0.50 (LTAP has to achieve more than 50% of the effect of UTAP 
compared to placebo to claim as non-inferior). The second step will be carried out 
based on the Fieller’s one-sided 97.5% lower confidence bound for the ratio of 
µLTAP −µPlacebo and   µUTAP −µPlacebo. If the lower bound of the 
confidence interval is greater than 50% then the null hypothesis, H02 is rejected 
(LTAP (the experimental approach) retains more than 50% efficacy of UTAP (the 
active reference) then non-inferiority of LTAP to UTAP will be declared. The 
formula for calculating Fieller’s confidence bound is presented in Pigeot et al 
(2003) and will be implemented using The R package ‘ThreeArmedTrials’ 
developed by Tobias Muetze (2016). 
 
Analysis of Secondary Endpoints: 
 
The secondary endpoints of 24-hour cumulative post-operative opioid analgesic 
requirement expressed in morphine equivalent dose (MED), intraoperative time 
taken to complete the surgical block, total operating room time and surgical time 
will be summarized using median, 1st and 3rd quartiles and minimum and 

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20 
maximum values. A Kruskal-Wallis analysis of variance will be used to compare 
the cumulative MED requirement (time to complete the surgical block, total 
operating room time and surgical time) among the three intervention groups with 
all pairwise comparisons made between groups using the Dwass-Steel-Critchlow-
Fligner procedure (Dwass 1960; Steel 1960; Critchlow and Fligner 1991).15–17 
 
The secondary endpoint of antiemetic medication use will be reported as the 
number and percentage of patients that require antiemetic medication during their 
hospital stay within each intervention group. A Chi-Square will be used to 
compare percentages across groups. A log-binomial regression model will be used 
to estimate and compare the prevalence ratios (PR) and corresponding 95% 
confidence intervals (CI) for antiemetic medication use among patients in the 
three intervention groups.  
 
The secondary endpoints, including length of hospital stay and days to return of 
bowel function will be analyzed depending on existence of event censoring and/or 
occurrence of competing events at the time of analysis. Length of hospital stay 
will be calculated as the number of days between the date of surgery and the date 
of discharge from the hospital. Days to return of bowel function will be calculated 
as the number of days between the date of surgery and the date of first bowel 
movement. If the event is observed in all patients and there is no censoring at the 
time of analysis, the mean and standard deviation (if normally distributed) or 
median and IQR (if skewed) will be presented and an analysis of variance (or 
Kruskal-Wallis analysis of variance )will be used to compare means (or 
distributions) among groups, respectively. If the event is not observed in all 
patients (censoring at time of analysis) then the method of Kaplan-Meier will be 
used to estimate the median times to event and corresponding 95% confidence 
intervals will be constructed based on the method of Brookmeyer and Crowley.18 
Comparisons of time to event distributions among intervention groups will be 
made with the log-rank test. If competing events are observed, such as death prior 
to the event of interest, then cumulative incidence functions (CIF) will be 
estimated in a competing risk setting. In these analyses, discharge and first bowel 
movement will be the defining events in each analysis while death without 
discharge or prior bowel movement will be considered the competing event. 
Patients who are alive and have not yet been discharged or have not had return of 
bowel function as of the data analysis cutoff will be censored. CIF comparisons 
among intervention groups will be made with Gray’s test.19 
 
The secondary endpoint of procedure related complications including bleeding or 
injection of anesthetic intravascular will be determined according to Common 
Terminology Criteria for Adverse Events (CTCAE v 4.0) and presented as 
frequency at each grade. A Poisson regression model will be used to test the 
difference in adverse event rates between the two groups. In this model, the 
numerator is the number of adverse events and the denominator (offset) is the 
natural log of the person days followed. 
11.0 
STUDY MANAGEMENT 

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21 
11.1 Conflict of Interest 
 
Any research personnel who have a conflict of interest with this study (patent 
ownership, intellectual property, royalties, or financial gain greater than the 
minimum allowable by their institution, etc.) must declare their conflict of interest 
to the appropriate institutional review bodies. Local institutional conflict of 
interest policies will be followed for all research personnel associated with the 
research project.   
 
10.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
 
11.3 Data Management and Monitoring/Auditing 
 
10.3.1 Elements of a Data and Safety Monitoring Plan 
 
List the name(s) of the individual(s) at the Icahn School of Medicine at Mount 
Sinai (ISMMS) who will be responsible for data and safety monitoring of this 
study. For each individual, indicate their role, name, title, and department 
information.  
 
ISMMS Principal Monitor: (principal investigator) 
 
Last Name: Mehrazin 
First Name: Reza 

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Academic Title: Assistant Professor 
Department: Urology 
Mailing Address: 1468 Madison Ave 
Phone: 212-241-4812 
E-mail: reza.mehrazin@mountsinai.org 
 
Dr. Mehrazin is closely involved in the care of his patients and cares deeply that 
his patients, as well as those of his colleagues, are receiving the best possible care 
regardless of their involvement in a study.   
 
Specific items that will be monitored for safety include adverse events, drop outs, 
and patient concerns. This information will be regularly reviewed biweekly 
during recruitment period. As participant involvement lasts no more than one 
week, this will assure that all subjects are being carefully monitored. Data accrued 
throughout the project will also be evaluated with the same regularity to ensure 
accuracy and completeness in reporting. 
 
Should a temporary or permanent suspension of your study occur, in addition to 
the 
PPHS, the organization’s IRB will be informed. 
 
In addition, a DSMB of senior physicians in Urology and a biostatistician will 
monitor the study on a biannual basis.  
 
11.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.  
11.4.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB approval.  
 
  
11.4.2 Other Reportable New Information and Protocol 
Deviations/Violations 
In accordance with local IRB requirements, the following information must be 
reported within five (5) business days.  
 Non-compliance with federal regulations governing human research or 
with the requirements or determinations of the IRB, or an allegation of such 
non-compliance 
 Failure to follow the protocol due to the action or inaction of the 
investigator or research staff. 
 Breach of confidentiality 

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23 
 Premature suspension or termination of the research by the sponsor or 
investigator.  
 
11.5 
Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator. It should also be noted 
that when an amendment to the protocol substantially alters the study design or 
the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent 
to the IRB for approval prior to implementation.  
11.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
must retain all study documentation pertaining to the conduct of a clinical trial. In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) 
region. In all other cases, study documents should be kept on file until three years 
after the completion and final study report of this investigational study. 
11.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will 

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be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 
 
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