Continuous Post-operative Lidocaine Infusion Following Major Reconstructive Spine Surgery in the Elderly to Minimize Delirium and Opiate Use: A Randomized Control Trial
Phase: PHASE3
Conditions: Postoperative Delirium, Postoperative Pain, Spinal Fusion
Sponsor: University of California, San Francisco

LIMPP (Continuous Post-operative Lidocaine Infusion 
Following Major Reconstructive Spine Surgery in the Elderly to 
Minimize Delirium and Opiate Use: A Randomized Control 
Trial) 
 
 
 A randomized controlled trial to reduce postoperative delirium and opiate 
use through 48-hour postoperative lidocaine infusion in older surgical 
patients undergoing spinal surgery 
 
 
Clinical trial number and registry URL: [Pending] 
 
 
 
Version date: 03/31/2021 
 
 
 
Principal Investigator: 
Marc A. Buren, MD, MS 
Assistant Professor 
Department of Anesthesia and Perioperative Care 
University of California, San Francisco 
521 Parnassus Avenue, Room 0104, Box 4319 
San Francisco, CA 94143 
E-mail: marc.buren@ucsf.edu 
 
 
 

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University of California, San Francisco 
PROTOCOL TEMPLATE 
 
Instructions to User: 
1. Sections and text that are in regular font and that have not been 
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review the language carefully to make sure that it is accurate for your study. 
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5. When your protocol is complete, review it to ensure that all highlighting and 
italics have been removed. 
 
 
 
This template protocol is based upon work supported in 2007 by the Cystic Fibrosis Foundation for the 
Therapeutics Development Network (TDN) and used with TDN Coordinating Center permission. 
 
 

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MARC BUREN 
Clinical Research Protocol 
A CLINICAL TRIAL OF POSTOPERATIVE LIDOCAINE INFUSION ON 
COGNITION AND OPIOID CONSUMPTION FOLLOWING MAJOR SPINE 
SURGERY 
Protocol Number: 
20-32383 
Version Date: 
11/23/2020 
Investigational Product: 
Lidocaine 
IND Number: 
N/A 
Development Phase: 
2 
Sponsor: 
Marc Buren 
Box 0648 
Department of Anesthesia & Perioperative Care 
University of California, San Francisco 
521 Parnassus Avenue, San Francisco, CA 94143-0730 
Funding Organization: 
N/A 
Principal Investigator: 
Name:  
Marc Buren 
Telephone: 
314-374-9427 
Fax: 
 
 
E-mail: 
marc.buren@ucsf.edu 
Medical Monitor: 
Name:  
 
Telephone: 
 
Fax: 
 
 
E-mail: 
 
Coordinating Center: 
If applicable 
 
Approval: 
 
 
11/23/2020 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Dr. Marc Buren with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide 
by the terms of this protocol. 
 
Protocol Number:  20-32383 
 
Protocol Title:  Postoperative Lidocaine after Major Spine Surgery 
 
Protocol Date:  TBD 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 

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TABLE OF CONTENTS 
 
1 
BACKGROUND ................................................................................................................. 4 
1.1 
Overview of Non-Clinical Studies .............................................................................. 12 
1.2 
Overview of Clinical Studies ...................................................................................... 12 
2 
STUDY RATIONALE ........................................................................................................ 12 
2.1 
Risk / Benefit Assessment ........................................................................................... 13 
3 
STUDY OBJECTIVES ....................................................................................................... 14 
3.1 
Primary Objective ....................................................................................................... 14 
3.2 
Secondary Objectives .................................................................................................. 14 
4 
STUDY DESIGN ................................................................................................................. 14 
4.1 
Study Overview ........................................................................................................... 14 
5 
CRITERIA FOR EVALUATION ..................................................................................... 14 
5.1 
Primary Efficacy Endpoint .......................................................................................... 14 
5.2 
Secondary Efficacy Endpoints .................................................................................... 14 
5.3 
Safety Evaluations ....................................................................................................... 15 
6 
SUBJECT SELECTION .................................................................................................... 16 
6.1 
Study Population ......................................................................................................... 16 
6.2 
Inclusion Criteria ......................................................................................................... 16 
6.3 
Exclusion Criteria ....................................................................................................... 16 
7 
CONCURRENT MEDICATIONS .................................................................................... 17 
7.1 
Allowed ....................................................................................................................... 17 
7.2 
Prohibited .................................................................................................................... 17 
8 
STUDY TREATMENTS .................................................................................................... 17 
8.1 
Method of Assigning Subjects to Treatment Groups .................................................. 17 
8.2 
Blinding ....................................................................................................................... 17 
8.3 
Test and Control Formulation ..................................................................................... 17 
8.4 
Supply of Study Medication at the Site ....................................................................... 18 
8.5 
Study Medication Accountability ............................................................................... 18 
8.6    Study Drug Accountability 
 
 
 
 
 
 
19 
8.7 
Measures of Treatment Compliance ........................................................................... 18 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 18 
9.1 
Clinical Assessments ................................................................................................... 19 
10 EVALUATIONS BY VISIT ............................................................................................... 20 
10.1 Visit 1 (1-7 Days prior to Scheduled Surgyer) ............................................................ 20 
10.2 Visit 2 (POD #0-7) ...................................................................................................... 20 
10.3 Visit 3 (Surgical Clinic Followup) .............................................................................. 20 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 21 
11.1 Adverse Events ........................................................................................................... 21 
11.2 Serious Adverse Experiences (SAE) ........................................................................... 22 

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12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS................................... 23 
12.1 Withdrawal of Subjects ............................................................................................... 23 
12.2 Replacement of Subjects ............................................................................................. 24 
12.3. Replacement of Subjects 
13 PROTOCOL VIOLATIONS ............................................................................................. 24 
14 DATA SAFETY MONITORING ...................................................................................... 24 
15 STATISTICAL METHODS AND CONSIDERATIONS ............................................... 25 
15.1 Data Sets Analyzed ..................................................................................................... 25 
15.2 Demographic and Baseline Characteristics ................................................................. 25 
15.3 Analysis of Primary Endpoint ..................................................................................... 25 
15.4 Analysis of Secondary Endpoints ............................................................................... 25 
15.5 Sample Size and Randomization ................................................................................. 25 
16 DATA COLLECTION, RETENTION AND MONITORING ....................................... 25 
16.1 Data Collection Instruments ........................................................................................ 26 
16.2 Data Management Procedures ..................................................................................... 26 
16.3 Archival of Data .......................................................................................................... 26 
16.4 Availability and Retention of Investigational Records ............................................... 26 
16.5 Monitoring .................................................................................................................. 27 
16.6 Subject Confidentiality................................................................................................ 27 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 27 
17.1 Protocol Amendments ................................................................................................. 27 
17.2 Institutional Review Boards and Independent Ethics Committees ............................. 27 
17.3 Informed Consent Form .............................................................................................. 28 
17.4 Publications ................................................................................................................. 29 
17.5 Investigator Responsibilities ....................................................................................... 29 
 

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LIST OF ABBREVIATIONS 
Add all other abbreviations referenced in the protocol and delete any not referenced in 
the protocol. 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HR 
ICF 
Hour 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
KG 
MG 
Intravenous 
Kilogram 
Milligram 
PI 
Principal Investigator 
PK 
pharmacokinetic 
SAE 
serious adverse experience 

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PROTOCOL SYNOPSIS 
TITLE 
A CLINICAL TRIAL OF POSTOPERATIVE LIDOCAINE 
INFUSION ON COGNITION AND OPIOID CONSUMPTION 
FOLLOWING MAJOR SPINE SURGERY 
SPONSOR 
Marc Buren 
FUNDING 
ORGANIZATION 
N/A 
NUMBER OF SITES 
1 
RATIONALE 
Spine procedures are a particularly painful class of surgery (1).  
Opioids are the mainstay of postoperative analgesic management, and 
while effective, often come with a host of significant side effects 
including a risk of delirium and altered cognition, 
dependence/addiction, respiratory depression, immune suppression, 
and gastrointestinal dysfunction (2). Lidocaine, an amide local 
anesthetic with class 1 antiarrhythmic, sedative, and anti-
inflammatory properties has been increasingly utilized as part of a 
multi-modal anesthetic adjunct in a variety of surgical procedures (3-
6). 
 
While there is literature that supports the use of postoperative 
infusions of lidocaine for additional benefits such as a decrease in 
opioid requirements, decreased hospital length of stay and faster 
return of bowel function, the data are limited in scope and quality (7-
9).  Additionally, there is essentially no data that has examined the 
effects of postoperative lidocaine on cognition.  However, given the 
well described effects of opioids on cognition and delirium, we hope 
that if a postoperative infusion of lidocaine decreases opioid usage, it 
would then lead to a decreased risk of cognitive dysfunction (10-11) 
 
This pilot RCT will study a 48-hour postoperative infusion of 
lidocaine following major spine surgery to assess safety, and study the 
effects on opioid usage, delirium, and cognition. 
 
 
 
STUDY DESIGN 
Randomized, Double Blinded, Placebo Controlled 
PRIMARY 
OBJECTIVE 
To assess the safety and feasibility of using a postoperative infusion 
of lidocaine for the analgesic management of major spine surgery 
patients. 
 

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SECONDARY 
OBJECTIVES 
To compare pain and the amount of opioid used postoperatively 
between the placebo vs. lidocaine infusion groups. 
 
To compare the incidence of postoperative delirium and cognitive 
dysfunction between the placebo and the lidocaine infusion group. 
 
NUMBER OF 
SUBJECTS 
60 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
•Major elective spine surgery patients (with instrumentation and 
fusion) with expected length of stay 3 days or greater  
•Spinal fusion > 2 levels 
•American Society of Anesthesiologists Classification Rating of 1-3 
Age over 60  
 
 
Exclusion Criteria: 
•Sensitivity or allergy to lidocaine. Significant heart disease  
•2nd or 3rd degree heart block-except when a pacemaker is in place. 
Severe cardiac failure (EF <30%), 
Adams-stokes, Wolff-Parkinson-White syndrome, or active 
dysrhythmia.  
•Stable atrial fibrillation/atrial flutter is not a contraindication.  
•Concurrent treatment with a class 1 antiarrhythmic (lidocaine, 
procainamide, propafenone, quinidine, disopyramide, phenytoin, 
flecainide) or amiodarone use <3 months.  
•Severe hepatic impairments (bili>1.46) Renal impairment (GFR <30)
History of uncontrolled seizure 
Acute porphyria  
 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
Intravenous Lidocaine at 1.33mg/kg/hr for a 48 hour infusion to begin 
in the post-anesthesia care unit. 

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OF 
ADMINISTRATION 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Normal Saline at an equivalent rate to the comparable lidocaine dose 
(1.33mg/kg/hr) for a 48-hour infusion to begin in the post-anesthesia 
care unit. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on the study for the duration of their hospitalization, 
and at follow up in their surgeon’s office. 
Screening:  up to 7 days 
Treatment:  2 days (or duration of their hospital stay) 
Follow-up:  3 months (for data to be collected during surgical post-
operative visit). 
 
The total duration of the study is expected to 12-24 months.  12-24 
months for subject recruitment and 3 months for final subject 
follow-up. 
CONCOMMITANT 
MEDICATIONS 
Allowed: Standard postoperative analgesic meds as dictated by the 
surgical service. 
 
Prohibited: Ketamine Infusion 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
 
Difference in opioid usage between groups. 
SECONDARY 
ENDPOINTS 
 
Difference in pain scores, incidence of cognitive dysfunction, 
functional status, and length of hospitalizations. 
OTHER 
EVALUATIONS 
N/A 
SAFETY 
EVALUATIONS 
Adverse events (AEs) will be graded by the principal investigator 
using the 0-5 point scale where 0 = no AE or within normal limits or 
not clinically significant, 1 = mild AE, did not require treatment, 2 = 
moderate AE, resolved with treatment, 3 = severe AE, resulted in 
inability to carry on normal activities and required professional 
medical attention, 4 = life threatening or disabling AE, and 5 = fatal 
AE 
  
The principal investigator will determine the relationship of AEs to 
the test study drug as one of the following: Not related, Possibly 

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related, and Definitely related 
Description of Anticipated Adverse Events 
1. Sedation – will be evaluated by the Richmond Agitation and 
Sedation Scale and also the “Analgesic sedation assessment form” 
developed by the Department of Clinical Pharmacy and 
Pharmaceutical Services at our institution.  
2. Dizziness (self report)  
3. Tinnitus or decreased hearing (self report) 
4. Perioral Numbness or a metallic taste (self report) 
5. Tremors (self report)  
Safety Data to be Evaluated 
The data that will be evaluated (after every ten patients enrolled) will 
include subjects’ interview, vital signs, physical examination results, 
clinical test results such as creatinine, and postoperative analgesic 
dosages. All the above data will be evaluated by the PI. Additionally, 
functional status and neurocognitive data will be evaluated by the PI. 
Plan for Adverse Event Reporting 
All significant adverse events (both anticipated and unanticipated) 
will be reported to the following entities: 
University of California, San Francisco Committee on Human 
Research, National Institutes of Health, NIH Office of Biotechnology 
Activities (OBA), and Food and Drug Administration (if indicated) 
Events that may cause Termination/Drop out of a Participant from the 
Study: 
Adverse events (anticipated or unanticipated), Subject’s unwillingness 
to continue with the study, Treating physician’s request 
 
PLANNED INTERIM 
ANALYSES  
Given the limited scope of the present study, and small sample size.  
No interim analysis is planned. 

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STATISTICS 
Primary Analysis Plan 
We will compare the VAS pain scores between the placebo and 
lidocaine groups using unpaired t-test.  We will compare the amount 
of opioid used between groups using the unpaired t-test. 
Rationale for Number 
of Subjects 
This is a pilot RCT to help determine effect size and consider the 
safety of a lidocaine infusion.  Published studies have shown a 50% 
decrease in opioid consumption when using a lidocaine infusion.  
Based on the average reduction and associated variance in those data, 
we should have an 80% chance to detect a 50% reduction at the 0.05% 
level of significance with a total sample size of 60 patients. 
 
 

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1 
BACKGROUND 
Lidocaine, an amide local anesthetic with class 1 antiarrhythmic, sedative, and anti-
inflammatory properties has been increasingly utilized as part of a multi-modal anesthetic 
adjunct in a variety of surgical procedures (3-6).  Infusions decrease postoperative opioid 
requirements, speed return of bowel function, and may decrease the risk of chronic post-
surgical pain.   
1.1 
Overview of Non-Clinical Studies 
N/A 
1.2 
Overview of Clinical Studies 
Intravenous infusions of lidocaine have been used extensively during the intraoperative 
period, and while less common, have also been used postoperatively for the management 
of acute pain.  Intraoperative dosing has utilized a variety of doses included boluses at the 
beginning of the procedure (typically with induction of anesthesia) that range from 1-2 
mg/kg follow by infusions that range from 0.5-3 mg/kg/hr based on actual vs. lean vs. 
adjusted vs. ideal body weight. 
 
Published data on posteroperative intravenous infusions of lidocaine for actue pain are 
much rarer.  Prospective studies include Adair (2009) using 0.77mg/kg/hr and negative 
results for reduction in opioid usage.  Lauwick (2009) using 1mg/kg/hr for 24 hours with 
positive results for clinically significant reduction in opioid consumption at 48 hours.  
Kaba (2009) used 1.3mg/kg/hr for 24 hours after laparoscopic colectomies, and showed a 
greater than 50% reduction of opioid consumption without any adverse results reported.  
Recently, De Oliveira (2020) reported retrospective results with infusions typically at 
1mg/kg/hr for an average of 68 hours.  In this cohort there were a total of 36 minor 
adverse events, and 1 serious adverse event requiring intervention.   
 
In terms of cumulative effects there is conflicting evidence.  Old data from LeLorier 
(1977) suggest that the elimination half-life increases after 24 hours to 3.22h from 100min 
in infusions less that 24 hours.  More recent authors such at Eipe (2016) suggest that there 
is no accumulation over time.  Additionally, the acute pain service at UCSF has 
significant experience with intravenous infusions for acute pain, and dose ranges are 
typically between 1-1.5mg/kg/hr, with an allowable dose of 2mg/kg/hr for 48 hours. 
 
Based on the safety data from De Oliveira, the efficacy data from Kaba, and the data 
about plasma accumulation from LeLorier and Eipe and historical experience we have 
decided on an infusion of 1.33mg/kg/hr with close patient monitoring by a standardized 
nursing protocol and daily investigator questionnaires. 
2 
STUDY RATIONALE 
Spine procedures are a particularly painful class of surgery. Opioids are the mainstay of 
postoperative analgesic management, and while effective, often come with a host of 
significant side effects including the risk of delirium and altered cognition, 

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dependence/addiction, respiratory depression, immune suppression, and gastrointestinal 
dysfunction.  
Lidocaine, an amide local anesthetic with class 1 antiarrhythmic, sedative, and anti- 
inflammatory properties has been increasingly utilized as a part of a multi-modal 
anesthetic adjunct in a variety of surgical procedures. Infusions decrease postoperative 
opioid requirements, speed return of bowel function, and may decrease the risk of chronic 
post- surgical pain.  
While there is literature that supports the use of postoperative infusions of lidocaine for 
additional benefits such as a decrease in opioid requirements, decreased hospital length of 
stay, and faster return of bowel function, the data are limited in scope and 
quality. Additionally, there is essentially no data that has examined the effects of 
postoperative lidocaine on cognition.  
This small RCT will study a 48-hour postoperative infusion of lidocaine following major 
spine surgery to assess safety, and study the effects on opioid usage, delirium, and 
cognition following major spine surgery.  
2.1 
Risk / Benefit Assessment 
1. We will carefully monitor the recruitment, enrollment and retention of study subjects. 
2. We will exclude patients with a history of renal or hepatic dysfunction.  Hepatic 
dysfunction will be assessed during a chart review for a known diagnosis of liver disease.  
Renal dysfunction will be based on the patient’s preoperative renal function, which will be 
measured by serum creatinine levels and calculated glomerular filtration rate (GFR).  
Patients with a GFR <30 will be excluded. 
The Cockroft and Gault Equation will be used to calculate creatinine clearance. 
•Men Creatinine clearance = {140 – (age in yrs X weight in kg)}/ 72 X serum creatinine = 
mL/min 
•For women, the value will be multiplied by 85% 
3. We will monitor for all possible side effects related to the drugs which may include 
sedation, dizziness, tinnitus, perioral numbness, metallic taste, decreased hearing, slurred 
speech, tremors, cardiovascular issues, and GI problems.  This will be assessed daily by 
either the PI or research assistant using the “Lidocaine Safety Questionnaire" form-see 
attachment.  This will also be assessed by nursing according to the current order set 
protocol (every 2 hours for the first 4 hours, then every 4 hours for the duration of the 
infusion).   
4 Adverse events will be monitored in real time for safety. 

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5. All study end-points will be closely defined to facilitate ease of monitoring. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To assess the safety and efficacy of using a postoperative intravenous infusion of 
lidocaine after major spine surgery in order to improve analgesic management. 
3.2 
Secondary Objectives 
To assess the effect of a postoperative infusion of lidocaine on cognitive function and 
delirium following major spine surgery. 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a prospective, double-blind, placebo-controlled study of 60 patients, >60 years of 
age, undergoing major spine surgery at the UCSF Medical Center.  Patients will be 
randomized to receive either placebo (normal saline) or postoperative intravenous 
lidocaine, at 1.33mg/kg/hr, for 48 hours, starting upon arrival in the post-anesthesia care 
unit.  Intraoperative anesthetic and other postoperative pain management strategies will be 
standardized.  Postoperative delirium will be measured using structured interviews.  
Cognitive function will be measured using a battery of neurocognitive tests pre- and post-
operatively.  Using an intention to treat strategy, we will compare the amount of 
postoperative pain, opioid requirements, and postoperative delirium and cognitive 
dysfunction between the two groups.  We will also assess any impact on length of stay, 
and functional outcome by comparing pre and postoperative results of the SF-36 and ODI. 
 
 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
Primary efficacy endpoint will be a statistically significant reduction in opioid usage 
during the subject’s hospitalization. 
5.2 
Secondary Efficacy Endpoints 
Pain: Pain will be measured daily by the 11-point visual analog scale (0=no pain and 
10=the worst possible pain) both at rest and with movement preoperatively and daily 
postoperatively for the first week.  If the patient is in the hospital longer than 1 week after 
surgery, we will do a weekly evaluation until discharge.  In addition, the site and 
treatment of pain, and the maximal level of pain experienced postoperatively will be 
measured.  The measurement of pain is done routinely even if a subject does not enroll in 
the study. 

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Delirium: We will assess for delirium before surgery and after surgery daily for the first 
week.  If the patient is in the hospital longer than 1 week after surgery, we will do a 
weekly evaluation until discharge.  We will use the Confusion Assessment Method 
(CAM) (12) to determine the occurrence of delirium.  This assessment tool was developed 
as a screening instrument based on the operationalization of DSM-III-R criteria for use by 
nonpsychiatric clinicians in high-risk settings.  This method has a sensitivity of 94-100% 
and a specificity of 90-95% and has higher interobserver reliability (12), and has 
convergent agreement with four other mental status tests. 
Lidocaine Safety: Tolerability and safety of lidocaine will be assessed according to the 
nursing protocol, which is part of the current lidocaine infusion order set.  This 
protocol/order set was predetermined by acute pain service and predates this study.  
Patients will be assessed once per day by an investigator using a standardized script.  The 
patient's labs will be monitored for lidocaine levels during their stay in the hospital 
on POD#1, POD#2 and the day after the infusion is complete (POD#3). 
Functional Outcomes:  Functional outcomes will be measured by comparing preoperative 
and postoperative scores on the Short-Form 36, Oswestry Disability Index (13).  Both of 
these forms are collected by the spine clinic.  Postoperative scores will be collected 
approximately 3 months after surgery at standard surgical follow-up visits. 
 
5.3 
Safety Evaluations 
Adverse events (AEs) will be graded by the principal investigator using the 0-5 point 
scale where 0 = no AE or within normal limits or not clinically significant, 1 = mild 
AE, did not require treatment, 2 = moderate AE, resolved with treatment, 3 = severe 
AE, resulted in inability to carry on normal activities and required professional 
medical attention, 4 = life threatening or disabling AE, and 5 = fatal AE 
 The principal investigator will determine the relationship of AEs to the test study drug 
as one of the following: Not related, Possibly related, and Definitely related 
Description of Anticipated Adverse Events 
1. Sedation – will be evaluated by the Richmond Agitation and Sedation Scale and 
also the “Analgesic sedation assessment form” developed by the Department of 
Clinical Pharmacy and Pharmaceutical Services at our institution.  
2. Dizziness (self report)  
3. Tinnitus or decreased hearing (self report) 
4. Perioral Numbness or a metallic taste (self report) 
5. Tremors (self report)  
  
 
Safety Data to be Evaluated 

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The data that will be evaluated will include subjects’ interview, vital signs, physical 
examination results, clinical test results such as creatinine, and postoperative analgesic 
dosages. All the above data will be evaluated by the PI. Additionally, functional status 
and neurocognitive data will be evaluated by the PI. 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects presenting for major spine surgery who meet the inclusion and exclusion criteria 
will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
 
Major elective spine surgery patients (with instrumentation and fusion) with 
expected length of stay 3 days or greater 
o Spinal fusion > 2 levels 
 
American Society of Anesthesiologists Classification Rating of 1-3 
 
Age over 60 
1. Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal representative and ability for subject to comply with the requirements 
of the study. 
6.3 
Exclusion Criteria 
1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in 
the study. 
2. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
3. Sensitivity or allergy to lidocaine.   
4. Significant heart disease 
a. 2nd or 3rd degree heart block-except when a pacemaker is in place. 
b. Severe cardiac failure (EF <30%),  
c. Adams-stokes, Wolff-Parkinson-White syndrome, or active dysrhythmia.   
 
Stable atrial fibrillation/atrial flutter is not a contraindication.  
d. Concurrent treatment with a class 1 antiarrhythmic (lidocaine, 
procainamide, propafenone, quinidine, disopyramide, phenytoin, 
flecainide) or amiodarone use <3 months.   
5. Severe hepatic impairments (bili>1.46) 
6. Renal impairment (GFR <30) 
7. History of uncontrolled seizure 
8. Acute porphyria 

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7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy following major spine surgery is allowed except for treatments noted in 
the exclusion criteria described above and as noted in the prohibited medications section 
below.   
7.2 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be 
considered a protocol violation. 
Postoperative intravenous infusion of ketamine. 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Patients enrolled in the study will be randomized to one of the two study groups, either 
intervention or placebo, using block randomization. 
 
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients.  The following study procedures will be 
in place to ensure double-blind administration of study treatments. 
 
Access to the randomization code will be strictly controlled.   
 
Packaging and labeling of test and control treatments will be identical to maintain the 
blind.  
The study blind will be broken on completion of the clinical study and after the study 
database has been locked.  
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management. When possible, the 
Investigator should discuss the emergency with the Medical Monitor prior to unblinding.  
8.3 
Formulation of Test and Control Products 
8.3.1 
Formulation of Test Product 
The study drug is lidocaine, and the placebo will be normal saline.  Both are standard 
formulations provided by the UCSF pharmacy.  Both are colorless liquids of similar 
viscosity.  The pharmacy obtains lidocaine from various manufacturers. 
8.3.2 
Formulation of Control Product 
0.9% Saline will be the control product 

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8.3.3 
Packaging and Labeling 
Study medications will be supplied by the UCSF pharmacy.   Study drug and placebo will 
be placed in a 500ml intravia bag by pharmacy.  
8.4 
Supply of Study Drug at the Site 
Medication is standard formulation supplied by UCSF pharmacy. 
8.4.1 
Dosage/Dosage Regimen 
Intravenous lidocaine dose will be 1.33 mg/kg/hr based on adjusted body weight as a 
continuous infusion for 48 hours upon arrival in the post-anesthesia care unit. 
8.4.2 
Dispensing 
Drug will be dispensed by the pharmacy. 
8.4.3 
Administration Instructions  
MDs will have access to a study specific ERX (Apex drug order).  Medication will be 
delivered as a continuous intravenous infusion without any change in rate for 48 hours. 
8.5 
Supply of Study Drug at the Site 
Drug is supplied by the UCSF pharmacy 
8.5.1 
Storage 
No special storage requirements once dispensed by the pharmacy.  Both study medication 
and placebo are stable at normal room temperatures. 
8.6 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
8.7 
Measures of Treatment Compliance 
Treatment compliance will be monitored by checking the patients MAR and daily visits. 
9 
STUDY PROCEDURES AND GUIDELINES 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 

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9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented on the day of 
surgery.  Dose, route, unit frequency of administration, and indication for administration 
and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be obtained from apex. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent history, and 
information regarding underlying diseases will be obtained from apex. 
9.1.4 
Delirium/Cognitive Function 
Incident delirium present in any of the first three postoperative days will be the 
secondary outcome. Delirium will be measured preoperatively and daily on the first three 
postoperative days by trained research assistants using the Confusion Assessment Method 
(CAM), a screening instrument based on the Diagnostic and Statistical Manual-III-R 
criteria and was validated by health care providers. (1) Patients will be considered to be 
delirious if the CAM assessment reveals acute onset or fluctuating course of mental status 
change, inattention, and either disorganized thinking or altered level of consciousness. If a 
CAM assessment is missing for any of the three days post-surgery, delirium will be 
determined from the patient’s medical record in accordance with the chart-based CAM 
delirium identification method developed by Inouye et al. (2),(3) 
In addition to measuring incident postoperative delirium on any of the first three 
days, we will also measure the severity of delirium using the Memorial Delirium 
Assessment Scale (MDAS). (4)  
Cognitive function will be measured by a battery cognitive tests used commonly in 
our UCSF IRB approved studies. These include the digit symbol substitution test, (5) the 
timed verbal fluency test, (6) and the word list learning task (7) in order to assess the 
cognitive domains of  memory and learning (word list), verbal and language skills (verbal 
fluency), attention, concentration, and perception (digit symbol test). For each test, we 
will determine whether the patient experience a significant decline from preoperative 
baseline using prediction intervals. (8) A decline from preoperative performance of 4 or 
more points for the word list, or 7 or more points for the verbal fluency and the digit 
symbol tests will be considered significant decline and the subject will be classified as 
having POCD for that day. If decline in performance is observed for at least one 
postoperative day, we will conclude that POCD occurs for that patient. (9) The above 
scores were determined in earlier studies of community living older adults similar in 
demographic and clinical characteristics to the subjects in this study, but who had not 
undergone an intervention that could cause cognitive change.(10-12) In addition to the 
above tests, cognitive status will also be measured preoperatively using the Telephone 
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Mental Status Examination. The TICS allows us to evaluate the baseline cognitive status 
of patients but patients will not excluded based on the TICS values.  
9.1.5 
Functional Outcomes 
Functional outcomes will be measured by comparing preoperative and postoperative 
scores on the Short-Form 36, Oswestry Disability Index (13).  Both of these forms are 
collected by the spine clinic.  Postoperative scores will be collected approximately 3 
months after surgery at standard surgical follow-up visits. 
9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the Serious Adverse Events (SAE) report form 
9.1.7 
Sleep/Pain Assessment 
Pain will be measured daily by the 11-point visual analog scale (0=no pain and 10=the 
worst possible pain) both at rest and with movement preoperatively and daily 
postoperatively for the first week.  If the patient is in the hospital longer than 1 week after 
surgery, we will do a weekly evaluation until discharge.  In addition, the site and 
treatment of pain, and the maximal level of pain experienced postoperatively will be 
measured.  The measurement of pain is done routinely even if a subject does not enroll in 
the study. 
 
Sleep Quality and quantity will be measured daily using a questionnaire including 
duration or sleep, number of awakenings, daytime somnolence, need for pharmaceutical 
adjuncts, and subjective assessment of quality. 
 
9.1.8 
Lidocaine Safety 
Tolerability and safety of lidocaine will be assessed according to the nursing protocol, 
which is part of the current lidocaine infusion order set.  This protocol/order set was 
predetermined by acute pain service and predates this study.  Patients will be 
assessed once per day by an investigator using a standardized script. 
 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (1-7 days prior to scheduled Surgery) 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate. 
2. 
Perform Initial Delirium Screening 
10.2 Visit 2 (POD#0-7) 
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1. 
Ensure Patient is receiving study medication or has had study medication 
discontinued according to the protocol 
2. 
Administer Lidocaine Safety Questionnaire 
3. 
Administer Sleep/Pain Assessment 
4. 
Administer CAM for delirium assessment. 
10.3 Visit 3 (Surgical Clinic Follow Up) 
1. Patient completes standard post-surgical follow-up health forms including SF-36 
and ODI at the surgeon’s clinic.  This usually takes place 1-3 months following 
surgery. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
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Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 

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 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
   
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:  
 
Subject withdrawal of consent (or assent) 
 
Subject is not compliant with study procedures 
 
Adverse event that in the opinion of the investigator would be in the best interest of 
the subject to discontinue study treatment 
 
Protocol violation requiring discontinuation of study treatment 
 
Lost to follow-up 
 
Sponsor request for early termination of study 
 
Positive pregnancy test (identified via medical records review) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents. 

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12.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  
12.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
Subjects who withdraw from the study will be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
 
Failure to meet inclusion/exclusion criteria 
 
Use of a prohibited concomitant medication 
 
Early termination of study drug 
 
Incorrect administration of study drug (as administered by pharmacy) 
 
Escalation of pain management protocol to include ketamine 
 
Additional surgery during study period 
 
Failure to obtain informed consent prior to study procedures. 
 
Failure to administer clinical assessments relating to safety, pain, and delirium during 
study period. 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
14 DATA SAFETY MONITORING 
The UCSF Data Safety Monitoring Board (DSMB) will establish a Data Monitoring 
Committee (DMC) to review data relating to safety and efficacy, to conduct and review 
interim analyses, and to ensure the continued scientific validity and merit of the study, 
according to the UCSF Data Safety Monitoring Board Operations Manual and a DMC 

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Charter to be established for this protocol. There will not be an interim review conducted 
by the DMC given the limited trial size and daily safety monitoring already conducted.   
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the 
study drug (the Safety Population) will be included in the safety analysis. 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, gender, age, 
height, weight, ASA status, medical conditions, preoperative opioid use, location and 
extent of planned procedure. 
15.3 Analysis of Primary Endpoint 
We will compare the VAS pain scores between the placebo and lidocaine groups using 
unpaired t-test.  We will compare the amount of opioid used between groups using the 
unpaired t-test. 
15.4 Analysis of Secondary Endpoints 
Safety and tolerability data will be summarized by treatment group.   
We will compare the incidence of side effects between the placebo and lidocaine groups 
using the chi-squared test. 
We will compare the incidence of postoperative delirium and cognitive dysfunction 
between the two groups using the chi-square test.  Multivariate logistic regression will be 
used to determine the independent predictive value of the use of lidocaine on 
postoperative delirium and cognitive dysfunction. 
The data will be analyzed locally at UCSF. 
Detailed methods of VAS pain measurements, opioid doses, and cognitive function 
assessment will be described in the other sections. 
15.5 Sample Size and Randomization 
This is a pilot RCT to help determine effect size and consider the safety of a lidocaine 
infusion.  Published studies have shown a 50% decrease in opioid consumption when 
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those data, we should have an 80% chance to detect a 50% reduction at the 0.05% level of 
significance with a total sample size of 60 patients. 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.  These data will be recorded on various forms as detailed in other sections 
of this protocol. 
Subjects will not be identified by name in the study database or on any study documents 
to be collected by the Sponsor (or designee), but will be identified by a site number, 
subject number and initials. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of all data collection forms will 
remain at the Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
The data will be entered into a validated database. Database lock will occur once quality 
assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
16.4 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 

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has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason. 
16.5 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 
16.6 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation submitted 
to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 

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Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor or designee prior to the shipment of study 
supplies to the site.  This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 

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17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.

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