Clinical trial NCT04398316
Conditions: Abdominal Pain Renal Colic
Keywords: lidocaine hydromorphone abdominal pain
Sponsor: Hennepin Healthcare Research Institute
Start date: 2021-02-18; Completion date: 2021-06-30
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Intravenous lidocaine will be given at a dose of 2 mg/kg intravenously to patients in the emergency department with a diagnosis of acute abdominal pain. Its efficacy will be compared to 1 mg of intravenous hydromorphone, with a primary endpoint of mean improvement of pain at 90 minutes.

Detailed description:
Abdominal pain is a common chief complaint for patients presenting to the emergency department (ED) in the United States. Intravenous opioids are commonly used to treat acute abdominal pain in the ED. These medications are highly efficacious and, when used in a monitored setting such as the ED, extremely safe. Use of opioids has fallen out of favor because of a spike in opioid-related overdose deaths throughout the United States. While use of opioids in the ED is unlikely to contribute to outpatient opioid deaths, minimizing the use of opioids in the ED will contribute to an opioid free culture, in which opioids are used only when absolutely necessary. A variety of different types of medications can be used in lieu of opioids. One such medication, intravenous lidocaine, has been used extensively for neuropathic pain, in the peri- and post-operative surgical setting, the cardiac care unit, and most recently in the emergency department.

Intravenous lidocaine has long been used to treat pain. In publications dating back to 1980, intravenous lidocaine has been shown to be an effective treatment for neuropathic pain. In the postoperative setting, intravenous lidocaine decreased pain and decreased the need for opiates. More recently, emergency medicine investigators in Iran demonstrated that intravenous lidocaine decreased pain associated with renal colic and limb ischemia. An ED-based study in the United States showed comparable efficacy between morphine and intravenous lidocaine when used for acute pain. Most recently, a prospective RCT showed 120 mg of intravenous lidocaine was efficacious for abdominal pain, albeit not as effective as 1 mg of hydromorphone. However, a subgroup analysis showed that when lidocaine was dosed at 2 mg/kg, it was equally as effective as hydromorphone.

Over the years, intravenous lidocaine has been used for a variety of indications including arrhythmia prophylaxis in patients with acute coronary syndromes. Known side effects of intravenous lidocaine range from transient neurological symptoms (dizziness, paresthesias), to cardiac dysrhythmias and seizure. To date, no deaths have been attributed to its use for treating pain, and the only documented significant complication was due to an unintentional overdose when a patient received ten times the normal dose. All reported side effects in pain patients have been transient and resolved by either stopping the drug, decreasing the infusion rate or by observation alone. Additionally, doses of 2 mg/kg have been tolerated well in the outpatient setting, operating room and ED without any serious side effects. Thus, intravenous lidocaine is an emerging medication for safe and rapid relief of pain, has no known addictive properties, and creates a potential for a pain practice paradigm shift in the United States.

We therefore propose a randomized, double blind, comparative efficacy trial to address the following aim:

To determine if a 2 mg/kg dose of intravenous lidocaine is as equally efficacious as a single dose of 1 mg intravenous hydromorphone for acute abdominal pain in the emergency department.

Arms: arm 1: Administered at a dose of 2 mg/kg over 5 minutes arm 2: Administered at a dose of 1 mg over 5 minutes
Interventions: intervention 1: Lidocaine Iv intervention 2: HYDROmorphone Injection
Intervention descriptions: intervention 1: 2 mg/kg over 5 minutes intervention 2: 1 mg over 5 minutes

Protocol documents:
Prot_SAP_000.pdf: 
Attachment UUU
High Dose IV Lidocaine vs Hydromorphone for Abdominal Pain in the Emergency
Department (HIDO-LIDO)
NCT = NCT04398316
Document Date = 7/21/2020
Template version: March 27, 2019
Template adapted from: Children’s Hospital of Philadelphia Research Institute


Attachment UUU
Title:
HIgh DOse Intravenous LIDOcaine vs Hydromorphone for
Acute Abdominal Pain in the Emergency Department: A
Prospective, Blinded, Randomized, Comparative Efficacy
Trial (HIDO-LIDO)
Drug or Device
Name(s):
Lidocaine
FDA IND/IDE
151174
Sponsor:
Elliott Chinn, DO
Protocol Date:
Revision Date(s):
5/27/2020
6/25/2020
6/23/2020
7/21/2020
Elliott Chinn, DO:
Hennepin Healthcare
Department of Emergency Medicine, R2
Minneapolis, MN, 55415
Phone: 612-873-3508
email: elliott.chinn@hcmed.org
Template version: March 27, 2019
Template adapted from: Children’s Hospital of Philadelphia Research Institute


PROTOCOL SYNOPSIS
Study Title
HIgh DOse Intravenous LIDOcaine vs Hydromorphone for Acute
Abdominal Pain in the Emergency Department: A Prospective,
Blinded, Randomized, Comparative Efficacy Trial (HIDO-LIDO)
Funder
Department of Emergency Medicine
Clinical Phase
Phase IV
Study Rationale
The rationale for this study is to find an alternative to opioids for treating
acute pain in the emergency department. In a subgroup analysis of a
recently published study, intravenous lidocaine at a dose of 2 mg/kg had
equivalent efficacy for acute abdominal pain compared to 1 mg of
hydromorphone, thus warranting further investigation with a prospective,
randomized clinical trial (14).
Study Objective(s)
Primary
●
To determine the analgesic efficacy of intravenous lidocaine
dosed at 2 mg/kg for acute abdominal pain in the emergency
department, as compared to a single 1 mg dose of
hydromorphone.
Secondary
●
To compare the safety of intravenous lidocaine dosed at 2 mg/kg
compared to a single 1 mg dose of hydromorphone.
Test Article(s)
(If Applicable)
Lidocaine, administered intravenously at a dose of 2 mg/kg, over 5
minutes.
Hydromorphone, administered intravenously at a dose of 1 mg, over
5 minutes.
Study Design
This will be a prospective, randomized, double blinded, comparative
efficacy trial.
Subject Population
Key Criteria for
Inclusion and Exclusion:
Patients aged 18-64 presenting to the emergency department with
severe (defined as requiring an intravenous opiate) acute (defined as
duration of 7 days or less) abdominal pain (anywhere on the
abdomen or flank).
Number Of Subjects
Total Number of Subjects: 187
Total Number at Hennepin Healthcare: 187
Total Number of Sites:1
Study Duration
Each subject’s participation will last one week.
The entire study is expected to last twelve months.
Study Phases
Screening
This study will have three phases. Screening and intervention will
occur on the same day in the emergency department. Follow up will
occur 7 days later.


Intervention
Follow-Up
Efficacy Evaluations
The primary outcome for this study will be mean pain score
improvement after 90 minutes from administration of study drug.
Pharmacokinetic
Evaluations
Not applicable
Safety Evaluations
Patient reported side effects, medications required to treat side
effects, administration of naloxone, change in disposition attributed
to study drug and incidence of any serious adverse events.
Statistical And Analytic
Plan
Intention to treat. Statistical analysis will be primarily t-tests and
chi-square tests.
Data And Safety
Monitoring Plan
A DSMB will be in place.


5
TABLE 1: SCHEDULE OF STUDY PROCEDURES
Screenin
g
Minutes from initiation of infusion
7
Days
0
15
30
60
90
120
150
180
Informed
Consent
x
Review
Inclusion and
Exclusion
Criteria, Including History &
Physical Exam, Review of
CMP, PTT and PT/INR
x
Record Demographic
Information,Medical
History
x
Record Height and Weight
x
Pregnancy Test
x
Screening EKG
x
Pain Score
x
x
x
x
x
x
x
x
Adverse events and side
effects
x
x
x
x
x
x
x
x
Heart Rate
x
x
x
x
x
x
x
x
Respiratory Rate
x
x
x
x
x
x
x
x


6
TABLE 1: SCHEDULE OF STUDY PROCEDURES (CONTINUED)
Screenin
g
Minutes from initiation of infusion
7
Days
0
15
30
60
90
120
150
180
Systolic Blood Pressure
x
x
x
x
x
x
x
x
Diastolic Blood Pressure
x
x
x
x
x
x
x
x
Pulse Ox
x
x
x
x
x
x
x
x
Sufficient Pain Relief
x
x
x
x
x
x
x
Medication Preference
x
x
Adverse events Requiring
Intervention
x
x
x
x
x
x
x
Administration of Naloxone
x
x
x
x
x
x
x
Disposition Change
x
x
x
x
x
x
x
Presence of misdiagnosis
x


7
FIGURE 1: STUDY DIAGRAM
.


1
BACKGROUND INFORMATION AND RATIONALE
1.1
Name and Description of Investigational Product or Intervention
There are two investigational medications, lidocaine and hydromorphone.
1.2
Findings from Non-Clinical and Clinical Studies
Opiate abuse continues to be an epidemic in the United States. Between 2015 to 2016, the
number of unintentional opiate overdose deaths doubled (39). While national attention to this has
made slight improvements, recent data show that deaths due to opiates are four times higher than
they were 20 years ago (40).  The majority of those with an opiate use disorder can trace their
first encounter with an opiate to a prescription opiate (38). It is intuitive that if patients require an
opiate in the emergency department for their care, they are more likely to require a prescription
for an opiate upon discharge. Data varies on how many of these patients will go on to develop an
opiate use disorder after a prescription, but recent data showed that 1% of patients in one ED
would go on to develop opiate use disorder (defined by them as 6 more more opiate prescriptions
in 6 months).  While that percentage may be small, one should consider that pain of any kind is
the most common chief compliant of patients who present to the emergency department, with
45% of patients between 2000-2010 having pain as their chief complaint (41).
One way to combat the opioid epidemic is to use non-narcotic medications to treat acute
pain. Intravenous lidocaine is a non-narcotic medication which may be a suitable candidate for
this. A previously conducted clinical trial by this group tested lidocaines efficacy against
hydromorphone, a commonly administered narcotic in the emergency department, for acute
abdominal pain. Briefly, patients with acute abdominal pain received either 120 mg of
intravenous lidocaine (approximating a 1.5 mg/kg dose) or 1 mg of hydromorphone. While
lidocaine improved pain scores at 90 minutes, it did not improve them as well as hydromorphone
(3.8 improvement compared to 5 on a pain scale of 1-10). However, a subgroup analysis showed
that patients who received a dose of 2 mg/kg (because they weighed less) had their pain
improved by 5 points, equal to that of hydromorphone. This subgroup analysis is the impetus for
this clinical trial. If in fact 2 mg/kg of intravenous lidocaine can treat pain as well as
hydromoprhone, the need for narcotics in the emergency department could be significantly
reduced which could minimize the need for prescribing opiates from the emergency department.
1.2.1
Non-Clinical Studies
Below you will find animal data in support of the use of intravenous lidocaine. This is
directly from the IND application.
Malavasi et al. (16) studied how adding intravenous lidocaine to propofol affected
hemodynamics in adult goats receiving abdominal surgery. Goats were randomized to receive
either a bolus of lidocaine  at 2.5 mg/kg over 20 minutes followed by lidocaine infusion at 100
mcg/kg/min or placebo (saline). There were 23 goats in total, 12 in the lidocaine group and 11 in
the saline group. Goats received continuous cardiac monitoring, invasive blood pressure
measurements (arterial lines), and continuous end-tidal CO2 monitoring. No goats experienced
any hemodynamic changes. Two episodes of bradycardia were noted in goats receiving lidocaine


and per protocol, they received atropine, however they experienced no changes  in blood
pressure. The authors noted that these episodes of bradycardia occurred while the goats were
having their bladders manipulated, suggesting it may have been due to a vagal response rather
than due to the lidocaine. Additionally, the lidocaine or saline was given in addition to 0.13
mg/kg of intramuscular xylazine, 2.2 mg/kg of intravenous ketamine, and 0.1 mg/kg of
intravenous butorphanol. To summarize, goats received a comparative dose of intravenous
lidocaine to the dose we are proposing without any  major adverse cardiopulmonary events and
only two clinically insignificant events which were unlikely to have been due to lidocaine.
Cerasoli et al. (17) studied the effects of intravenous lidocaine before induction of
anesthesia with propofol on healthy dogs, assessing for quality of intubation, cough reflex and
adverse effects. All dogs received intramuscular 1mcg/kg dexmedetomidine, 0.2 mg/kg
intramuscular methadone, and were randomized to either 2 mg/kg of intravenous lidocaine given
over 30 seconds minutes or placebo (saline). There were no major adverse events and both
groups had one dog develop first degree heart block (not statistically different). Both groups had
decreases in heart rate and blood pressure compared to their presurgical baseline, however no
measurements were abnormal or required any intervention and there was no statistically
significant difference between the two groups. To summarize, a 2 mg/kg bolus given over 30
seconds caused no significant adverse events in dogs receiving surgery.
MacDougall et al. (18) studied the use of intravenous lidocaine on adult dogs in an
outpatient setting. Dogs were randomized to receive either a bolus of intravenous lidocaine or
saline at a dose of 2 mg/kg over 60 seconds following by an infusion of lidocaine at doses of
either 10 mcg/kg/min, 25mcg/kg/min, 50 mcg/kg/min, 75mcg/kg/min or 100 mcg/kg/min, over
12 hours. Each dog had previously served as its own control, receiving placebo (saline) at a
minimum of one week before. Several measurements were taken, including heart rate, blood
pressure (automated), respiratory rate (measured visually), sedation score (on a scale of 1-4), and
nociceptive threshold. These were taken at time 0, 10 minutes, 30 minutes, 1 hour, 2 hours, 4
hours, 8 hours, 12 hours, 12.25 hours, 12.5 hours, 13 hours, and at 24 hours after the onset of the
infusion. Throughout the study, there were no significant changes to heart rate. At 4 hours, there
was a paradoxical increase in blood pressure (MAP) for dogs receiving an infusion rate of 100
mcg/kg/min, this resolved at the next measurement. Decreases in respiratory rate were measured
at multiple infusion rates (25, 50, 75 and 100) beginning at 2 hours and resolving by 12 hours  15
minutes after initiation of lidocaine infusion. Sedation scores ranged from 1 to 2 as early as 10
minutes after initiation of infusion at all doses. Scores were either 1, defined as "Moderate
sedation, easy to handle, still spontaneously active, responds to name, but slower" or 2, defined
as “Moderate-heavy sedation, less spontaneous activity, verbal encouragement needed to rise,
minimal resistance to handling”.
There were two raters for each dog and the median scores were reported. Dogs receiving
a rate of 10 mcg/kg/min had sedation scores of 1, those with rates of 25mcg/kg/min ranged from
0.5 to 1, those with rates at 25mcg/kg/min had scores ranging from 1 to 1.5, those receiving rates
at 75mcg/kg/min had sedation scores from 0.5 to 2 and those receiving rates at 100 mcg/kg/min
had scores from 0.5 to 2.
Curiously, there were multiple instances where receiving lower infusion rates had higher
sedation scores. At all times throughout the study, dogs were able to walk and no dog had a
seizure. Toxic doses for lidocaine in dogs are at 11.2mcg/ul. No dog had a concentration greater


than 9mcg/ul and most had levels below 7mcg/ml. To summarize, no dog suffered any
significant hemodynamic events and while most dogs had some degree of sedation, none
required any intervention and no dog had plasma concentrations that went over the toxic range.
1.2.2
Clinical Studies
1.2.2.1
Human Pharmacokinetics
Below you will find data in support of the broadened use of intravenous lidocaine at a dose of 2
mg/kg, specifically for patients who are taking medications that inhibit lidcaoines metabolism. This is
directly from the IND application.
Lidocaine is metabolized primarily by CYP1A2 and less so by CYP3A4. Given that some
patient may be taking medications that are inducers of these pathways or that affect liver
function, a literature review was conducted to justify not excluding patients who are on
medications that inhibit CYP1A2 and CYP3A4 or medications that slow down hepatic flow.
Lidocaine is metabolized primarily by CYP1A2 and less so by CYP3A4. Given that some
patient may be taking medications that are inducers of these pathways or that affect liver
function, a literature review was conducted to justify not excluding patients who are on
medications that inhibit CYP1A2 and CYP3A4 or medications that slow down hepatic flow.
First, the majority of lidocaine research referenced in this application did not exclude
patients taking drug that inhibit CYP1A2 and CYP3A4 or drugs that decrease hepatic flow (10,
11, 13, 14). This includes patients who received a dose of 2 mg/kg (12, 20, 21, 22). One article
excluded patients taking any medication without justification why (23).
While one study excluded patients who received cimetidine (an inhibitor of CYP1A2),
they included patients who took propranolol (19). The dose of lidocaine was 3 mg/kg. The worst
side effects were a few cases where mean arterial blood pressure dropped below 65, requiring a
dose of ephedrine, however all of those patients had received 30 mcg/kg (cumulatively) of
fentanyl, 0.12 mg/kg of morphine and 2mg of lorazepam two hours before surgery, and in the
morning had received their cardiac medications, either a calcium channel blocker, beta blocker,
or nitrates. These patients were all having sternotomies done with subsequent cardiac bypass
surgery. Opiates within the previous week would exclude someone from this study, as per the
protocol, so it is reasonable to believe that patients in the proposed study would not have similar
side effects (hypotension).
Second, the dose I am suggesting is actually similar to the FDA dosing for a ventricular
arrhythmia. While the initial bolus is 1.5 mg/kg, additional doses at 0.5 mg/kg can be given up to
three times every five minutes. Therefore, if a patient were to receive the first and second dose of
lidocaine, it would be a total of 2 mg/kg over five minutes.
Third, this article specifically addresses the concern of taking a CYP1A2 medication
while receiving lidocaine (24). Healthy volunteers took 6 days of fluvoxamine, a potent CYP1A2
inhibitor, then on day 6, received a 1 mg/kg intravenous bolus of lidocaine over one minute.
While it did have a negative effect on metabolism, plasma level did not begin to approach a level
of toxicity. Referencing Figure 1, the apparent maximum plasma concentration is 1000 ng/ml


which would be 1 mg/L. Central nervous system (CNS) and cardiovascular toxicity (CV) starts
at 8 ng/L which is remarkably higher than the effect observed in the study. Furthermore, only a
few patients experienced any side effects and they were all mild and transient (last paragraph of
page 5). Yes, CYP1A2 and CYP3A4 will increase plasma concentrations of lidocaine, but not in
a way that is clinically relevant. While they recommend decreasing doses of lidocaine in patients
taking drugs that inhibit CYP1A2, they recommend that for infusions, not for one time boluses
(second bullet point, page 8).
Fourth, medications that decrease hepatic blood flow (propranolol) would cause similar
effects to those seen in patients with chronic liver disease (Child Pugh A). Patients did not have
any serious toxicity when they were given the same bolus as the previously mentioned study (1
mg/kg over 1 minute)(24).
Fifth, another article shows that when you give erythromycin (CYP3A4 inhibitor) and
fluvoxamine (CYP1A2 inhibitor), with a lidocaine infusion of 1.5 mg/kg over 60 minutes,
lidocaine levels do not approach toxicity (25). The mean plasma concentration of lidocaine was
1028 ng/mL (SD 403) when both drugs were given. Again, the beginning of CNS or CV toxicity
is 8000 ug/mL (or 8mg/L).
Sixth, in the largest meta-analysis of intravenous lidocaine, 48 studies were included in
their analysis and 45 had explicit exclusion criteria (3). Three did not have exclusion criteria
available. The only one that did have exclusion criteria resembling what is being requested
would be the article cited above that excluded patients taking cimetidine. So, 44 studies did not
feel it necessary to have the exclusion criteria being requested.
Seventh, an in-depth review of the exclusion criteria in the meta-analysis for neurparthic
pain (2), out of the eleven articles I could manually review (27-37), none of them had exclusion
criteria matching or similar to what is being requested. Many of the doses in those studies went
up to 5 mg/kg over as little as 30 minutes.
To summarize, a thorough review of the literature does not support excluding patients
who, within 2 weeks or 5 half-lives of taking intravenous lidocaine, have taken either a
medication that inhibits CYP1A2, inhibits CYP3A4, or decreases hepatic flow.
1.2.2.2
Clinical Studies in Adults
\
Below you will clinical human data in support of the use of intravenous lidocaine and at a
dose of 2 mg/kg. This is directly from the IND application.
Lidocaine HCl is FDA approved for the treatment of ventricular arrhythmias in
myocardial dysfunction and in cardiac surgery. The dose for that indication is 1.5 mg/kg, with
repeat doses 0.5-0.75 mg/kg up to a total dose of 3 mg/kg over 15 minutes. Given that this
indication is for the treatment of an arrhythmia, some may consider it unfair to compare the
safety of that dose range for patients without a cardiac arrhythmia, since one of the most feared
complications from intravenous lidocaine is an arrhythmia. To support the safety of our intended
use, acute abdominal pain, we have conducted a literature of peer reviewed articles who have
used lidocaine at a dose of 2 mg/kg for the treatment of pain, either in the operating room or in
the emergency department.


Kasten et al. (19) investigated whether adding a 3 mg/kg dose of intravenous lidocaine
with infusion of 0.05 mg/kg/min to a fentanyl infusion at 5mcg/kg/min would prevent
hyperdynamic changes in patients undergoing cardiac surgery. Ten patients would ultimately
receive lidocaine. This was a  double blinded, randomized comparative efficacy trial. Prior to
receiving either of these medications. The morning of the surgery, patients had received beta
blockers, calcium channel blockers and nitrates. Forty five minutes prior to the surgery, patients
received an intramuscular injection of morphine at 0.12 mg/kg and 2 mg of lorazepam. If there
were increases in a patient's blood pressure or heart rate, pushes of fentanyl were given and if
that was insufficient, patients received a nitroglycerin infusion and isoflurane until
hemodynamics returned to baseline. Serious adverse events in those who received lidocaine
occurred in three patients. Their mean arterial blood pressure dropped below 60 and per study
protocol, required intravenous ephedrine to increase it. This was limited to when patients were
intubated. Outside of that time period, no patients who received lidocaine had any serious
adverse events.
While this article had the highest rate of serious adverse events, it had the sickest patients
and there was significant polypharmacy involved. Several inclusion criteria were the patient
must have been on a beta blocker, had an ejection fraction between 45-60%, and each patient had
to have angiogram proven coronary artery disease. The study we are proposing would exclude
patients if they had received any opiates prior to the study, primarily to eliminate a confounding
variable but now also to eliminate potential hypotension. Additionally, we are excluding any
patient with an EKG showing any prolonged intervals. Therefore, taking into account that we are
using a lower dose and taking precautions to prevent the adverse events that occurred in this
study, we believe it ultimately supports our use of it.
Kuo et al. (20) compared intravenous lidocaine at a 2 mg/kg bolus followed by an
infusion at 3 mg/kg/h to thoracic epidural analgesia (TEA) with a lidocaine bolus and infusion at
the same dose to a placebo group in patients receiving scheduled thoracotomies. This was a
double blinded, randomized clinical trial. The amount of perioperative and postoperative opiates
required was lowest in the TEA group followed by the intravenous lidocaine group and control
group. There were only three instances of hemodynamically insignificant bradycardia in the
lidocaine group. There was no difference between the three groups regarding the need for
atropine or ephedrine for hemodynamic compromise. To summarize, intravenous lidocaine safely
improved abdominal pain in patients receiving planned thoracotomies.
Saadawy et al. (21) compared intravenous magnesium sulfate (50 mg/kg) to intravenous
lidocaine (2 mg/kg) to placebo, measuring post-operative analgesia requirements in patients
undergoing a laparoscopic cholecystectomy. Each group also got an infusion of the same
medication, with magnesium  at 25 mg/kg/h and lidocaine at 2 mg/kg/h. This was a randomized,
double blinded comparative efficacy trial with 40 patients in each arm. There were zero major
adverse events across all groups in the study, and there were no differences between each group
with recorded heart rates or mean arterial blood pressures. The lidocaine arm required the least
amount of postoperative morphine and the least amount of intraoperative fentanyl and
sevoflurane. To summarize, lidocaine improved abdominal pain with zero serious adverse events.
Yardeni et al. (22) compared intravenous lidocaine bolus at 2 mg/kg followed by an
infusion at 2 mg/kg to placebo for patients receiving scheduled transabdominal hysterectomies.
This was a prospective double blinded clinical trial and there were thirty patients in each arm.


The primary outcome was mean pain score postoperatively and lidocaine was superior to placebo
up to 8 hours postoperatively, however there was no difference in opiate requirements
postoperatively. There were no adverse events reported in this trial. To summarize, intravenous
lidocaine bolus and infusion improved patients’ post-operative pain up to 8 hours.
Yang et al. (23) compared intravenous lidocaine to thoracic epidural analgesia to placebo
for patients receiving scheduled thoracotomies. This was a prospective, single blinded,
comparative efficacy trial. There were 20 patients in each group. The main outcomes were time
to loss of consciousness, anesthesia requirements intraoperatively (amount of propofol) to
maintain normal vital signs. Essentially, these were surrogates of patient discomfort which is
why it is pertinent to the study we are proposing. There were no significant adverse events in any
group.
Vahidi et al. (12) compared intravenous lidocaine at 2 mg/kg bolus to morphine 0.1
mg/kg bolus in patients with critical limb ischemia in the emergency department. There were 20
patients in each arm and it was a prospective, randomized comparative efficacy trial. Primary
endpoints were mean improvement in pain at 15 and 30 minutes. At both times, intravenous
lidocaine had better pain improvement compared to intravenous morphine. There were zero
adverse events in this study.
Chinn et al. (14) administered either lidocaine at a set dose of 120 mg intravenously or 1
mg of intravenous hydromorphone for patients suffering from acute abdominal pain in the ED.
Patients were excluded if they weighed less than 60kg or more than 120kg and were eligible for
a repeat dose after 30 minutes. Therefore, it was theoretical that some patients could get a dose
of 4 mg/kg over 45 minutes. A subgroup analysis showed that intravenous lidocaine was equally
efficacious as 1 mg of hydromorphone if patients received an intravenous dose of lidocaine at 2
mg/kg without any increase in adverse events. Zero serious adverse events occurred in this study
and there was no difference in adverse events between either group.
To summarize the available data on intravenous lidocaine dosed at 2 mg/kg or higher,
most studies have been done in the operating room and one has been done in the emergency
department. The only study with any significant adverse events was in the first trial done by
Kasten et al. These events were hemodynamically significant hypotension. However, all of these
patients had critical ischemic heart disease (proven by angiography), had received a beta blocker
that day, and shortly before receiving the study drugs, received morphine and lorazepam.
Furthermore, neither group received intravenous lidocaine by itself, it was fentanyl with or
without intravenous lidocaine. Finally, the dose they chose was 3 mg/kg, significantly higher
than the dose we are proposing. The rest of the studies show, at a minimum, improved analgesia
compared to placebo and at best, superior analgesia to morphine.
1.2.2.3
Clinical Studies in Children
Not applicable, only patients aged 18-64 will be recruited for this study.
1.3
Selection of Drugs and Dosages
Lidocaine (NDC 0338-0411-02) will be dosed at 2 mg/kg and given intravenously over 5
minutes. Hydromorphone (NDC 0409-1283-31) will be given at a dose of 1 mg, intravenously
over 5 minutes. These are the maximum daily doses for each medication under this protocol,


however more hydromorphone can be given at the discretion of the treating provider if the
patient has insufficient analgesia.
1.4
Compliance Statement
This study will be conducted in full accordance of all applicable Hennepin Healthcare
Research Policies and Procedures and all applicable Federal and State laws and regulations. All
episodes of noncompliance will be documented and reported according to the Prompt Reporting
Guidelines, Attachment EEE, of the Hennepin Healthcare IRB Policies and Procedures.
The investigators will perform the study in accordance with this protocol, will obtain
consent and assent, unless waiver of consent or other alteration is approved, and will report
unanticipated problems involving risks to subjects or others and SAEs in accordance with The
Hennepin Healthcare IRB Policies and Procedures and all Federal requirements. Collection,
recording, and reporting of data will be accurate and will ensure the privacy, health, and welfare
of research subjects during and after the study.
2
STUDY OBJECTIVES
The overall objective of this study is to determine if intravenous lidocaine can have equal
analgesic efficacy as hydromorphone while having an equal safety profile in patients with acute
abdominal pain.
2.1
Primary Objective (or Aim)
The primary objective of this study is to determine whether intravenous lidocaine dosed at
2 mg/kg has equal analgesic efficacy as intravenous hydromorphone at 1 mg, as measured by the
improvement in pain score after 90 minutes following administration of study drug.
2.2
Secondary Objectives (or Aim)
The secondary objectives are to:
●
Measure improvement in pain at 15 minutes, 30 minutes, 60 minutes, 120 minutes, 150
minutes and 180 minutes following administration of study drug.
●
Measure frequency of sufficient pain relief, defined as no need for pain medication outside
of investigational drug.
●
Measure the safety of lidocaine, as determined by comparing its rate of side effects,
frequency of medication administration required to treat side effects, the frequency of
serious adverse events, disposition change attributed to study drug, and frequency of missed
diagnosis to hydromorphone.
●
To measure patient preference for the study drug they received (would they want it again).


3
INVESTIGATIONAL PLAN
3.1
General Schema of Study Design
Patients presenting to the emergency department with abdominal pain will be screened for
eligibility. Once deemed eligible, they will be randomized to receive either intravenous lidocaine
or hydromorphone. The patient, ED nurse and physician will all be blinded to the study drug.
Only the research pharmacist will know the drug that the patient is receiving. Primary and
secondary endpoints will be measured from the time just before the patient receives the study
drug and for the next 180 minutes then once again 7 days later (please refer to Table 1 for timing
and specific data being measured). The two drugs will then be compared against one another.
Much of each patient’s care will be “standard of care”, most likely to include intravenous
access, venipuncture, labs, imaging, and potentially consultations by other services. Please refer
to Figure 1 for an illustration of study interventions. Standard care can take place at anytime on
Figure 1.
3.1.1
Screening Phase and Baseline Assessment
The “screening phase” will take place in triage or in a treatment area in the emergency
department and will be considered to take place from when the patient arrives to the emergency
department to when then patient completes their consent form, during the same visit.
Inclusion and exclusion criteria will be posted throughout the emergency department.
Any staff member can notify a physician or advanced practice provider if a patient may
meet study criteria, once that has been determined, staff will notify a study research associate to
ensure patient has all inclusion criteria and no exclusion criteria and then obtain informed
consent.
The attending physician will ensure that each patient has capacity to participate in
informed consent and will document this on the patients consent form.
3.1.2
Study Intervention
The study intervention will be the administration of either lidocaine or hydromorphone
and will take place during the “intervention phase” of the study. Both drugs will be given as a
drip over 5 minutes. This is for the purpose of blinding, as hydromorphone is generally given as
a push dose or very slowly, and lidocaine is safest when given over a slow infusion, typically
5-15 minutes. Giving hydromorphone over 5 minutes will increase its safety as this will decrease
its chances of causing respiratory depression or euphoria Lidocaine will be dosed at 2 mg/kg of
patients recorded weight, hydromorphone will be dosed at 1 mg. Intravenous hydromorphone
meets standard of care for severe pain in the emergency department. Intravenous lidocaine has
been shown to be effective for severe pain however it would not be considered standard of care
and is not FDA approved for treating pain (when administered intravenously).


3.1.3
Follow-up
The “follow up phase” will take place 7 days after administration of study drug and will be
completed by a study research associate via phone call.
3.2
Allocation to Groups and Blinding
Prior to the initiation of the study, a list will be generated which will randomly assign 187
patients to either lidocaine or hydromorphone in a roughly 50/50 distribution. This list will be
generated by someone not involved with the study and will be given to the research pharmacists.
Patients will be randomized by the research pharmacist in accordance with the list.
Ultimately research pharmacists will give the study drug to a nurse in a bag of saline. The
only identifying information on the bag will be a standardized label as follows
Header (**INVESTIGATIONAL MED**), Patient name, age, medical record number,
location, tube number, order number, due time and date, drug name (INV lidocaine or
hydromorphone in NaCL 0.9% 100 ml IVPB), intravenous, once, 100ml, infuse over: 5
minutes, time label printed, signature for preparer and checker, expiration, and “Caution:
New Drug - Limited by Federal (or United States) law to investigational use”
3.3
Study Duration, Enrollment and Number of Sites
3.3.1
Duration of Study Participation
Participants will participate for 7 days, however that participation on day 1 is limited to
180 minutes after administration of study drug. Patients will then be asked to participate 7 days
after administration of study drug, via a phone call, conducted by a study research associate.
3.3.2
Total Number of Study Sites/Total Number of Subjects Projected
The study will only be conducted in the Hennepin County Medical Center Emergency
Department. Recruitment will stop after 187 patients have been consented.
3.4
Study Population
3.4.1
Use of Vulnerable Populations and Patients Who Opt Out of Research
No vulnerable patients will be considered eligible for this study. Neonates and children
do not meet the minimum age of inclusion criteria. Pregnant women and fetuses will be excluded
by positive pregnancy test (urine or blood). Only patients who have capacity to consent,
ultimately determined and documented by the attending physician, can participate so patients
with diminished capacity to consent will be excluded. Adult prisoners will not be approached for


eligibility. Any patient who opts out of research will not be included in this study as consent is
required for study participation.
3.5   Inclusion and Exclusion Criteria
3.5.1   Inclusion Criteria
1) Adults at least 18 years of age but no more than 64
2) Abdominal (abdomen or flank) pain severe enough to warrant intravenous narcotics (as
determined by the clinical team), for a duration of 7 days or less
3.5.2   Exclusion Criteria
1) Pregnant or breast feeding
2) Prolonged cardiac intervals on EKG (QTc duration > 0.5s, QRS duration > 0.12s, PR interval
<0.12s or > 0.2s) or any cardiac history, defined as “cardiac arrhythmias, heart blocks,
congestive heart failure, or known cardiovascular disease, or deemed to have clinical signs of
heart failure on physical exam”. This EKG must be from the same day.
3) Renal impairment, defined as CKD > 2 (CKD 1 and 2 are acceptable), as verified by blood
work in the preceding 12 months, or evidence of renal impairment by history and/or physical
examination
4) Liver impairment, defined as Childs-Pugh B or greater, as verified by blood work in the preceding
12 months, or evidence of liver disease by history and/or physical exam
5) Hemodynamically unstable (as determined by attending physician)
6) Allergy to lidocaine or hydromorphone
7) Self-report of any opioid use within the previous 7 days
8) Diagnosis of chronic pain, defined as using any pain medication more days than not in the
previous 30 days
9) Inability to provide informed consent
10) Not wanting to participate in research
11) History of seizures
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of
these criteria must be reported in accordance with IRB Policies and Procedures.
4
STUDY PROCEDURES
4.1
Screening Visit and Baseline Assessment
Please refer to Table 1 for specific timing of procedures


●
Screen for meeting inclusion and exclusion criteria
●
Obtaining informed consent (including attending physician certifying the
patient is appropriately able to give consent
●
Recording of patients demographics and medical history (age, gender, history
of diabetes, high blood pressure, high cholesterol, heart disease defined as coronary
artery disease or congestive heart failure, seizures), history and physical exam to
exclude any clinical evidence of acute cardiac, renal or liver disease
●
Pregnancy test
●
EKG
4.2
Study Intervention
4.2.1
Time Zero
●
Pain score (1-10)
●
Patient placed on monitor
●
Vital signs recorded (heart rate, respiratory rate, systolic blood pressure,
diastolic blood pressure, pulse oximetry, source of oxygen)
●
Study drug administered by patient’s nurse (mixed by research pharmacist and
sent to the nurse) over 5 minutes
4.2.2
15 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified at this point as adverse events)
●
Recording of sufficient pain relief (yes or no)
●
Recording of any medications to treat adverse events (yes or no). If yes,
document was medication was administered, why, and when.
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of any change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)


4.2.3
30 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified at this point as adverse events)
●
Recording of sufficient pain relief (yes or no)
●
Recording of any medications to treat adverse events (yes or no)
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of  change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)
4.2.4
60 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified at this point as adverse events)
●
Recording of sufficient pain relief (yes or no)
●
Recording of any medications to treat adverse events (yes or no)
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of  change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)
4.2.5
90 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified at this point as adverse events)
●
Recording of sufficient pain relief (yes or no)


●
Recording of any medications to treat adverse events (yes or no)
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of  change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)
4.2.6
120 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified at this point as adverse events)
●
Recording of sufficient pain relief (yes or no)
●
Recording of any medications to treat adverse events (yes or no)
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of  change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)
4.2.7
150 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified at this point as adverse events)
●
Recording of sufficient pain relief (yes or no)
●
Recording of any medications to treat adverse events (yes or no)
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of  change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)


4.2.8
180 minutes after the study drug was started (not after it finished), up to a 15
minute delay will be tolerated
●
Pain score
●
Vital Signs (same as above)
●
Recording of any new symptoms (classified as this point as adverse events)
●
Recording of sufficient pain relief (yes or no)
●
Recording of any medications to treat adverse events (yes or no)
●
Recording on whether or not naloxone has been administered (yes or no)
●
Recording of  change in disposition thought to be due to study drug (yes or
no)
●
Recording of any serious adverse event (yes or no)
4.3
Follow Up
Patients will be called 7 days after their visit to the emergency department by a research
associate. If they cannot be contacted on that day, they will be contacted the next day (until they
are reached, up to one week), and asked to answer the same questions but based off of how they
felt 7 days after their visit. This will take place whether or not the patient is admitted or
discharged.
4.3.1
7 days after visit to emergency department
●
Any new adverse events (yes or no and if yes, list them)
●
Record and report any serious adverse event that has been reported by
participant
●
Medication preference (If the patient were to come back for the same
complaint, would they want the same drug? Yes, no or unsure)
●
Missed diagnosis (if they present to another emergency department and
receive a diagnosis different than what they were discharged with)
4.4
Missed Measurements
●
In the event one of the numerical secondary outcomes is missed, an average of the
measurements before and after will be used as a substitute. Any other data point
will not be substituted and recorded as missed. These, in addition to allowing up
to a 15 minute delay in measuring a variable, will not be counted as protocol
deviations.


●
If a patient leaves the emergency department prior to 180 minutes, they will no
longer be followed for timed measurements. They will still be contacted for the
follow up portion of the study.
4.5
Rescue Medication Administration
If at any point the patient expressed inadequate analgesia and the treating provider wants to
administer a new pain drug, they will be eligible to do so however that will be marked as
“Insufficient pain relief”. The patient can continue with the study unless at any point they wish to
withdraw. Rescue medication will be administered at the discretion of the treating physician or
advance practice provider. Rescue medication will not be lidocaine and will never be given to a
patient more than once in this study.
4.6
Subject Completion/Withdrawal
Subjects may withdraw from the study at any time without prejudice to their care.  They
may also be discontinued from the study at the discretion of the Investigator if it is later
discovered that they have any exclusion criteria, as determined by chart review or “Care
Everywhere”. If the Investigator becomes aware of any serious, related adverse events after the
subject completes or withdraws from the study, they will be recorded in the source documents
and on the CRF and reported to the IRB.
4.6.1
Early Termination Study Visit
If a subject wishes to withdraw from the study, their entire study packet will be kept but not
used for any study related analysis. The subject will be marked in REDCap as withdrawing from
study but no statistical analysis will be undertaken.
5
STUDY EVALUATIONS AND MEASUREMENTS
5.1
Screening and Monitoring Evaluations and Measurements
5.1.1
Medical Record Review
Include a listing of the variables that will be abstracted from the medical chart (paper or
electronic).
●
Date of birth
●
Biologic sex
●
Height (inches)
●
Weight (kilograms)
●
Medical history (diabetes, hypertension, high cholesterol, coronary artery
disease, heart failure)


5.1.2
Vital Signs
All vital signs will be recorded off the patients monitor. Blood pressure will be automated
and set to record at the required intervals. The arm without the IV in it will be used for placement
of the blood pressure cuff. Measurements will be taken while the patient is laying down in the
supine position. If more than one blood pressure is recorded (in the event of an abnormal blood
pressure), the one thought to be more accurate will be documented (as determined by the
physician or advanced practice provider).
5.1.3
Laboratory Evaluations
With the exception of drawing a lidocaine level in the event of a serious adverse event,
blood work is not part of the study. Any abnormal labs thought to be due to the study drug will
be recorded if labs were ordered as standard of care, provided they were drawn after the study
drug was administered. Pregnant patients cannot be enrolled and whichever pregnancy test is
used in their standard of care workup will be used to determine eligibility for the study. Women
of childbearing age presenting to the emergency department with abdominal pain nearly
universally have a pregnancy test measured at ED presentation as standard of care to evaluate for
pregnancy or ectopic pregnancy.
5.1.4
Other Evaluations, Measures
EKG’s will be performed on all patients the day of their presentation to the emergency
department and prior to them being allowed to participate in the study as an EKG with an
abnormal interval would exclude them from the study.
5.2
Safety Evaluation
Subject safety will be monitored by serious adverse events, reported adverse events, vital
signs, physical examinations, laboratory data (obtained through standard care), and medications
required to treat any adverse events thought to be due to the study drug. In the event of any
serious adverse event, a lidocaine level will be drawn on the patient.
6
STATISTICAL CONSIDERATIONS
6.1
Primary Endpoint
The primary endpoint is mean improvement in pain score, defined as the difference
between pain score at the beginning of the study drug infusion (time zero) and 90 minutes after
the study drug was administered (time zero). The mean pain improvement will be compared
between each study drug using a two tailed t-test with an alpha level of 0.05 and confidence
interval.
6.2
Secondary Endpoints
Secondary endpoints will include the following:
●
The mean pain improvement at time 15, 30, 60, 120, 150 and 180 minutes (using same test
as primary end point).


●
Difference in proportion of patients with adverse events, who experience serious adverse
events, require medication to treat adverse events, report insufficient pain relief, require
naloxone, have a change in disposition, and a missed diagnosis will be evaluated using a
Chi-Square test with an alpha level of 0.05.
●
Proportion of patients who prefer to receive the same drug at a future visit will be compared
as proportions using a Chi-Square test with an alpha level of 0.05.
8.1
Statistical Methods
6.2.1
Baseline Data
Baseline and demographic characteristics and medical history will be summarized by
standard descriptive summaries. Mean and standard deviation will be recorded for age.
Percentages will be recorded for categorical variables.
6.2.2
Efficacy Analysis
The primary outcome will be assessed using a two-tailed t-test using an alpha level of
0.05. A 95% confidence interval will be recorded for each mean. The same test will be used for
all numerical pain outcomes. All other tests will use a chi-square test with an alpha level of 0.05
and confidence interval of 95%.
6.2.3
Pharmacokinetic Analysis
No pharmacokinetic analysis will take place.
6.2.4
Safety Analysis
All subjects entered into the study will be included in the safety analysis, with the
exception of those who wish to withdraw from the study. The frequencies of AEs by type will be
summarized. Serious adverse events will be described in detail.  Incidence of all safety outcomes
will be summarized along with the corresponding exact binomial 95% two-sided confidence
intervals.
6.3
Sample Size and Power
Our sample size was calculated using an alpha level of 0.05, beta level of 80%, standard
deviation (SD) of 3 (previous research showed a SD of 3.1 for IV lidocaine and 2.9 for
hydromorphone), and a minimal importance clinical difference in pain score of 1.3. This resulted
in 85 patients per arm. Anticipating a loss of 10% of patients per arm, our final sample size was
187.
6.4
Interim Analysis
The decision to stop the study for efficacy or safety will be primarily determined by the
Data Safety Monitoring Board (DSMB). After 94 patients have been enrolled, they will complete
an interim analysis.
The stopping boundary for efficacy will be met if the P-value using a t-test for the
difference between groups in the primary outcome is 0.001 or less.  Using this conservative


Haybittle–Peto boundary (P ≤ 0.001) will allow the final analysis to be performed using an
unchanged level of significance.
The stopping boundary for safety will be met if the P-value using a chi-square test for the
difference between groups in the serious adverse event outcome is 0.025 or less.
7
STUDY MEDICATION (DRUG, DEVICE, OR OTHER STUDY INTERVENTION)
7.1  Description
Study drugs will include lidocaine and hydromorphone.
7.1.1  Packaging
Study drugs will be prepared by the research pharmacist who will place each drug in a
non-descriptive 100cc bag of saline. Both medications are clear and if placed side by side in a
bag of saline, would be indistinguishable as the research staff will be blinded to medication
assignment.
7.1.2  Labeling
Each study drug will be labeled with the standardized label below:
Header (**INVESTIGATIONAL MED**), Patient name, age, medical record number, location,
tube number, order number, due time and date, drug name (INV lidocaine or hydromorphone in
NaCL 0.9% 100 ml IVPB), intravenous, once, 100ml, infuse over: 5 minutes, time label printed,
signature for preparer and checker, expiration, and “Caution: New Drug - Limited by Federal (or
United States) law to investigational use
7.1.3  Dosing
Lidocaine will be dosed at 2 mg/kg. The patients recorded weight will be used.
Hydromorphone will be dosed at 1 mg. Both drugs will be given over 5 minutes through an
infusion pump.
The IV lidocaine solution that we are using for the Lidocaine component is premixed in
5% Dextrose.  The appropriate amount based on milligrams will be removed from the Lidocaine
and Dextrose 5% bag and added to a bag of 100 ml 0.9% Sodium Chloride.  Prior to adding the
lidocaine solution to the Sodium Chloride 100 ml bag, the volume equivalent to the amount to be
added will be removed from the saline bag. The NDC for the 0.9% Sodium Chloride 100 ml is
0338-0049-18.
The expiration for prepared lidocaine and hydromorphone bags are 24 hours but will be
given as quickly as possible after they are mixed, most likely in less than 30 minutes.
7.1.4  Treatment Compliance and Adherence


Not applicable.
7.1.5  Drug Accountability
A list of which drug each participant received will be maintained by the research
pharmacist. It will only be made available to the DSMB by request and to the prinicpal
investigator after 187 patients have been recruited and their data has been recorded.
8  SAFETY MANAGEMENT
8.1 Clinical Adverse Events
Clinical adverse events (AEs) will be monitored throughout the study.
8.2  Adverse Event Reporting
Unanticipated problems related to the research involving risks to subjects or others that
occur during the course of this study and SAEs will be reported to the IRB in accordance with
IRB Attachment EEE: Prompt Reporting Guidelines. AEs that are not serious but that are notable
and could involve risks to subjects will be summarized and submitted to the IRB at the time of
continuing review. Abnormal blood work will only be reported as an adverse event if it was
drawn after the patient received the study medication and is a departure from baseline lab work.
8.3  Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a subject receiving a test article
and which the occurrence does not necessarily have a causal relationship with the treatment.  An
adverse event can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with the use of the test article,
whether or not related to the product.
All AEs (including SAEs) will be noted in the study records and on the case report form
with a full description including the nature, date and time of onset, determination of non-serious
versus serious, intensity (mild, moderate, severe), duration, causality, and outcome of the event.
8.4  Definition of a Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that:
●
results in death,
●
is life-threatening,
●
requires inpatient hospitalization or prolongation of existing hospitalization,
●
results in a persistent or significant disability/incapacity, or
●
is a congenital anomaly/birth defect.


8.4.1  Relationship of SAE to study drug or other intervention
The relationship of each SAE to the study intervention should be characterized using one
of the following terms: certain, probable/likely, possible, unlikely/unrelated, or unassessable.
8.5  IRB/IEC Notification of SAEs and Other Unanticipated Problems
The Investigator will promptly notify the IRB of all internal (occurring in subjects enrolled at
this site) unanticipated problems involving risks to subjects or others, and Serious Adverse
Events that are related to the research activity. Reports will be submitted to the IRB in
accordance with the timeline below.
Category of Prompt Report
Initial Notification
Internal (occurring in subjects enrolled at this
site), related (or more likely related than
unrelated) SAE
5 days
Internal, unrelated SAE
30 days
Unanticipated Problems Involving Risks to
Subjects or Others
5 days
8.5.1  Follow-up report
If an SAE has not resolved at the time of the initial report and new information arises that
changes the investigator’s assessment of the event, a follow-up report including all relevant new
or reassessed information (e.g., concomitant medication, medical history) should be submitted to
the IRB. The investigator is responsible for ensuring that all SAE are followed until either
resolved or stable.
8.6  Investigator Reporting of a Serious Adverse Event to Sponsor
The Principal Investigator is also the Sponsor but will report all events to Hennepin
Healthcare Research Institute which is functioning as a Sponsor.
8.7  Medical Emergencies
Participants will be in the emergency department while receiving their study drug and
will have comprehensive resources immediately available to treat any medical emergencies
potentially related to the study drug. This can include oxygen, cardiac drugs, defibrillators,
naloxone, equipment to put the patient on a ventilator, etc.
9  STUDY ADMINISTRATION


9.1  TREATMENT ASSIGNMENT METHODS
9.1.1  Randomization or Other Assignment
The research pharmacist will be in charge of randomizing patients to either study drug.
They will maintain the unblinded subject list.
9.1.2  Blinding
The research pharmacist will randomly select which patient will receive which
medication prior to enrollment. No one else will know which medication the patient received
during the study. Each bag of medication will only have the subject number on it, an HCMC ID
sticker identifying the patient, and the clinical trial name (HIDO-LIDO).
9.1.3  Unblinding
The DSMB can request unblinded data at any time if required to analyze a serious adverse
event or during the interim analysis. The principal investigator can only receive unblinded data
after all subjects have been recruited and their data has been completely recorded. In the unlikely
event of a medical emergency, the treating providers can request which medication the patient
received from the research pharmacist.
9.2  Data Collection and Management
1. Confidentiality: Each subject will have a dedicated study packet. Each page in the study
packet will have the participant’s subject number on it. Only the first page of the packet
will have the patients PHI on it, all other pages will have no PHI on them. All forms will
be locked in the research office. Data will then be transferred from hand written data to
electronic data in REDCap.
2. Security:  Once a week, the REDCap file will be downloaded onto a HCMC password
protected laptop.
3. Anonymization, de-identification, or destruction: Only data from REDCap will be used
for statistical analysis. When files are to be downloaded for importing into statistical
software, only de-identified data will be downloaded. All study packets will be locked in
the research office and will only be made available to the IRB, DSMB, or the FDA if
necessary. All subject data will be kept for the legally required amount of time, after that
it will be destroyed. Each packet will have a “destroy by this date” label on the front of it.
9.3  Confidentiality
All data and records generated during this study will be kept confidential in accordance
with Institutional policies and HIPAA on subject privacy. The Principal Investigator and other
site personnel will not use such data and records for any purpose other than conducting the study.
Safeguards to protect participant privacy include locking up each study packet and storing all
digital data on REDCap which is password protected.
No identifiable data will be used for a future study without first obtaining IRB approval.
The investigator will obtain a data use agreement between the provider (the PI) of the data and


any recipient researchers (including others at Hennepin Healthcare) before sharing a limited
dataset (PHI limited to dates and zip codes).
9.4  Regulatory and Ethical Considerations
9.4.1  Data and Safety Monitoring Plan
A monitor plan will be put in place throughout the study to verify study compliance with
regulations (ensuring all consent forms are complete along with other monitoring requirements).
An independent DSMB will also be utilized. No member of the DSMB will be an author on the
study. The DSMB procedure is described in detail in the IND application.
9.4.2  Risk Assessment
Hydromorphone has been well studied and there are no specific risks for using it in this
clinical trial that are unique to the risks encountered in routine clinical care.
Lidocaine is FDA approved for ventricular arrhythmias at an initial dose of 1.5 mg/kg
(IV push) and up to three repeat doses of 0.5 mg/kg at intervals of 5 minutes after the initial
bolus. We are using a dose of 2 mg/kg over 5 minutes and for the indication of abdominal pain.
While the initial dose is marginally higher, it will be given over 5 minutes which will improve
the safety profile compared to giving it as an IV push. Additionally, the cumulative dose will be
less than the maximum dose available for an FDA approved use.
Side effects from lidocaine will be prevented by eliminating subjects most likely to
experience them. This is part of the exclusion criteria. Lidocaine is metabolized by the liver and
cleared from the body by the kidneys, so any patient with significant renal or hepatic impairment
will be excluded. Lidocaine can also affect the heart, so any patient with an abnormal EKG
(defined as any interval abnormality) will be excluded. Geriatric patients can be more sensitive
to intravenous lidocaine, so patients aged 65 and older will be excluded.
Patients will be on a cardiac monitor throughout the study (unless taken away for imaging
but usually this would happen after at least 30 minutes from the patient receiving the study drug),
thus allowing the treatment team to quickly identify any arrhythmia from lidocaine. If the patient
is off of a cardiac monitor, they will continue to be closely supervised. If a patient is eligible for
discharge prior to 180 minutes of cardiac monitoring, they will be asked to re remain in the
department until 180 minutes but will not be placed on a hold if they decide to leave. They will
not be excluded from the study if they elect to leave before 180 minutes of monitoring.
Finally, lidocaine toxicity has a typical course, generally starting with perioral anesthesia
then moving on to feeling light headed or having mildly slurred speech with increased toxicity.
These potential side effects will be explained to the patient so if they experience them, the
infusion can be stopped and once the symptoms clear, started again but over a period of 10
minutes, not 5 minutes.
9.4.3  Potential Benefits of Trial Participation
Participants will have no direct benefit from participating in the study. While treatment
for their pain is part of the study, they do not have to participate in research to have that and this
will be made clear to them when they are approached to participate in the study.


9.4.4  Risk-Benefit Assessment
As stated above, there are minimal risks for participating in this study. While patients will
not directly benefit from participating in this study, future patients can benefit if lidocaine has
equal analgesic efficacy as hydromorphone. Essentially, it would minimize the need for narcotics
to treat acute abdominal pain in the emergency department.
9.5  Recruitment Strategy
Subjects will all be recruited from the HCMC emergency department. Anyone involved in
the patients care can refer them to either a physician or advanced practice provider for meeting
the primary inclusion criteria of acute abdominal pain severe enough to require an intravenous
opiate. Once that has been met, a research associate can formally screen them for the rest of the
inclusion and exclusion criteria. Research associates can also scan the track board of patients in
the emergency department to see if patients may be a good candidate for the study.
9.6  Informed Consent/Assent and HIPAA Authorization
Written informed consent will be obtained only by personnel certified to do so. This will
include research associates, physicians or advanced care providers who have the required IRB
approval to obtain consent for this study. Additionally, the attending physician must see the
patient and determine if they have capacity to sign the consent form. This requirement is in place
because the patients being recruited in this study have severe pain which may impair their ability
to participate in the informed consent process.
9.6.1  Waiver of Consent
Not applicable.
9.6.2  Waiver of Assent
Not applicable.
9.6.3  Waiver of HIPAA Authorization
Not applicable.
9.7  Payment to Subjects/Families
Not applicable.
9.7.1  Reimbursement for travel, parking, and meals
Not applicable.
9.7.2  Payments to parent for time and inconvenience (i.e. compensation)
Not applicable.
9.7.3  Payments to subject for time, effort, and inconvenience (i.e. compensation)
Not applicable.


9.7.4  Gifts
Not applicable.
10 REFERENCES
14. Chinn E, Friedman BW, Naeem F, Irizarry E, Afrifa F, Zias E, Jones MP, Pearlman S,
Chertoff A, Wollowitz A, Gallagher EJ. Randomized Trial of Intravenous Lidocaine Versus
Hydromorphone for Acute Abdominal Pain in the Emergency Department. Ann Emerg Med.
2019 Aug;74(2):233-240. doi: 10.1016/j.annemergmed.2019.01.021. Epub 2019 Feb 26.
PubMed ID: 30819520
11 APPENDIX