Chloroprocaine Lavage to Improve Outcomes Related to Operative Cesarean Delivery
Phase: EARLY_PHASE1
Conditions: Cesarean Section
Sponsor: Oregon Health and Science University

Togioka 
 
                                                            
              IRB# 19021  
11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 1 of 15 
 
 
Chloroprocaine Lavage to Improve Outcomes Related to Operative Cesarean Delivery 
CLOR-PRO 
Phase 1 Protocol and Statistical Analysis Plan 
NCT03760718, Unique Protocol ID 19021 
November 30, 2018 
 
Principal Investigator:  
 Brandon Togioka, MD  
 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
 
 (503) 494-4572 
 
 3181 SW Sam Jackson Park Road 
 
 Mail Code SJH-2 
 
 Portland, OR 97239 
 
 togioka@ohsu.edu 
 
Co-investigators:  
 
Miriam Treggiari, MD, PhD, MPH  
 
 
 
 
Department of Anesthesiology and Perioperative Medicine 
(503) 494-8311 
 
 
 
 
3181 SW Sam Jackson Park Road  
 
 
 
 
Mail Code UHN-2 
 
 
 
 
Portland, OR 97239 
 
 
 
 
treggiar@ohsu.edu 
 
Norbert David Yanez, PhD 
Oregon Clinical and Translational Research Institute 
(503) 494-5354 
OHSU – GH 155 
yanezn@ohsu.edu 
 
Collaborator:   
  
Dennis Koop, PhD 
 
 
 
 
Department of Physiology and Pharmacology 
 
 
 
 
Oregon Health & Science University 
 
 
 
 
3181 SW Sam Jackson Park Road 
 
 
 
 
Portland, OR 97239 
koopd@ohsu.edu 
 
Research Coordinator: 
Janna Higgins, MSW 
Department of Anesthesiology and Perioperative Medicine 
higginsj@ohsu.edu 
 
Sponsor: 
 
 
The Collins Medical Trust 
Funding: 
 
 
$30,000, PPQ#1016328 
 
 

Togioka 
 
                                                            
              IRB# 19021  
11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 2 of 15 
INTRODUCTION 
 
Compared to general anesthesia, neuraxial anesthesia (spinals and epidurals) is associated with a 
lower risk for maternal aspiration and airway compromise, exposes the baby to less anesthetic, and 
allows for greater maternal involvement in the birth process.  For these reasons, it has become the 
preferred method of anesthesia for cesarean delivery.1–3  A spinal anesthetic is a one-time injection 
of numbing medicine (local anesthetic) and typically opioid into the intrathecal space.  Spinals have 
a limited duration.  Spinals that are placed to facilitate cesarean delivery have a duration of one to 
two hours.  Currently, if that duration is exceeded patients must have general endotracheal 
anesthesia. 
 
Suboptimal surgical anesthesia is not uncommon with neuraxial anesthesia. In a prospective 
observational study of 3568 cesarean deliveries, Rukuwe et al found a 9% incidence of spinal failure.4 
The rate of required conversion from regional to general anesthesia was found to be 2% for elective 
cesarean sections,5 and 5% when a labor epidural was already in place6. In addition, incomplete 
neuraxial anesthesia may raise the concern of legal liability.7,8 Currently, patients with suboptimal 
neuraxial anesthesia must have general endotracheal intubation.  
 
In 1975 Ranney et al described using intraperitoneal local anesthetic (IPLA) instillation in 218 patients 
that underwent cesarean section under local field block alone.9  Patients were administered up to 
100 ml of 1% procaine.  Some of this was injected into the skin and fascia, and the remainder was 
diluted to 0.5% and “spilled” into the peritoneum.9  Although IPLA received little attention following 
this publication, recent publications have surfaced showing that IPLA can treat intraoperative pain, 
prevent postoperative nausea, decrease early postoperative pain and opioid administration, and 
shorten hospital length of stay. 10–16 In this manner, IPLA may be useful as part of a multimodal 
approach to avoiding general endotracheal intubation when neuraxial anesthesia is failing. 
 
We have shown in a 40-month case series that 2-chloroprocaine, a local anesthetic, may be used as 
an agent for IPLA to facilitate women with inadequate pain relief avoiding general anesthesia.  In this 
case series, no patients exhibited clinical signs of systemic local anesthetic toxicity.  To our knowledge, 
this was the first study to report the effect of IPLA instillation on intraoperative pain scores during 
cesarean delivery as well as the first study evaluating 2-chloroprocaine (3%) as an effective agent for 
IPLA administration.  Chloroprocaine is advantageous due to its short plasma half-life (11 to 21 
seconds) and the possibility of significant vascular uptake when poured into a surgical wound that 
may have open venous channels.17   
 
Our long-term goal is for intraperitoneal chloroprocaine to be used as an alternative option to avoid 
general anesthesia during cesarean sections, to alleviate women’s discomfort from surgical pain, 
reduce complications, and improve the birth experience.  To achieve our goal, we need to accomplish 
the following aims: (1) Determine the amount of chloroprocaine that is absorbed into the blood after 
intraperitoneal administration to ensure that blood levels are low and do not raise safety concerns, 
(2) define a safe dose of chloroprocaine for intraperitoneal administration and (3) Demonstrate that 
intraperitoneal chloroprocaine decreases intraoperative pain, decreases the use of rescue sedatives 
and opioid class medications, and can be used as a safe alternative to help women avoid general 
anesthesia.  Aim 3 will be pursued after the completion of Aim 1 and Aim 2. This protocol only 
addresses Aim 1 and Aim 2. 
 

Togioka 
 
                                                            
              IRB# 19021  
11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 3 of 15 
 
 
STUDY OBJECTIVES 
 
Aim 1: Primary Objective (to be determined with Aim 2) 
 
To determine the amount of chloroprocaine that is absorbed in the blood after intraperitoneal 
administration to ensure that blood levels are low and do not raise safety concerns.  There is no 
generally agreed upon threshold for the upper limit of “low” chloroprocaine plasma concentrations.  
In mice studies the median lethal dose of chloroprocaine with intravenous administration is 97 mg/kg 
and the median lethal dose with subcutaneous administration is 950 mg/kg18.   The lowest 
concentration of intravascular chloroprocaine that has been reported to cause symptoms of systemic 
toxicity in humans is 2.8 mg/kg19.  For purposes of this study, low plasma concentration will be 
defined as less than 0.97 mg/kg or 1/100 of the median lethal dose in mice. 
 
Aim 2: Primary Objective  
 
To define a safe concentration of chloroprocaine for intraperitoneal administration using a parallel 
dose comparison study.   
 
STUDY OVERVIEW 
 
Aims 1 & 2 Study Design: Phase I Safety and Dose Finding Trial Phase 
 
Design:  Open label, uncontrolled, single center, parallel group, multiple dose escalation study 
 
Intervention: Three level doses are planned for administration after delivery of the baby with 5 
subject per dose level: (Dose level 1) 40 ml of preservative-free 1% chloroprocaine; (Dose level 2) 40 
ml of preservative-free 2% chloroprocaine; and (Dose level 3) 40 ml of preservative-free 3% 
chloroprocaine.  The planned dose escalation scheme may be altered based upon emerging 
pharmacokinetic and tolerability results.  Enrollment of each dose cohort will not occur until data 
analysis is complete for the previous dose cohort. 
 
Number of Subjects: 15 subjects will be enrolled with 5 subjects per dose level. 
 
Research Integrity: The study will be assessed for initial approval by the Institutional Review Board 
(IRB) at OHSU, Portland, OR, USA, and given a unique identifier for ongoing review. 
 
Study Location: Single center study performed at OHSU in Portland, OR, USA.  Subjects will be called 
at home prior to the date of their scheduled surgery to assess interest.  Subjects will be enrolled and 
consented at a preoperative visit or on the labor and delivery unit (OHSU Floor 12C) on the day of 
their scheduled surgery.  All study interventions will occur in the preoperative area for 12C, the 
operating rooms on 12C, or in the Post-Anesthesia Care Unit on 12C.  Data collection will occur in the 
operating room and in the PACU.     
 
Timeline: In a review of scheduled cesarean sections from 9/1/17 to 3/31/18, a total of 99 cases were 
found.  Assuming 25% enrollment we should be able to enroll the necessary 15 subjects in 4 months, 
with a projected enrollment of one subject per week.    

Togioka 
 
                                                            
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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 4 of 15 
 
 
SUBJECTS 
 
 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
• 
Subjects ≥ 18 to 50 years of age having scheduled cesarean sections on 12C (Labor 
and Delivery) within Oregon Health & Science University (OHSU). 
• 
Only subjects having spinal anesthesia will be eligible.   
• 
Only subjects that can have a Pfannenstiel incision will be enrolled. 
 
Exclusion Criteria 
• 
Subjects with chronic narcotic usage  
• 
Subjects that are deemed to need a combined spinal epidural due to the expected 
duration of surgery 
• 
Patients who are unable to successfully get a spinal block 
• 
Subjects with known atypical cholinesterase activity 
• 
American Society of Anesthesiologist physical status IV or higher 
• 
Patients with contraindication to neuraxial anesthesia (coagulopathy, infection) 
• 
Subjects with stage 4 chronic kidney disease or worse (eGFR < 30 ml/min) 
• 
Subjects with significant hepatic dysfunction (AST or ALT > 2x the upper limit of 
normal) 
• Subjects with allergies to drugs required for this protocol.   
• Subjects with multifetal gestations 
• Subjects with BMI > 40 kg/m2 
 
Vulnerable Populations - The following protected populations will be excluded from the study:  
• Children (age < 18 years) 
• Prisoners 
• Decisionally impaired adults 
 
There will be a two-step process to ensure that vulnerable populations are not approached for 
inclusion in the study.  First, the research coordinator will review the electronic medical record 
to screen for vulnerable population status.  Second, the research coordinator will consult with 
the labor and delivery nurse caring for the patient to ensure that the patient is not included in a 
vulnerable population.    
 
Due to the nature of the study, pregnant subjects will have to be enrolled to obtain the medical 
knowledge that we seek.  We have attempted to minimize risk by administering the study drug 
after delivery of the fetus so that the fetus is not immediately exposed to the study drug.  A very 
small quantity of drug may possibly be transferred to the fetus through breast milk, but we 
believe the risk to the fetus is not greater than minimal.  Chloroprocaine has a long history of safe 
use in pregnant women and the maternal half-life is very short (mean 11.2 seconds, SD 2.8 
seconds).  In this manner, the drug concentration can be considered to be negligible after 45 
seconds (4 half-lives), which is long before first latch.     
 

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              IRB# 19021  
11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 5 of 15 
 
Recruitment Methods 
Most subject recruitment is expected to occur by approved study staff as early as two months prior 
to a potential subject’s scheduled cesarean section via a review of the OHSU Labor and Delivery 
surgical schedule as posted in Epic (Verona, Wisconsin). The study staff will work with obstetricians 
to identify and screen for potential eligible subjects. We will review all the inclusion/exclusion criteria 
as early as two months prior to a potential subject’s scheduled surgery.  If a potential subject has 
been identified as meeting all inclusion criteria and none of the exclusion criteria, an approved 
member of the study team will call the subject, using an approved phone script (included in ‘Consent 
Form and Recruitment Materials’ section of application) to introduce the study. If the subject is 
amenable to the study, study staff will make arrangements to meet with the subject to provide formal 
consent materials and signature at their pre-op visit or day of surgery. If the subject is not interested 
in participating in the study, the inclusion/exclusion criteria and any other information related to this 
subject will be destroyed. 
 
The study will be listed on ClinicalTrials.gov to provide subjects, family members, and the public 
background information on the study. 
 
Other than posting this study on OHSU Study Participation Opportunities, we do not expect to create 
advertisements for the study.   
 
Subjects that complete the study protocol will be given a $100 VISA gift card.   
 
Consent Process 
The consent process will take place in a private and confidential area. All subjects that are approached 
for recruitment will hear a description of the study, reasons for pursuing this research study, options 
for opting out the research protocol or not completing data collection, and potential risks, 
advantages, and disadvantages from participating.    We will ask subjects to reiterate their 
understanding of how the study will affect their care and allow time for questions before collecting a 
signature for consent. Subjects that agree to participate in the study will be asked to sign a written 
informed consent that has been approved by our Institutional Review Board. An electronic copy of 
the signed consent will be scanned into the subject’s medical records system. A copy of the signed 
consent, describing the research study and providing contact information for the principal 
investigators will be given to subject. 
 
Medical Monitor 
Dr. Michael Aziz will serve as medical monitor and will conduct periodic reviews to ensure that proper 
consent devoid of coercion is being collected, steps outlined in this protocol are followed to ensure 
human subject protection, and data safety monitoring is conducted with integrity as the study 
progresses.  Dr. Aziz is the Vice Chair for Clinical Anesthesia and has significant experience conducting 
and serving as a safety monitor for clinical trials. 
 
Study Procedures 
 
Aims 1 & 2 Study Design: Phase I Safety and Dose Finding Trial Phase 
 

Togioka 
 
                                                            
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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 6 of 15 
Maternal plasma concentrations of chloroprocaine after intraperitoneal instillation have not been 
previously established and a safe concentration for intraperitoneal chloroprocaine has not been 
defined. To accomplish aims 1 and 2, we propose a safety trial in which 15 healthy patients scheduled 
for elective cesarean sections under spinal anesthesia are administered intraperitoneal 
chloroprocaine after cesarean delivery.   
 
Before starting the cesarean section, the following baseline demographic data will be collected: 
• 
Maternal age 
• 
Height 
• 
Weight at time of cesarean delivery 
• 
Body mass index at time of cesarean delivery 
• 
Gestational age 
• 
Parity 
• 
History of previous cesarean delivery 
• 
History of previous abdominal surgery 
 
All subjects will receive a spinal anesthetic in the operating room with a standardized solution 
containing 1.6 mL of hyperbaric 0.75% bupivacaine, 15 mcg fentanyl, and 150 mcg preservative-free 
morphine.  Subjects will receive a 1 liter co-load of crystalloid (Ringer’s Lactate or Normal Saline) 
solution during spinal placement.  The patient will then be positioned supine on the operating room 
table with placement of a bump under their right hip to maintain left lateral tilt position.  Non-invasive 
blood pressures will be obtained every 2 minutes after spinal placement and a phenylephrine infusion 
will be started at 0.4 mcg/kg/min and titrated to maintain maternal blood pressure within 20% of 
baseline.  In accordance with standard practice all patients will have telemetry monitoring during 
surgery and during PACU recovery. 
 
After obtaining spinal anesthesia, an intravenous line will be placed into the subject’s lower extremity 
for study purposes.  The subject’s lower extremity will be numb at this time, which should help to 
minimize discomfort.  Immediately after the intravenous line is placed 2 mL of blood will be drawn to 
determine the subject’s dibucaine number.  This blood will be placed in a purple top tube and kept 
by the research coordinator until the subject has completed the study protocol.  No special 
temperature control is necessary. The purple top tube will then be walked to the clinical core lab.  
The core lab will send the sample to the ARUP Laboratories in Salt Lake City for analysis. The official 
title of the Dibucaine number test is “Pseudocholinesterase, Dibucaine Inhibition,” lab order 
LAB00576 in EPIC. The turnaround time for the lab is 2-6 business days. The dibucaine number will 
be used to differentiate subjects with decreased butyrylcholinesterase (plasma cholinesterase) 
enzyme function.  Butyrylcholinesterase is the enzyme responsible for metabolizing chloroprocaine. 
Dibucaine is an amide local anesthetic that inhibits normal butyrylcholinesterase. In normal 
individuals, dibucaine will inhibit 80% of enzyme activity, which corresponds to a dibucaine number 
of 80. Dibucaine numbers less than 70 are associated with atypical butyrylcholinesterase. Around 
1.3% of the population is known to have atypical cholinesterase activity and pregnancy can decrease 
cholinesterase activity. 
Prior to skin incision the study drug will be transferred to a sterile receptacle on the surgical scrub 
field.  After Pfannenstiel incision, uterine incision and extraction of the baby, the uterus will be 
exteriorized and intraperitoneal chloroprocaine will be administered.  Chloroprocaine will be 

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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 7 of 15 
administered in the following manner: the uterus will be retracted in a caudal direction to expose the 
intraperitoneal space, chloroprocaine will be poured in, two sides of the Pfannenstiel incision will be 
grasped by an obstetrician and the solution will be agitated with a goal of widespread dissemination.  
The uterus, parietal peritoneum and fascia will be closed according to obstetrician preference.   
 
After receiving intraperitoneal chloroprocaine a small volume of blood will be taken from the lower 
extremity venous line (the lower extremity will be numb from spinal anesthesia) at 1, 5, 10, 20, and 
30 minutes after chloroprocaine instillation. Plasma samples will be mixed with a cholinesterase 
inhibitor to prevent hydrolysis after blood collection. A custom assay for measuring plasma 
concentrations of chloroprocaine and its major metabolite, chloroaminobenzoic acid, has been 
established in the Bioanalytical Shared Resource/Pharmacokinetics Core Lab showing good sensitivity 
and accuracy (see accompanying document “Chloroprocaine stability, sensitivity, and accuracy 
curves). This was accomplished by altering an existing assay for lidocaine that uses liquid 
chromatography tandem mass spectrometry. PK study will allow us to determine the plasma 
concentration-time profile after intraperitoneal chloroprocaine administration.  
A research coordinator will be with the patient throughout their time in the operating room and the 
PACU.  Active, non-standard of care, monitoring for the following signs and symptoms of local 
anesthetic toxicity will occur in the operating room and PACU at the following time intervals after 
chloroprocaine administration: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes, upon 
PACU arrival and upon discharge from the PACU: 
• 
seizures 
• 
tinnitus 
• 
metallic taste 
• 
anxiety 
• 
agitation 
• 
muscle twitching 
• 
sedation 
• 
respiratory depression with desaturation (sat < 88%) 
• 
dizziness 
• 
nausea 
• 
vomiting 
• 
vision changes 
• 
paresthesias 
• 
perioral numbness 
• 
hypotension (drop in MAP > 20% within 5 minutes of chloroprocaine administration) 
• 
arrhythmias 
Manifestations of significant systemic local anesthetic toxicity will prompt saline lavage of the 
abdomen with 60 ml of 0.9% normal saline followed by immediate suctioning.  For purposes of this 
study, significant clinical manifestations will include the following: seizures, respiratory 
depression with desaturation (sat < 88%), hypotension (drop in MAP > 20%), any arrhythmias 
associated with hypotension, and cardiac arrest. 
Patients that exhibit seizures, arrhythmias, hypotension (drop in MAP >20%), or cardiac arrest will be 
immediately administered intralipid.  Intralipid is already available on labor and delivery in the 
epidural cart.  Intralipid would be dosed according to the American Society of Regional Anesthesia 

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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 8 of 15 
guideline (i.e. initial bolus of 1.5 ml/kg followed by 0.25 ml/kg/minute).  The intralipid infusion would 
be continued for 10 minutes after restoration of hemodynamic stability.  All patients that require 
intralipid will have telemetry monitoring on the floor. 
After the patient leaves the PACU, the research coordinator will review the electronic medical record 
to determine and record the following: 
• 
Did the patient receive a tubal ligation at the time of their cesarean section 
• 
Was the patient’s peritoneum closed 
• 
What was the length of the surgery (time from skin incision to surgery end as documented in 
EPIC) 
Subjects enrolled that do not have intraperitoneal instillation of the study drug, for any reason, may 
be withdrawn from the study without their consent.  In addition, a subject may be removed from the 
study if the investigator or funder stops the study, the subject’s clinical status changes, or if the 
subject does not follow study instructions. In the event that such a situation occurs the subject would 
be informed at the earliest reasonable time. 
 
The subject’s status in the research project will show up clearly in their electronic medical record 
problem list, until the subject’s participation is complete.  A progress note will be placed in the 
subject’s chart to allow other providers to easily contact study investigators.   
 
Subjects that enroll in the study and then decide to withdraw before chloroprocaine administration 
will be excluded from further data collection and analysis.  In the event that a subject withdrawal 
occurs an additional subject would be recruited. 
 
DATA and SPECIMENS 
 
Handling of Data and Specimens 
Study subjects will be assigned a unique study number after enrollment in the study.  All data points, 
procedure related data, and electronic files for data analysis will be linked only to this unique study 
number.  This study number will not contain any of the 18 HIPAA identifiers such as: geographic 
location, dates related to the individual, medical record number, account numbers, etc.  The key 
linking study subjects to study code will be kept in an OHSU approved cloud location with special 
protection for confidential and restricted health information (the OHSU Box).  Only the principal 
investigator and other study staff will have access to this key.  The key will be maintained for 3 years 
after publication in accordance with the US Department Office of Research Integrity guidelines for 
responsible data management in scientific research.   
 
Clinical data will be entered into APOM OCEAN, a 21 CFR Part 11-compliant electronic data capture 
system provided by the Department of Anesthesiology and Perioperative Medicine. The EDC includes 
password protection. Secure data will be stored in APOM OCEAN DCS for 3 years after publication.  
Data in the EDC will be linked only to subject study code, not to any of the 18 HIPAA identifiers.   
 
The following clinical data will be entered into APOM OCEAN: 
• 
Baseline demographic and surgical parameters 
o Maternal age 
o Height 

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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 9 of 15 
o Weight at time of cesarean section 
o Body mass index at time of cesarean section 
o Previous cesarean section history 
o Abdominal surgery history 
o Tubal ligation history 
o Whether the peritoneum was closed during the cesarean section 
o Cesarean Section duration 
• 
Signs and symptoms of local anesthetic toxicity 5 minutes, 10 minutes, 15 minutes, 30 
minutes, 60 minutes, upon PACU arrival and upon discharge from the PACU 
o Seizures 
o Tinnitus 
o Metallic taste 
o Anxiety 
o Agitation 
o Muscle twitching 
o Sedation 
o Respiratory depression with desaturation (sat <88%) 
o Dizziness 
o Nausea 
o Vomiting 
o Vision changes 
o Paresthesias 
o Perioral numbness 
o Hypotension (drop in MAP >20% within 5 minutes of chloroprocaine administration) 
o Arrhythmias  
• 
Data obtained from the patient’s plasma 
o Dibucaine number 
o Chloroprocaine plasma concentrations 1, 5, 10, 20, and 30 minutes after 
chloroprocaine administration 
 
Any data that is shared will be transmitted in an encrypted manner over a secure network.  
Transmitted data will be labeled only with the study code, none of the 18 HIPAA identifiers.  When 
data is transmitted, the transmitter (research personnel with access to APOM OCEAN EDC) will be 
responsible for sending the data in a protected manner.   Any person receiving data will then assume 
responsibility for patient confidentiality and data integrity.   
 
Plasma samples will be kept on ice in the operating room until all samples for a given subject are 
obtained.  Samples will then be prepared by centrifuge at 2000xg at 4C for 15 minutes.  Samples will 
be stored in a freezer at -80C in the Maternal Fetal Medicine Research Refrigerator located next to 
the obstetric operating rooms.  This is a secure locked area used for research.  Samples will be stored 
in this room for 1 to 4 weeks.  Samples will be batched and taken to the Bioanalytical Shared 
Resource/Pharmacokinetics Core at OHSU where they will be analyzed and discarded in accordance 
with blood waste guidelines in the Bioanalytical Shared Resource/Pharmacokinetics Core at OHSU. 
There will be no long term storing of plasma samples in the Bioanalytical Shared 
Resource/Pharmacokinetics Core. 
 

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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 10 of 15 
Sharing of Results with Subjects 
Study results will not be available to subjects at the time of participation.  All subjects will be given 
the contact information of the principal investigator and told that they may contact him to obtain 
their individual data once analysis is complete.  Patients will also be able to obtain a free copy of any 
published data should they indicate interest.  Chloroprocaine plasma concentration-time profiles for 
study subjects will be made available by request.  The Plasma concentration-time profiles will be 
created in the Bioanalytical Shared Resource/Pharmacokinetics Core, which is a research lab and thus 
not CAP/CLIA certified.  Dibucaine numbers will be made available upon request. Dibucaine numbers 
will be run in a CAP/CLIA certified lab. This study will not generate genetic information or imaging 
studies. 
 
Data and Specimen Banking 
Data will not be stored in a repository for 3 years after publication.  Plasma samples will not be 
banked. 
 
Data Analysis - Power/Sample Size: 
Aims 1 &2 Study Design: Phase I Safety and Dose Finding Trial Phase 
We estimate that a sample of 5 subjects will allow us to determine if intravascular concentrations of 
chloroprocaine reach concerning levels after intraperitoneal instillation at each dose level.   
The chloroprocaine plasma concentration-time profile for each dose level will be examined after each 
cohort has completed the study.  Enrollment of a subsequent dose cohort will not occur until data 
analysis is complete for the previous dose cohort.   
Adverse events will be tallied.  Baseline characteristics and surgical details will be presented in 
summary. 
The statistical software STATA (Stata Corporation, College Station, TX) will be used for all analyses.   
 
PRIVACY, CONFIDENTIALITY AND DATA SECURITY 
The results of the study as well as all other information collected on the data collection sheet will be 
stored in the locked office of the research coordinator.  The office requires a key for entry.  Only 
research personnel are allowed access to the office. No protected health information or other data 
collected during the completion of this randomized controlled trial will be taken off campus.  All data 
gathered for this study will be coded before any analysis or publication occurs. 
 
This study number will not contain any of the 18 HIPAA identifiers such as: geographic location, dates 
related to the individual, medical record number, account numbers, etc.  The key linking study 
subjects to study code will be kept in an OHSU approved cloud location with special protection for 
confidential and restricted health information (the OHSU Box).  Only the principal investigator and 
IRB approved study staff will have access to this key. 
 
Clinical data (including adverse events (AEs) and expected adverse reactions data) and laboratory 
data will be entered into APOM OCEAN, a 21 CFR Part 11-compliant electronic data capture system 
provided by the Department of Anesthesiology and Perioperative Medicine. The EDC includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 

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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 11 of 15 
 
In order to maintain patient privacy, data capture tools, study drug accountability records, study 
reports, and communications will identify the patient only by the assigned patient number. The 
investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authorities access to the patient’s original medical records, including medical history, laboratory 
studies, and medication administrations, for verification of data gathered and to audit the data 
collection process. This information will be accessed for the duration of the research study, including 
the follow-up period, for the purpose of data reconciliation. The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF SUBJECTS 
DSMP submitted as a separate document. 
 
A finding of plasma chloroprocaine concentrations > 0.97 mg/kg will halt the study and we will 
immediately (within two working days) report the finding to the IRB.  In addition, the exposed patient 
will be notified and the medical team will be notified.  Due to the short plasma half-life of 
chloroprocaine patients will have cleared the drug long before any data on plasma concentrations 
can be obtained. 
Significant clinical manifestations of local anesthetic systemic toxicity will similarly halt the study and 
prompt immediate (within two working days) notification of the IRB.  In addition, all medical teams 
involved in the patient’s care will be notified and the patient will receive a detailed summary of the 
event upon resolution of the event.  In the scenario that the patient lacks the ability to comprehend 
the adverse event the patient’s family will be notified.  For purposes of this study significant clinical 
manifestations will include the following: 
• 
Seizures 
• 
Respiratory Depression with desaturation (sat < 88%) 
• 
Hypotension defined as a greater then 20% drop in mean arterial pressure within 5 minutes 
of receiving chloroprocaine 
• 
Any arrhythmias associated with hypotension 
• 
Cardiac Arrest 
 
RISKS AND BENEFITS 
Risks to Subjects 
As with all studies, breach of confidentiality is a common risk.  In addition, there is the possibility of 
slightly increased anxiety on the day of surgery for patients approached for inclusion in the study.  
There is also likely to be a loss of free time in the preoperative area as consent and study education 
will likely take 20 minutes to complete. As data collection will continue to occur throughout the 
patient’s surgery and postoperative care, inconvenience is possible. 
 
Chloroprocaine has a long history of safe use and is assumed to have a low potential for systemic 
toxicity because of its very short maternal (mean 11.2 seconds, SD 2.8)20 and fetal plasma half-life 
(mean 15.4 seconds, SD 5.2)20 and relatively high maximum recommended dosage (11 mg/kg without 
epinephrine).  
 

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11.30.18   Phase 1                                                                   CLOR-PRO – Protocol                                                                    Page 12 of 15 
The clinical presentation of local anesthetic systemic toxicity is quite variable21.  Most case reports 
describe local anesthetic systemic toxicity after administration of local anesthetics with a much longer 
duration of action than chloroprocaine21,22.  In general, local anesthetics first cause central nervous 
system excitation (e.g. anxiety, agitation, muscle twitching, seizures) followed by central nervous 
system depression (e.g. sedation, respiratory depression) and then cardiovascular effects (e.g. 
bradycardia, hypotension, arrhythmias, cardiac arrest)21.    
 
In a review of reported cases of local anesthetic systemic toxicity published in 2015 there were no 
cases of local anesthetic systemic toxicity attributed to chloroprocaine.21  A search of PubMed and 
Google revealed 3 articles that describe systemic toxicity from chloroprocaine19,23,24.  Cladis et al24 
described a 30 second self-limited wide complex bradycardia after a 30 mg/kg inadvertent vascular 
injection through a caudal catheter in a 2 month old infant.  Hernandez et al23 described a 40 second 
self-limited seizure after a 28.7 mg/kg inadvertent vascular injection through a paravertebral catheter 
in a 9 month old infant.  Marsch et al19 described 34 patients with non-life threatening symptoms of 
local anesthetic systemic toxicity after direct intravenous injection of 200 to 400 mg of chloroprocaine 
into patients with an average weight of 70 kg (2.8-5.7 mg/kg).  Symptoms lasted 3 to 11 minutes and 
included the following: dizziness (34 patients), tinnitus (13 patients), metallic taste (10 patients), 
nausea or vomiting (4 patients), and slight bradycardia (2 patients).  None of the patients described 
in any of the 3 articles had any long term morbidity or mortality19,23,24.  
 
Chloroprocaine has been touted as the preferred local anesthetic for providing epidural anesthesia 
to laboring women with a decompensating fetus because it does not participate in ion trapping like 
other local anesthetics. Local anesthetics are weak bases which become ionized when exposed to 
acidotic environments.  Ion trapping occurs when non-ionized local anesthetics cross the placenta 
and become ionized by the more acidotic fetal circulation, compared to maternal blood pH.  After 
local anesthetics become ionized they cannot cross back into maternal circulation.  Accumulating 
local anesthetic causes the fetus to become more acidotic which results in more ion trapping.  
Placental transfer of chloroprocaine has not been shown to be influenced by the degree of fetal 
acidosis.25 
 
Literature describing chloroprocaine instillation into the intraperitoneal space is sparse.  Accordingly, 
there is a possibility of local anesthetic systemic toxicity in this study.  To this extent adverse 
experience reporting will include monitoring for and publishing the occurrence of any of the following 
adverse events associated with chloroprocaine instillation:  
• 
Seizures 
• 
Tinnitus 
• 
Metallic taste 
• 
Anxiety 
• 
Agitation 
• 
Muscle twitching 
• 
Sedation 
• 
Respiratory Depression with desaturation (sat < 88%) 
• 
Dizziness 
• 
Nausea 
• 
Vomiting 
• 
vision changes 
• 
paresthesias 

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• 
perioral numbness 
• 
Hypotension (drop in MAP >20% within 5 minutes of chloroprocaine administration) 
• 
Arrhythmias defined as a change in EKG rhythm 
• 
Cardiac Arrest 
 
Participants will not incur any additional cost for participating in this study. 
 
Potential Benefits to Subjects 
We are performing this study because the incidence of intraoperative pain during cesarean sections 
is high and standard practice in developed countries is to induce general endotracheal anesthesia 
when spinals are inadequate.  General endotracheal anesthesia in the pregnant population is 
associated with an increased incidence of pulmonary and airway complications, compared to 
neuraxial anesthesia.   Furthermore, general anesthesia hinders early maternal-baby bonding.  
Whether intraperitoneal chloroprocaine can safely and effectively treat intraoperative pain is 
unknown.  We anticipate that patients that receive intraperitoneal chloroprocaine will have less 
intraoperative pain, require less systemic narcotics, and have less nausea.  Intraperitoneal 
chloroprocaine may also decrease the need to convert to general endotracheal anesthesia during 
cesarean sections.  While the purpose of this study is not to assess intraoperative pain, narcotic usage, 
and nausea, patients may still receive these benefits. 
 
DRUGS  
Chloroprocaine is an ester type local anesthetic that decreases pain by blocking sodium channels and 
preventing transmission of pain signals to the brain.  It is available as a 1%, 2% and a 3% solution.  On 
labor and delivery at OHSU we stock 20 ml vials of 2-chloroprocaine (3%).  There are case reports of 
neurologic complications after chloroprocaine injection into the intrathecal space.  There are now 
thought to be related to the preservative sodium bisulfate.26  Consequently, the chloroprocaine 
stocked at OHSU is preservative free.  Chloroprocaine is FDA approved as well as approved for OHSU 
use by the Pharmacy and Therapeutic Committee. FDA indications include infiltration, nerve block, 
spinal, epidural and caudal anesthesia.  Chloroprocaine is not FDA approved for intraperitoneal 
lavage. It was introduced into anesthetic practice decades ago and has been used safely to provide 
rapid and reliable epidural blockade for obstetric procedures. The mean in vitro half-life of 
chloroprocaine in maternal and fetal plasma is 11.2 seconds (SD 2.8) and 15.4 seconds (SD 5.2), 
respectively.20  Placental transfer of chloroprocaine is minimal because of the drug’s high rate of 
metabolism. 
 
The chloroprocaine available in the anesthesia cart will be used for intraperitoneal administration.  A 
researcher involved in the study will dilute chloroprocaine to the desired concentration with sterile 
saline.   
 
Each patient will be administered all 40 ml of study solution.  There will not be residual medication 
after patient administration that requires disposal.  Any unused study drugs at the conclusion of the 
study will be destroyed at OHSU in a manner consistent with ICH/GCP guidelines, city of Portland 
regulations, state of Oregon regulations, federal policy, and OHSU institutional policy.  
 
BUDGET 
The cost to create the collection protocol that included inhibition of chloroprocaine degradation after 
collection and liquid chromatography tandem mass spectrometry assay for measuring blood 

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concentrations of chloroprocaine and its major metabolite, chloroaminobenzoic acid, with validation 
was under $5000.  An OHSU SOM Research Core Grant was used to fund this.  We received funding 
for this study from The Collins Medical Trust in the amount of $30,000 (PPQ#1016328).  Departmental 
support was obtained to fund study initiation. 
 
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